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Metastatic site influences driver gene function in pancreatic cancer bioRxiv. Cancer Biol. Pub Date : 2024-03-18 Kaloyan M. Tsanov, Francisco M. Barriga, Yu-Jui Ho, Direna Alonso-Curbelo, Geulah Livshits, Richard P. Koche, Timour Baslan, Janelle Simon, Sha Tian, Alexandra N. Wuest, Wei Luan, John E. Wilkinson, Ignas Masilionis, Nevenka Dimitrova, Christine A. Iacobuzio-Donahue, Ronan Chaligne, Dana Pe'er, Joan Massague, Scott W. Lowe
Driver gene mutations can increase the metastatic potential of the primary tumor, but their role in sustaining tumor growth at metastatic sites is poorly understood. A paradigm of such mutations is inactivation of SMAD4 - a transcriptional effector of TGFβ signaling - which is a hallmark of multiple gastrointestinal malignancies. SMAD4 inactivation mediates TGFβ's remarkable anti- to pro-tumorigenic
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Lack of dominant-negative activity for tumor-associated ZNRF3 missense mutations at endogenous expression levels bioRxiv. Cancer Biol. Pub Date : 2024-03-18 Shanshan Li, JIahui Niu, Ruyi Zhang, Sanne Massaar, Jenna van Merode, Nicky de Schipper, Lisa van de Kamp, Maikel P Peppelenbosch, Ron Smits
ZNRF3, a negative regulator of beta-catenin signaling, removes Wnt receptors from the membrane. Currently, it is unknown which tumor-associated variants can be considered driver mutations and through which mechanisms they contribute to cancer. Here we show that all truncating mutations analyzed at endogenous levels exhibit loss-of-function, with longer variants retaining partial activity. Regarding
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Deconstructing Intratumoral Heterogeneity through Multiomic and Multiscale Analysis of Serial Sections bioRxiv. Cancer Biol. Pub Date : 2024-03-18 Patrick G. Schupp, Samuel J. Shelton, Daniel J. Brody, Rebecca Eliscu, Brett E. Johnson, Tali Mazor, Kevin W. Kelley, Matthew B. Potts, Michael W. McDermott, Eric J. Huang, Daniel A. Lim, Russell O. Pieper, Mitchel S. Berger, Joseph F. Costello, Joanna J. Phillips, Michael C. Oldham
Tumors may contain billions of cells including distinct malignant clones and nonmalignant cell types. Clarifying the evolutionary histories, prevalence, and defining molecular features of these cells is essential for improving clinical outcomes, since intratumoral heterogeneity provides fuel for acquired resistance to targeted therapies. Here we present a statistically motivated strategy for deconstructing
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Glutamine deprivation alters TGF-β signaling in hepatocellular carcinoma bioRxiv. Cancer Biol. Pub Date : 2024-03-17 Caroline Gelabert, Sabrina Campisano, Irene C Golan, Nateneal T. Beyene, Carl-Henrik Heldin, Andrea N. Chisari, Patricia Sancho, Aristidis Moustakas, Laia Caja
Metabolic reprogramming is one of the hallmarks of cancer. Glutamine is one of the most important nutrients that fuels the TCA cycle and therefore takes part in the production of energy. Glutamine is used as starting metabolite for the synthesis of nucleotides, fatty acids and non-essential amino acids. Since nutrients are uptaken from the blood stream, and considering the 3-dimensional state of solid
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Fluorescence Lifetime Imaging for Quantification of Targeted Drug Delivery in Varying Tumor Microenvironments bioRxiv. Cancer Biol. Pub Date : 2024-03-17 Amit Verma, Vikas Pandey, Catherine Sherry, Christopher James, Kailie Matteson, Jason T Smith, Alena Rudkouskaya, Xavier Intes, Margarida Barroso
Rationale: Trastuzumab (TZM) is a monoclonal antibody that targets the human epidermal growth factor receptor (HER2) and is clinically used for the treatment of HER2-positive breast tumors. However, the tumor microenvironment can limit the access of TZM to the HER2 targets across the whole tumor and thereby compromise TZMs therapeutic efficacy. An imaging methodology that can non-invasively quantify
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A mathematical model for pancreatic cancer during intraepithelial neoplasia bioRxiv. Cancer Biol. Pub Date : 2024-03-17 Joshua Briones-Andrade, Guillermo Ramirez-Santiago, J. Roberto Romero-Arias
Cancer is the result of complex interactions of intrinsic and extrinsic cell processes, which promote sustained proliferation, resistance to apoptosis, reprogramming and reorganization. To understand the evolution of any type of cancer it is necessary to understand the role of the microenvironmental conditions and the impact of some molecular complexes and mechanisms on certain signalling pathways
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Evaluation of Gene Set Enrichment Analysis (GSEA) tools highlights the value of single sample approaches over pairwise for robust biological discovery. bioRxiv. Cancer Biol. Pub Date : 2024-03-17 Courtney Bull, Ryan M Byrne, Natalie C Fisher, Shania M Corry, Raheleh Amirkhah, Jessica Edwards, Lily Hillson, Mark Lawler, Aideen Ryan, Felicity Lamrock, Philip D Dunne, Sudhir B Malla
Background: Gene set enrichment analysis (GSEA) tools can be used to identify biological insights from transcriptional datasets and have become an integral analysis within gene expression-based cancer studies. Over the years, additional methods of GSEA-based tools have been developed, providing the field with an ever-expanding range of options to choose from. Although several studies have compared
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Mapping the breast tumor microenvironment: proximity analysis reveals spatial relationships between macrophage subtypes and metastasis-initiating cancer cells bioRxiv. Cancer Biol. Pub Date : 2024-03-17 Eloise M. Grasset, Atul Desphande, Jae W Lee, Yeonju Cho, Sarah M. Shin, Erin M. Coyne, Alexei Hernandez, Xuan Yuan, Ashley Cimino-Matthews, Andrew J. Ewald, Won Jin Ho
The development of metastasis, responsible for the majority of cancer-related fatalities, is the most dangerous aspect of breast cancer, the predominant malignancy affecting women. We previously identified specific cancer cell populations responsible for metastatic events which are cytokeratin-14 (CK14) and E-cadherin positive in luminal tumors, and E-cadherin and vimentin positive in triple-negative
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Heterogeneous and Novel Transcript Expression in Single Cells of Patient-Derived ccRCC Organoids bioRxiv. Cancer Biol. Pub Date : 2024-03-17 Tülay Karakulak, Hella Anna Bolck, Natalia Zajac, Anna Bratus-Neuenschwander, Qin Zhang, Weihong Qi, Tamara Carrasco Oltra, Hubert Rehrauer, Christian von Mering, Holger Moch, Abdullah Kahraman
Splicing is often dysregulated in cancer, leading to alterations in the expression of canonical and alternative splice isoforms. This complex phenomenon can be revealed by an in-depth understanding of cellular heterogeneity at the single-cell level. Recent advances in single-cell long-read sequencing technologies enable comprehensive transcriptome sequencing at the single-cell level. In this study
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Direct measurement of RNA Polymerase II hypertranscription in cancer FFPE samples bioRxiv. Cancer Biol. Pub Date : 2024-03-16 Steven Henikoff, Jorja G. Henikoff, Ronald M. Paranal, Jacob E. Greene, Ye Zheng, Zachary R. Russell, Frank Szulzewsky, Sita Kugel, Eric C. Holland, Kami Ahmad
Hypertranscription is widespread in aggressive human cancers. However detection relies on mRNAs, which are heavily processed and have variable half-lives, and on accurate cell number estimations. Previously we introduced FFPE-CUTAC, a genome-wide method for mapping RNA Polymerase II in formalin-fixed paraffin-embedded (FFPE) sections. Here we apply FFPE-CUTAC on slides and curls to demonstrate hypertranscription
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Impact of genomic background and developmental state on signaling pathways and response to therapy in Glioblastoma patient-derived cells bioRxiv. Cancer Biol. Pub Date : 2024-03-16 Artem D Berezovsky, Oluwademilade Nuga, Indrani Datta, Kimberly Bergman, Thais Sabedot, Katherine Gurdziel, Susan Irtenkauf, Laura Hasselbach, Yuling Meng, Claudius Mueller, Emanuel Petricoin, Stephen Brown, Neeraja Purandare, Sidhesh Aras, Tom Mikkelsen, Laila Poisson, Houtan Noushmehr, Douglas M Ruden, Ana deCarvalho
Glioblastoma (GBM) tumors encompass several subgroups, reflecting diversity in the genomic epigenomic, and transcriptional landscape. Additionally, remarkable intratumoral heterogeneity, a hallmark of glioblastomas, poses significant challenges to the standard of care, comprised of treatment with radiation (RT) and with the DNA-alkylating agent temozolomide (TMZ). In this study, using targeted proteomics
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EHMT2 Inactivation in Pancreatic Epithelial Cells Shapes the Transcriptional Landscape and Inflammation Response of the Whole Pancreas bioRxiv. Cancer Biol. Pub Date : 2024-03-16 Gareth Pollin, Angela Mathison, Thiago Milech de Assuncao, Anju Thomas, Lida Zeighami, Ann Salmonson, Hongfei Liu, Guillermo Urrutia, Pallavi Vankayala, Stephen J Pandol, Michael T Zimmermann, Juan L Iovanna, Victor X. Jin, Raul A Urrutia, Gwen A Lomberk
The Euchromatic Histone Methyl Transferase Protein 2 (EHMT2), also known as G9a, deposits transcriptionally repressive chromatin marks that play pivotal roles in the maturation and homeostasis of multiple organs. Recently, we have shown that EHMT2 inactivation alters growth and immune gene expression networks, antagonizing KRAS-mediated pancreatic cancer initiation and promotion. Here, we elucidate
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A Novel ex-vivo platform for personalized treatment in metastatic ovarian cancer. bioRxiv. Cancer Biol. Pub Date : 2024-03-16 Alain Valdivia, Rachel Adebimpe Adefulajo, Morrent Thang, Luz Andrea Cuaboy, Catherine John, Breanna Elizabeth Mann, Andrew Benson Satterlee, Victoria Bae-Jump, Shawn David Hingtgen
The lack of functional precision models that recapitulate the pathology and structure/function relationship of advanced ovarian cancer (OC) within an appropriate anatomic setting constitutes a hurdle on the path to developing more reliable therapies and matching those therapies with the right patients. Here, we developed and characterized an Organotypic Mesentery Membrane Culture (OMMC) model as a
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Single cell view of tumor microenvironment gradients in pleural mesothelioma bioRxiv. Cancer Biol. Pub Date : 2024-03-15 Bruno Giotti, Komal Dolasia, william Zhao, Peiwen Cai, Robert Sweeney, Elliot Merritt, Evgeny Kiner, Grace Kim, Atharva Bhagwat, Samarth Hegde, Bailey Fitzgerald, Sanjana Shroff, Travis Dawson, Monica Garcia-Barros, Jamshid Abdul-Ghafar, Rachel Chen, Sacha Gnjatic, Alan Soto, Rachel Brody, Seunghee Kim-Schulze, Zhihong Chen, Kristin G Beaumont, Miriam Merad, Raja Flores, Robert Sebra, amir horowitz
Immunotherapies have shown great promise in pleural mesothelioma (PM), yet most patients still do not achieve significant clinical response, highlighting the importance of improving understanding of the tumor microenvironment (TME). Here, we utilized high-throughput, single-cell RNA-sequencing to de novo identify 54 expression programs and construct a comprehensive cellular catalogue of the PM TME
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Data Imbalance in Drug Response Prediction - Multi-Objective Optimization Approach in Deep Learning Setting bioRxiv. Cancer Biol. Pub Date : 2024-03-15 Oleksandr Narykov, Yitan Zhu, Thomas Brettin, Yvonne A. Evrard, Alexander Partin, Fangfang Xia, Maulik Shukla, Priyanka Vasanthakumari, James H. Doroshow, Rick L. Stevens
Drug response prediction (DRP) methods tackle the complex task of associating the effectiveness of small molecules with the specific genetic makeup of the patient. Anti-cancer DRP is a particularly challenging task requiring costly exper-iments as underlying pathogenic mechanisms are broad and associated with multiple genomic pathways. The scientific community has exerted significant efforts to generate
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Metabolic Reprogramming by Mutant GNAS Creates an Actionable Dependency in Intraductal Papillary Mucinous Neoplasms of the Pancreas bioRxiv. Cancer Biol. Pub Date : 2024-03-15 Yuki Makino, Kimal I Rajapakshe, Benson Chellakkan Selvanesan, Takashi Okumura, Kenjiro Date, Prasanta Dutta, Lotfi Abou-Elkacem, Akiko Sagara, Jimin Min, Marta Sans, Nathaniel Yee, Megan J Siemann, Jose Enriquez, Paytience Smith, Pratip Bhattacharya, Michael Kim, Merve Dede, Traver Hart, Anirban Maitra, Fredrik I Thege
Objective: Oncogenic ″hotspot″ mutations of KRAS and GNAS are two major driver alterations in Intraductal Papillary Mucinous Neoplasms (IPMNs), which are bona fide precursors to pancreatic ductal adenocarcinoma. We previously reported that pancreas–specific KrasG12D and GnasR201C co–expression in p48Cre, KrasLSL–G12D, Rosa26LSL–rtTA, Tg (TetO–GnasR201C) mice (″Kras,Gnas″ mice) caused development of
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A distinctive tumor compartment in pancreatic lobules defined by nascent stroma and classical tumor cell phenotype bioRxiv. Cancer Biol. Pub Date : 2024-03-15 Sara Ingrid Maria Söderqvist, Annika Viljamaa, Natalie Geyer, Carina Strell, Neda Hekmati, Jennie Engstrand, Ernesto Sparrelid, Caroline Salmén, Rainer L. Heuchel, Argyro Zacharouli, Poya Ghorbani, Sara Harrizi, Yousra Hamidi, Olga Khorosjutina, Stefina Milanova, Bernhard Schmierer, Béla Bozóky, Carlos Fernández Moro, Marco Gerling
Pancreatic ductal adenocarcinoma is a highly aggressive tumor type characterized by a particularly extensive stroma. While different types of cancer-associated fibroblasts (CAFs) in this desmoplastic stroma have been described, areas of early invasion and nascent stroma are understudied. Here, we identify a distinctive PDAC niche within the pancreatic lobules, a compartment dominated by pancreatic
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CDK4 is co-amplified with either TP53 promoter gene fusions or MDM2 through distinct mechanisms in osteosarcoma bioRxiv. Cancer Biol. Pub Date : 2024-03-14 Karim H Saba, Valeria Difilippo, Emelie Styring, Jenny Nilsson, Linda Magnusson, Hilda van den Bos, Diana C.J. Spierings, Floris Foijer, Michaela Nathrath, Felix Haglund de Flon, Daniel Baumhoer, Karolin H Nord
Amplification of the MDM2 and CDK4 genes on chromosome 12 is commonly associated with low-grade osteosarcomas. In this study, we conducted high-resolution genomic and transcriptomic analyses on 33 samples from 25 osteosarcomas, encompassing both high- and low-grade cases with MDM2 and/or CDK4 amplification. We identified four major subgroups: (i) low-grade osteosarcoma with chromosome 12 amplicons
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Inhibition of Acyl-CoA Synthetase Long Chain Isozymes Decreases Multiple Myeloma Cell Proliferation and Causes Mitochondrial Dysfunction bioRxiv. Cancer Biol. Pub Date : 2024-03-14 Connor S Murphy, Victoria E DeMambro, Samaa Fadel, Heather Fairfield, Carlos A Garter, Princess Rodriguez, Ya-Wei Qiang, Calvin P.H Vary, Michaela R. Reagan
Multiple myeloma (MM) is an incurable cancer of plasma cells with a 5-year survival rate of 59%. Dysregulation of fatty acid (FA) metabolism is associated with MM development and progression; however, the underlying mechanisms remain unclear. Acyl-CoA synthetase long-chain family members (ACSLs) convert free long-chain fatty acids into fatty acyl-CoA esters and play key roles in catabolic and anabolic
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Exploiting WEE1 kinase activity as FUS::DDIT3-dependent therapeutic vulnerability in myxoid liposarcoma bioRxiv. Cancer Biol. Pub Date : 2024-03-14 Lorena Heinst, Kwang Seok Lee, Ruth Berthold, Ilka Isfort, Svenja Wosnig, Anna Kuntze, Susanne Hafner, Bianca Altvater, Claudia Roessig, Pierre Aman, Eva Wardelmann, Claudia Scholl, Wolfgang Hartmann, Stefan Froehling, Marcel Trautmann
The pathognomonic FUS::DDIT3 fusion protein drives myxoid liposarcoma (MLS) tumorigenesis via aberrant transcriptional activation of oncogenic signaling. Since FUS::DDIT3 has so far not been pharmacologically tractable to selectively target MLS cells, this study investigated the functional role of the cell cycle regulator WEE1 as novel FUS::DDIT3 dependent therapeutic vulnerability in MLS. Here we
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Conditional c-MYC activation in catecholaminergic cells drives distinct neuroendocrine tumors: neuroblastoma vs somatostatinoma bioRxiv. Cancer Biol. Pub Date : 2024-03-14 JUN YANG, Tingting Wang, Lingling Liu, Jie Fang, Hongjian Jin, Sivaraman Natarajan, Heather Sheppard, Meifen Lu, Gregory Turner, Thomas Confer, Melissa Johnson, Jeffrey Steinberg, Larry Ha, Nour Yadak, Richa Jain, David Picketts, Xiaotu Ma, Andrew Murphy, Andrew Davidoff, Evan Glazer, John Easton, Xiang Chen, Ruoning Wang
The MYC proto-oncogenes (c-MYC, MYCN, MYCL) are among the most deregulated oncogenic drivers in human malignancies including high-risk neuroblastoma, 50% of which are MYCN-amplified. Genetically engineered mouse models (GEMMs) based on the MYCN transgene have greatly expanded the understanding of neuroblastoma biology and are powerful tools for testing new therapies. However, a lack of c-MYC-driven
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Preclinical Results: Canine Phase I Safety Study of CM-101, a Tumor Capillary Specific Streptococcal Polysaccharide Toxin, for application in Spontaneous Canine Cancer bioRxiv. Cancer Biol. Pub Date : 2024-03-14 Rhett W Stout, Bonnie Boudreaux, I Horia Inegulescu, Roger A Laine
Background: The study purpose was to evaluate canine safety of CM101, a polysaccharide Group B Streptococcus agalactiae tumor hemorrhagic toxin therapeutic. Hypothesis: CM101 specifically targets tumor vasculature as published in a human Phase 1 safety study that showed a wide therapeutic window. The hypothesis is that dogs should display a similar safety profile with low side-effects for CM101 canine
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Heterochromatin spreading in cancer cells through HDAC7 mediated histone H3.3 landscape reprogramming. bioRxiv. Cancer Biol. Pub Date : 2024-03-14 Ola Hassan, Mattia Pizzagalli, Laura Jinxuan Wu, David Karambizi, John P Zepecki, Eduardo Fajardo, Andras Fiser, Nikos Tapinos
Class IIa histone deacetylases (HDACs) are a family of enzymes that despite their name, do not have any measurable histone deacetylase activity but they function as multi-protein interaction hubs due to the presence of a prolonged N-terminal domain. Here we show that HDAC7, a member of the Class IIa HDAC family, is a chaperone for Histone H3.3 and, interacts with H3.3 and HIRA on chromatin. Specific
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Sequence-defined oligophosphoesters for selective inhibition of the KRAS G12D/RAF1 interaction bioRxiv. Cancer Biol. Pub Date : 2024-03-14 Bini R Claringbold, Steven Vance, Alexandra R Paul, Michelle D Garrett, Christopher D Serpell
Rat Sarcoma (RAS) genes are the most frequently mutated genes in cancer, with KRAS being the most predominant oncogene, yet they have proved extremely difficult to drug because they operate primarily through protein-protein interactions (PPIs) which lack an obvious pocket for small molecules. Sequence-defined synthetic oligomers could combine the precision and customisability of synthetic molecules
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Deciphering molecular mechanisms of synergistic growth reduction in kinase inhibitor combinations bioRxiv. Cancer Biol. Pub Date : 2024-03-14 Eirini Tsirvouli, Ana Martinez del Val, Liv Thommesen, Astrid Laegreid, Martin Kuiper, Jesper V Olsen, Asmund Flobak
In cancer treatment, the persistent challenge of unresponsiveness of certain patients to drugs or the development of resistance post-treatment remains a significant concern. Drug combinations that synergistically reduce tumor growth emerge as a promising avenue to address this issue. Here, we aimed to characterize the mechanism of action of two synergistic drug combinations that target PI3K together
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CDK4 and CDK6 upregulation promotes DNA replication stress, genomic instability and resistance to EGFR targeted therapy in lung cancer bioRxiv. Cancer Biol. Pub Date : 2024-03-14 Beatrice Gini, Philippe Gui, Wei Wu, D. Lucas Kerr, Lisa Tan, Dora Barbosa, Victor Olivas, Carlos Gomez, Sarah Elmes, Veronica Steri, Turja Chakrabarti, Trever G. Bivona, Collin M. Blakely
Genetic interactions impact both normal human physiology and human diseases, such as cancer. Here, we study genetic interactions through the lens of human lung cancers driven by oncogenic forms of the epidermal growth factor receptor (EGFR), which we and others previously showed harbor a rich landscape of genetic co-alterations and potential genetic interactions. Among the most common genetic co-alterations
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Proteomic Analysis Reveals Trilaciclib-Induced Senescence bioRxiv. Cancer Biol. Pub Date : 2024-03-14 Marina Hermosilla-Trespaderne, Mark X Hu-Yang, Abeer Dannoura, Andrew M Frey, Amy L George, Matthias Trost, Jose Luis Marin-Rubio
Trilaciclib, a CDK4/6 inhibitor, was approved as a myeloprotective agent for protecting bone marrow from chemotherapy-induced damage in extensive-stage small cell lung cancer (ES-SCLC). This is achieved through the induction of a temporary halt in the cell cycle of bone marrow cells. While it has been studied in various cancer types, its potential in haematological cancers remains unexplored. This
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Assessing Long-Term Stored Tissues for Multi-Omics Data Quality and Proteogenomics Suitability bioRxiv. Cancer Biol. Pub Date : 2024-03-14 Kyu Jin Song, Minsuh Kim, Yong Jin Heo, Kyung-Cho Cho, Jae-Won Oh, Dae Ho Kim, Chanwoong Hwa, Yeji Do, Seunghyuk Choi, Hee Sang Hwang, Kwoneel Kim, Kyunggon Kim, Seungjin Na, Eunok Paek, Joon-Yong An, Se Jin Jang, Min-Sik Kim, Kwang Pyo Kim
As research into the complexities of cancer biology deepens, the integration of multi-omics analyses has emerged as a powerful approach to unravel the complex molecular basis of cancers. However, challenges related to sample availability, including size, collection procedures, and storage duration, hinder the broad application of this methodology. Despite these limitations, there is a growing interest
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Metaplastic tuft cells transdifferentiate to neural-like progenitor cells in the progression of pancreatic cancer bioRxiv. Cancer Biol. Pub Date : 2024-03-13 Daniel J. Salas-Escabillas, Megan T. Hoffman, Jacee S. Moore, Sydney M. Brender, Hui-Ju Wen, Simone Benitz, Erick T. Davis, Dan Long, Allison M. Wombwell, Nina G. Steele, Rosalie C Sears, Ichiro Matsumoto, Kathleen E DelGiorno, Howard C Crawford
Background: Pancreatic cancer is partly derived from the transdifferentiation of acinar cells into metaplastic ducts that act as precursors of neoplasia and cancer. Tuft cells are solitary chemosensory cells not found in the normal pancreas but arise in metaplasia and neoplasia, gradually disappearing as neoplastic lesions progress to carcinoma. Metaplastic tuft cells (mTCs) functionally suppress tumor
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The Cyclin-Like Protein Spy1 Mediates Tumourigenic Potential of Triple Negative Breast Cancer bioRxiv. Cancer Biol. Pub Date : 2024-03-13 Bre-Anne Fifield, Claudia Pecoraro, Amy Basilious, Catalin Gramisteanu, Emily Mailloux, Rosa-Maria Ferraiuolo, Lisa A Porter
Triple negative breast cancer is an aggressive subtype of breast cancer that relies on systemic chemotherapy as its primary means of treatment. Cell cycle regulators are enriched in drug resistant forms of the disease supporting the potential of targeting cell cycle checkpoints as a therapeutic direction to re-sensitize patients to treatment. Spy1 is an atypical cyclin-like protein that can override
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Development of a series of genetically engineered NTRK fusion-driven pediatric-type high-grade glioma mouse models bioRxiv. Cancer Biol. Pub Date : 2024-03-13 Sebastian Schmid, Zachary R Russell, Alex Shimura Yamashita, Madeline E West, Abigail G Parrish, Julia Walker, Dmytro Rudoy, James Z Yan, David C Quist, Betemariyam N Gessesse, Neriah Alvinez, Patrick J Cimino, Debra K Kumasaka, Ralph E Parchment, Eric C Holland, Frank Szulzewsky
Infant-type and pediatric-type high-grade gliomas are genetically distinct from their adult counterparts and frequently harbor oncogenic gene fusions involving receptor tyrosine kinase genes, including the three neurotrophic tyrosine kinase receptor (NTRK) genes. In clinic trials, these tumors show high initial response rates to tyrosine kinase inhibition, however, ultimately recur due to the accumulation
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Hi-C profiling in tissues reveals 3D chromatin-regulated breast tumor heterogeneity and tumor-specific looping-mediated biological pathways bioRxiv. Cancer Biol. Pub Date : 2024-03-13 Lavanya Choppavarapu, Kun Fang, Tianxiang Liu, Victor X. Jin
Current knowledge in three-dimensional (3D) chromatin regulation in normal and disease states was mostly accumulated through Hi-C profiling in in vitro cell culture system. The limitations include failing to recapitulate disease-specific physiological properties and often lacking clinically relevant disease microenvironment. In this study, we conduct tissue-specific Hi-C profiling in a pilot cohort
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Evolutionary double-bind treatment using radiotherapy and NK cell-based immunotherapy in prostate cancer bioRxiv. Cancer Biol. Pub Date : 2024-03-13 Kimberly A Luddy, Jeffrey West, Mark Robertson-Tessi, Bina Desai, Taylor M Burrsell, Sarah Barrett, Jacintha O'Sullivan, Laure Marignol, Robert Gatenby, Joel S Brown, Alexander RA Anderson, Cliona O'Farrelly
Evolution-informed therapies exploit ecological and evolutionary consequences of drug resistance to inhibit the expansion of treatment-resistant populations and prolong time to progression. One strategy, termed an evolutionary double-bind, uses an initial therapy to elicit a specific adaptive response by the cancer cells, which is then selectively targeted by a follow-on therapy. Here we examine the
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The genomic trajectory of ovarian high grade serous carcinoma is determined in STIC lesions bioRxiv. Cancer Biol. Pub Date : 2024-03-13 Zhao Cheng, Darren P Ennis, Bingxin Lu, Hasan B Mirza, Chishimba Sokota, Baljeet Kaur, Naveena Singh, Olivia Le Saux, Giorgia Russo, Gaia Giannone, Laura A Tookman, Jonathan Krell, Jacqueline McDermott, Chris Barnes, Iain A McNeish
Ovarian high-grade serous carcinoma (HGSC) originates in the fallopian tube, with secretory cells carrying a TP53 mutation, known as p53 signatures, identified as potential precursors. p53 signatures evolve into serous tubal intraepithelial carcinomas (STIC) lesions, which, in turn, progress into invasive HGSC that readily spread to the ovary and disseminate around the peritoneal cavity. We recently
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Spatial interactions modulate tumor growth and immune infiltration bioRxiv. Cancer Biol. Pub Date : 2024-03-13 Sadegh Marzban, Sonal Srivastava, Sharon Kartika, Rafael Bravo, Rachel Safriel, Aidan Zarski, Alexander R. A. Anderson, Christine H Chung, Antonio L Amelio, Jeffrey West
Direct observation of immune cell trafficking patterns and tumor-immune interactions is unlikely in human tumors with currently available technology, but computational simulations based on clinical data can provide insight to test hypotheses. It is hypothesized that patterns of collagen formation evolve as a mechanism of immune escape, but the exact nature of the interaction between immune cells and
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PRMT5 maintains tumor stem cells to promote pediatric high-grade glioma tumorigenesis bioRxiv. Cancer Biol. Pub Date : 2024-03-13 John DeSisto, Ilango Balakrishnan, Aaron Knox, Gabrielle Link, Sujatha Venkataraman, Rajeev Vibhakar, Adam L Green
Background: Pediatric high-grade gliomas (PHGG) are aggressive, undifferentiated CNS tumors with poor outcomes, for which no standard-of-care drug therapy currently exists. Through a screen for epigenetic regulators, we identified PRMT5 as essential for PHGG growth. We hypothesized that, similar to its effect in normal cells, PRMT5 promotes self-renewal of stem-like PHGG tumor initiating cells (TICs)
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Determining Optimal Placement of Copy Number Aberration Impacted Single Nucleotide Variants in a Tumor Progression History bioRxiv. Cancer Biol. Pub Date : 2024-03-13 Chih Hao Wu, Suraj Joshi, Welles Robinson, Paul F. Robbins, Russell Schwartz, Cenk Sahinalp, Salem Malikić
Intratumoral heterogeneity arises as a result of genetically distinct subclones emerging during tumor progression. These subclones are characterized by various types of somatic genomic aberrations, with single nucleotide variants (SNVs) and copy number aberrations (CNAs) being the most prominent. While single-cell sequencing provides powerful data for studying tumor progression, most existing and newly
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NLRP3-induced systemic inflammation controls the development of JAK2V617F mutant myeloproliferative neoplasms bioRxiv. Cancer Biol. Pub Date : 2024-03-13 Ruth-Miriam Koerber, Calvin Krollmann, Kevin Cieslak, Elisabeth Tregel, Tim H Brümmendorf, Steffen Koschmieder, Martin Griesshammer, Ines Gütgemann, Peter Brossart, Radek Skoda, Carl Christian Kolbe, Eicke Latz, Dominik Wolf, Lino L Teichmann
The development of Philadelphia chromosome-negative classical myeloproliferative neoplasms (MPN) involves an inflammatory process that facilitates outgrowth of the malignant clone and correlates with clinical outcome measures. This raises the question to which extent inflammatory circuits in MPN depend on activation of innate immune sensors. Here, we investigated whether NLRP3, which precipitates inflammasome
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Transcriptional Regulation of Protein Synthesis by Mediator Kinase in MYC-driven Medulloblastoma bioRxiv. Cancer Biol. Pub Date : 2024-03-13 Dong Wang, Caitlin Ritz, Angela Pierce, Breauna Brunt, Yuhuan Luo, Nathan Dahl, Sujatha Venkataraman, Etienne Danis, Kamil Kus, Milena Mazan, Tomasz Rzymski, Bethany Veo, Rajeev Vibhakar
MYC-driven medulloblastoma (MB) is a highly aggressive cancer type with poor prognosis and limited treatment options. Through CRISPR-Cas9 screening across MB cell lines, we identified the Mediator-associated kinase CDK8 as the top dependence for MYC-driven MB. Loss of CDK8 markedly reduces MYC expression and impedes MB growth. Mechanistically, we demonstrate that CDK8 depletion suppresses ribosome
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BET inhibitors as a therapeutic intervention in gastrointestinal gene signature-positive castration-resistant prostate cancer. bioRxiv. Cancer Biol. Pub Date : 2024-03-13 Shipra Shukla, Dan Li, Holly Nguyen, Jennifer Conner, Gabriella Bayshtok, Woo Hyun Cho, Mohini Pachai, Nicholas Teri, Eric Campeau, Sarah Attwell, Patrick Trojer, Irina Ostrovnaya, Anuradha Gopalan, Eva Corey, Ping Chi, Yu Chen
A subgroup of castration-resistant prostate cancer (CRPC) aberrantly expresses a gastrointestinal (GI) transcriptome governed by two GI-lineage-restricted transcription factors, HNF1A and HNF4G. In this study, we found that expression of GI transcriptome in CRPC correlates with adverse clinical outcomes to androgen receptor signaling inhibitor treatment and shorter overall survival. Bromo- and extra-terminal
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Magnetic particle imaging reveals that iron-labeled extracellular vesicles accumulate in brains of mice with metastases bioRxiv. Cancer Biol. Pub Date : 2024-03-13 Victoria A Toomajian, Anthony Tundo, Evran E Ural, Emily M Greeson, Christopher H Contag, Ashley V Makela
The incidence of breast cancer remains high worldwide and is associated with a significant risk of metastasis to the brain that can be fatal; this is due, in part, to the inability of therapeutics to cross the blood brain barrier (BBB). Extracellular vesicles (EVs) have been found to cross the BBB and further, have been used to deliver drugs to tumors. EVs from different cell types appear to have different
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ADRA2A promotes the classical/progenitor subtype and reduces disease aggressiveness of pancreatic cancer bioRxiv. Cancer Biol. Pub Date : 2024-03-13 Paloma Moreno, Yuuki Ohara, Amanda J Craig, Huaitian Liu, Shouhui Yang, Lin Zhang, Gatikrushna Panigrahi, Tiffany H Dorsey, Helen Cawley, Azadeh Azizian, Jochen Gaedcke, Michael Ghadimi, Nader Hanna, S. Perwez Hussain
Pancreatic ductal adenocarcinoma (PDAC) manifests diverse molecular subtypes, including the classical/progenitor and basal-like/squamous subtypes, with the latter known for its aggressiveness. We employed integrative transcriptome and metabolome analyses to identify potential genes contributing to the molecular subtype differentiation and its metabolic features. Transcriptome analysis in PDAC patient
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A Mem-dELISA platform for dual color and ultrasensitive digital detection of colocalized proteins on extracellular vesicles bioRxiv. Cancer Biol. Pub Date : 2024-03-13 Himani Sharma, Vivek Yadav, Alice Burchett, Tiger Shi, Satyajyoti Senapati, Meenal Datta, Hsueh-Chia Chang
Accurate, multiplex, and ultrasensitive measurement of different colocalized protein markers on individual tumor-derived extracellular vesicles (EVs) and dimerized proteins with multiple epitopes could provide insights into cancer heterogeneity, therapy management and early diagnostics that cannot be extracted from bulk methods. However, current digital protein assays lack certain features to enable
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Epigenetic Reprogramming of Autophagy Drives Mutant IDH1 Glioma Progression and Response to Radiation bioRxiv. Cancer Biol. Pub Date : 2024-03-13 FELIPE J NUNEZ, Kaushik Banerjee, Anzar A Mujeeb, Ava Mauser, Claire E Tronrud, Ziwen Zhu, Ayman Taher, Padma Kadiyala, Stephen V Carney, Maria B Garcia-Fabiani, Andrea Comba, Mahmoud S Alghamri, Brandon L McClellan, Syed M. Faisal, Zeribe C Nwosu, Hanna S Hong, Tingting Qin, Maureen A Sartor, Mats Ljungman, Shi-Yuan Cheng, Henry D Appelman, Pedro R. Lowenstein, Joerg Lahann, Costas A Lyssiotis, Maria
Mutant isocitrate dehydrogenase 1 (mIDH1; IDH1R132H) exhibits a gain of function mutation enabling 2-hydroxyglutarate (2HG) production. 2HG inhibits DNA and histone demethylases, inducing epigenetic reprogramming and corresponding changes to the transcriptome. We previously demonstrated 2HG-mediated epigenetic reprogramming enhances DNA-damage response and confers radioresistance in mIDH1 gliomas harboring
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Advancements in Cardiovascular Disease Detection: Leveraging Data Mining and Machine Learning bioRxiv. Cancer Biol. Pub Date : 2024-03-13 Md. Sahadat Hossain, Md. Alamin Talukder, Md. Zulfiker Mahmud
Cardiovascular disease (CVD) is a significant global health concern, requiring early detection and accurate prediction for effective intervention. Machine learning (ML) offers a data-driven approach to analyzing patient data, identifying complex patterns and predicting CVD risk factors like blood pressure (BP), cholesterol levels, and genetic predispositions. Our research aims to predict CVD presence
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CXCL8 secreted by immature granulocytes inhibits wildtype hematopoiesis in chronic myelomonocytic leukemia bioRxiv. Cancer Biol. Pub Date : 2024-03-13 Paul Deschamps, Margaux Wacheux, Axel Gosseye, Margot Morabito, Arnaud Pages, Anne-Marie Lyne, Alexia Alfaro, Philippe Rameau, Aygun Imanci, Rabie Chelbi, Valentine Marchand, Aline Renneville, Mrinal M. Patnaik, Valerie Lapierre, Bouchra Badaoui, Orianne Wagner-ballon, Celine Berthon, Thorsten Braun, Christophe Willekens, Raphael Itzykson, Pierre Fenaux, Sylvain Thepot, Gabriel Etienne, francoise Porteu
Chronic myelomonocytic leukemia (CMML) is a severe myeloid malignancy with limited therapeutic options. Single-cell analysis of clonal architecture demonstrated early clonal dominance with few residual wildtype hematopoietic stem cells. Circulating myeloid cells of the leukemic clone and the cytokine they produce generate a deleterious inflammatory climate. Our hypothesis is that therapeutic control
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Mechanisms of genomic instability dictate cytosolic DNA composition and dendritic cell mediated anti-tumor immunity bioRxiv. Cancer Biol. Pub Date : 2024-03-13 Shayla R Mosley, Angie Chen, David NW Doell, Siwon Choi, Courtney Mowat, Felix Meier-Stephenson, Vanessa Meier-Stephenson, Kristi Baker
Patients with microsatellite instable (MSI) colorectal cancers (CRC) face better prognosis than those with the more common chromosomal instable (CIN) subtype due to improved anti-tumor immune responses characterized by high cytotoxic T cell infiltration. Previous investigation identified the cytosolic DNA (cyDNA) sensor STING as necessary for chemokine-mediated T cell recruitment in MSI CRCs. Here
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Explainable deep learning on 7500 whole genomes elucidates cancer-specific patterns of chromosomal instability bioRxiv. Cancer Biol. Pub Date : 2024-03-13 Mohamed Ali al-Badri, William CH Cross, Chris P Barnes
Chromosomal instability (CIN) refers to an increased rate of chromosomal changes within cells. It is highly prevalent in cancer cells and leads to abnormalities in chromosome number (aneuploidy) and structure. CIN contributes to genetic diversity within a tumour, which facilitates tumour progression, drug resistance, and metastasis. Here, we present a deep learning method and an exploration of the
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Long-term Hematopoietic Transfer of the Anti-Cancer and Lifespan-Extending Capabilities of A Genetically Engineered Blood System by Transplantation of Bone Marrow Mononuclear Cells bioRxiv. Cancer Biol. Pub Date : 2024-03-12 Jing-Ping Wang, Chun-Hao Hung, Yae-Huei Liou, Ching-Chen Liu, Kun-Hai Yeh, Keh-Yang Wang, Zheng-Sheng Lai, Biswanath Chatterjee, Tzu-Chi Hsu, Tung-Liang Lee, Yu-Chiau Shyu, Pei-Wen Hsiao, Liuh-Yow Chen, Trees-Juen Chuang, Chen-Hsin Albert Yu, Nan-Shih Liao, C-K James Shen
A causal relationship exists among the aging process, organ decay and dis-function, and the occurrence of various diseases including cancer. A genetically engineered mouse model, termed EklfK74R/K74R or Eklf(K74R), carrying mutation on the well-conserved sumoylation site of the hematopoietic transcription factor KLF1/ EKLF has been generated that possesses extended lifespan and healthy characteristics
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3D culture of pancreatic cancer cells in vitro recapitulates an aberrant mitochondrial oxidative phosphorylation genotype observed in vivo bioRxiv. Cancer Biol. Pub Date : 2024-03-12 Jonathan Mark Treherne, Krzysztof Kuś, Marcin Przemyslaw Krzykawski, David L Earnshaw, Renata Krzykawska, Beata Biesaga, Małgorzata Statkiewicz, Katarzyna Unrug-Bielawska, Zuzanna Sandowska-Markiewicz, Michal Mikula, Javier Antonio Alfaro
The treatment of many aggressive cancers remains a significant unmet medical need. An aberrant dependence of tumors on mitochondrial oxidative phosphorylation pathways has been well characterized in mediating the progression of pancreatic cancers, as well as some other malignancies. However, the discovery and development of new therapeutic strategies targeting or manipulating this pathway in pancreatic
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Integrated in vivo functional screens and multi-omics analyses identify alpha-2,3-sialylation as essential for melanoma maintenance bioRxiv. Cancer Biol. Pub Date : 2024-03-12 Praveen Agrawal, Shuhui Chen, Ana de Pablos, Faezeh Jame-Chenarboo, Eleazar Miera Saenz de Vega, Farbod Darvishian, Iman Osman, Amaia Lujambio, Lara K. Mahal, Eva Hernando
Glycosylation is a hallmark of cancer biology, and altered glycosylation influences multiple facets of melanoma growth and progression. To identify glycosyltransferases, glycans, and glycoproteins essential for melanoma maintenance, we conducted an in vivo growth screen with a pooled shRNA library of glycosyltransferases, lectin microarray profiling of benign nevi and melanoma patient samples, and
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Chemotherapy-driven de novo Wnt pathway activation dictates a dynamic shift to a drug-tolerant state in breast cancer cells bioRxiv. Cancer Biol. Pub Date : 2024-03-12 Frederic Lluis, Youssef Ellaithy, Willy Antoni Abreu de Oliveira, Anirudh Pabba, Alessandra Qualizza, Francois Richard, Paraskevi Athanasouli, Carla Rios Luci, Wout De Wispelaere, Larissa Mourao, Sian Hamer, Stijn Moens, Anchel De Jaime-Soguero, Maria Francesca Baietti, Stefan J Hutten, Jos Jonkers, Stephen-John Sammut, Stefaan Jan Soenen, Colinda LGJ Scheele, Alejandra Bruna, Christine Desmedt, Daniela
The efficacy of chemotherapy is often hindered by the enrichment of drug-tolerant persister (DTP) cells, which are known to drive therapy resistance. Unraveling and targeting the early events leading to therapy-induced DTP cell-enrichment presents a potential avenue for innovative therapeutic strategies. In this study, we identified the activation of the Wnt/β-catenin signaling pathway as a common
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Targeted Proteomics of Plasma Extracellular Vesicles Uncovers MUC1 as Combinatorial Biomarker for the Early Detection of High-grade Serous Ovarian Cancer bioRxiv. Cancer Biol. Pub Date : 2024-03-12 Tyler T. Cooper, Dylan Z Dieters-Castator, Jiahui Liu, Gabrielle M Siegers, Lorena Veliz, Desmond Pink, John D Lewis, Yangxin Fu, Francois Lagugne-Labarthet, Helen Steed, Gilles A Lajoie, Lynne M Postovit
Purpose: The five-year prognosis for patients with late-stage high-grade serous carcinoma (HGSC) remains dismal, underscoring the critical need for identifying early-stage biomarkers. This study explores the potential of extracellular vesicles (EVs) circulating in blood, which are believed to harbor proteomic cargo reflective of the HGSC microenvironment, as a source for biomarker discovery. Experimental
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Cell-type-specific nuclear morphology predicts genomic instability and prognosis in multiple cancer types bioRxiv. Cancer Biol. Pub Date : 2024-03-12 John Abel, Suyog Jain, Deepta Rajan, Harshith Padigela, Kenneth Leidal, Aaditya Prakash, Jake Conway, Michael Nercessian, Christian Kirkup, Syed Ashar Javed, Raymond Biju, Natalia Harguindeguy, Daniel Shenker, Nicholas Indorf, Darpan Sanghavi, Robert Egger, Benjamin Trotter, Ylaine Gerardin, Jacqueline A. Brosnan-Cashman, Aditya Dhoot, Michael C. Montalto, Chintan Parmar, Ilan Wapinski, Archit Khosla
While alterations in nucleus size, shape, and color are ubiquitous in cancer, comprehensive quantification of nuclear morphology across a whole-slide histologic image remains a challenge. Here, we describe the development of a pan-tissue, deep learning-based digital pathology pipeline for exhaustive nucleus detection, segmentation, and classification and the utility of this pipeline for nuclear morphologic
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Functional transcriptional signatures for tumor-type-agnostic phenotype prediction bioRxiv. Cancer Biol. Pub Date : 2024-03-12 Corey Weistuch, Kevin A Murgas, Jiening Zhu, Larry Norton, Ken A Dill, Allen R Tannenbaum, Joseph O Deasy
Cancer transcriptional patterns exhibit both shared and unique features across diverse cancer types, but whether these patterns are sufficient to characterize the full breadth of tumor phenotype heterogeneity remains an open question. We hypothesized that cancer transcriptional diversity mirrors patterns in normal tissues optimized for distinct functional tasks. Starting with normal tissue transcriptomic
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miR-644a is a tumor cell-intrinsic mediator of sex bias in glioblastoma bioRxiv. Cancer Biol. Pub Date : 2024-03-12 Ellen S Hong, Sabrina Z Wang, András K Ponti, Nicole Hajdari, Juyeun Lee, Erin E Mulkearns-Hubert, Josephine Volovetz, Kristen E Kay, Justin Lathia, Andrew Dhawan
Background: Biological sex is an important risk factor for glioblastoma (GBM), with males having a higher incidence and poorer prognosis. The mechanisms for this sex bias are thought to be both tumor intrinsic and tumor extrinsic. MicroRNAs (miRNAs), key post-transcriptional regulators of gene expression, have been previously linked to sex differences in various cell types and diseases, but their role
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The RNA demethylases ALKBH5 and FTO regulate translation of the ATF4 mRNA in sorafenib-treated hepatocarcinoma cells bioRxiv. Cancer Biol. Pub Date : 2024-03-11 Rachid Mazroui, Pauline Adjibade
Translation is one of the main gene expression steps targeted by cellular stress, commonly refereed as translational stress, which includes treatment with anticancer drugs. While translational stress blocks translation initiation of bulk mRNAs, it allows translation of a specific set of mRNAs known as short upstream open reading frames (uORFs)-mRNAs. Among these, ATF4 mRNA encodes a transcription factor
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SIGNAL-seq: Multimodal Single-cell Inter- and Intra-cellular Signalling Analysis bioRxiv. Cancer Biol. Pub Date : 2024-03-11 James W Opzoomer, Rhianna O'Sullivan, Jahangir Sufi, Ralitsa Radostinova Madsen, Xiao Qin, Ewa Basiarz, Christopher J Tape
We present SIGNAL-seq (Split-pool Indexing siGNalling AnaLysis by sequencing): a multiplexed split-pool combinatorial barcoding method that simultaneously measures RNA and post-translational modifications (PTMs) in fixed single cells from 3D models. SIGNAL-seq PTM measurements are equivalent to mass cytometry and RNA gene detection is analogous to split-pool barcoding scRNA-seq. By measuring both mRNA
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Functional multi-omics reveals genetic and pharmacologic regulation of surface CD38 in multiple myeloma bioRxiv. Cancer Biol. Pub Date : 2024-03-11 Priya Choudhry, Corynn Kasap, Bonell Patino Escobar, Olivia Gugliemini, Huimin Geng, Vishesh Sarin, Amrik Kang, Audrey Kishishita, Sham Rampersaud, Letitia Sarah, Yu-Hsiu Tony Lin, Neha Paranjape, Poornima Ramkumar, Makeba Marcoulis, Donghui Wang, Paul Phojanakong, Veronica Steri, Byron Hann, Martin Kampmann, Arun Wiita
CD38 is a surface ectoenzyme expressed at high levels on myeloma plasma cells and is the target for the monoclonal antibodies (mAbs) daratumumab and isatuximab. Pre-treatment CD38 density on tumor cells is an important determinant of mAb efficacy. Several small molecules have been found to increase tumor surface CD38, with the goal of boosting mAb efficacy in a co-treatment strategy. Numerous other
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Glutamine addiction is targetable via altering splicing of nutrient sensors and epitranscriptome regulators bioRxiv. Cancer Biol. Pub Date : 2024-03-11 Jodie Bojko, Madhu Kollareddy, Marianna Szemes, Jacob Bellamy, Evon Poon, Ahmad Moukachar, Danny Legge, Emma E Vincent, Nicholas Jones, Sally Malik, Alexander Greenhough, Alex Paterson, Ji Hyun Park, Kelli Gallacher, Louis Chesler, Karim Malik
About 50% of poor prognosis neuroblastoma arises due to MYCN over-expression. We previously demonstrated that MYCN and PRMT5 proteins interact and PRMT5 knockdown led to apoptosis of MYCN amplified (MNA) neuroblastoma. Here we evaluate PRMT5 inhibitors GSK3203591/GSK3326593 as targeted therapeutics for MNA neuroblastoma and show MYCN-dependent growth inhibition and apoptosis. RNAseq revealed dysregulated