Chromosomal instability (CIN) is a hallmark of cancer. While low levels of CIN can be tumor promoting, high levels of CIN cause cell death and tumor suppression. The widely used chemotherapeutic paclitaxel (TaxolTM) exerts its anti-cancer effects by increasing CIN above a maximally tolerated threshold. One significant outstanding question is whether the p53 tumor suppressor is required for the cell

There is accumulating evidence that continuous activation of the sympathetic nervous system due to psychosocial stress increases resistance to therapy and accelerates tumor growth via beta2-adrenoreceptor signaling (ADRB2). However, the effector mechanisms appear to be specific to tumor type. Here we show that activation of ADRB2 by epinephrine, increased in response to immobilization stress, delays

Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) is characterized by aberrant activation of signaling pathways and high risk of relapse. Approximately 50% of Ph-like ALL cases overexpress cytokine receptor-like factor 2 (CRLF2) associated with gene rearrangement. Activated by its ligand thymic stromal lymphopoietin (TSLP), CRLF2 signaling is critical for the development, proliferation, and

Regulator of chromosome condensation 2 (RCC2) is a protein located in the centrosome, which ensures that cell division proceeds properly. Previous reports show that RCC2 is overexpressed in some cancers and could play a key role in tumor development, but the mechanisms concerning how this occurs are not understood. Furthermore, no evidence exists regarding its role in esophageal cancer. We studied

RNF8 (ring finger protein 8), a RING finger E3 ligase best characterized for its role in DNA repair and sperm formation via ubiquitination, has been found to promote tumor metastasis in breast cancer recently. However, whether RNF8 also plays a role in other types of cancer, especially in lung cancer, remains unknown. We show here that RNF8 expression levels are markedly increased in human lung cancer

Non–small cell lung cancer (NSCLC) is characterized by genomic alterations, yet a targetable mutation has not been discovered in nearly half of all patients. Recent studies have identified amplification of RICTOR , an mTORC2-specific cofactor, as a novel actionable target in NSCLC. mTORC2 is one of two distinct mTOR complexes to sense environmental cues and regulate a variety of cellular processes

Triple negative breast cancer (TNBC) is a subtype of breast cancer that lacks expression of estrogen receptor, progesterone receptor and the epidermal growth factor receptor 2 (HER2) but is enriched with cancer stem cell-like cells (CSCs). CSCs are the fraction of cancer cells recognized as the source of primary malignant tumors that also give rise to metastatic recurrence. 5-hydroxymethylcytosine

Platinum resistance is a common occurrence in high-grade serous ovarian cancer and a major cause of ovarian cancer deaths. Platinum agents form DNA cross-links, which activate nucleotide excision repair (NER), Fanconi anemia, and homologous recombination repair (HRR) pathways. Chromatin modifications occur in the vicinity of DNA damage and play an integral role in the DNA damage response (DDR). Chromatin

Triple-negative breast cancers contain a spectrum of epithelial and mesenchymal phenotypes. SUM-229PE cells represent a model for this heterogeneity, maintaining both epithelial and mesenchymal subpopulations that are genomically similar but distinct in gene expression profiles. We identified differential regions of open chromatin in epithelial and mesenchymal cells that were strongly correlated with

Genetic alterations of CYLD lysine 63 deubiquitinase (CYLD), a tumor suppressor gene encoding a deubiquitinase (DUB) enzyme, are associated with the formation of tumors in CYLD cutaneous syndrome. Genome sequencing efforts have revealed somatic CYLD alterations in multiple human cancers. Moreover, in cancers commonly associated with human papilloma virus (HPV) infection (eg. head and neck squamous

Lung cancer, especially lung adenocarcinoma (LUAD), is one of the most common neoplasms worldwide. However, the mechanisms underlying its initiation, development, and metastasis are still poorly understood. Destrin (DSTN) is a member of ADF/cofilin family. Its detailed biological function remains unknown, although it is reported that DSTN is involved in cytoskeleton remodeling and regulation of actin

Drosophila melanogaster have proven to be an effective model system in uncovering both genetic and cellular contributions to human cancer. Many elusive genes and signaling pathways that control oncogenic growth were first identified using flies. In many cases, these discoveries weren't driven by a direct search for novel genes involved in cancer but rather stemmed from research programs to uncover

Due to its intricate heterogeneity and limited treatment, hepatocellular carcinoma (HCC) has been considered a major cause of cancer-related mortality worldwide. Increasing evidence indicates that G-coupled Estrogen Receptor 1 (GPER1) can promote estrogen-dependent hepatocellular proliferation by activating AKT signaling. The mTOR complex 2 (mTORC2), whose integrity and activity are modulated by its

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a highly desmoplastic reaction, warranting intense cancer-stroma communication. In this study we interrogated the contribution of the BET family of chromatin adaptors to the crosstalk between PDAC cells and the tumor stroma. Short-term treatment of orthotopic xenograft tumors with CPI203, a small molecule inhibitor of BET proteins, resulted

Tumor endothelial cells (TEC) play multiple roles in the regional specialization of vascular structure and physiology. Because TECs in the tumor microenvironment come in contact with circulating immune cells, they might influence not only trafficking but also the antitumor cellular immune response. In a mouse tumor implantation model with B16 melanoma cells, TECs expressed MHC class II, costimulating

Lipid uptake occurs through caveolae, plasma membrane invaginations formed by caveolins (CAV) and caveolae-associated protein 1 (CAVIN1). Genetic alterations of CAV1N1 and CAV1 modify lipid metabolism and underpin lipodystrophy syndromes. Lipids contribute to tumorigenesis by providing fuel to cancer metabolism and supporting growth and signaling. Tumor stroma promotes tumor proliferation, invasion

Patients with DNA mismatch repair–deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer represent a biomarker-defined population with distinct clinicopathologic features who are susceptible to immune checkpoint inhibitors (ICI). However, their survival outcomes vary considerably and nearly half of them exhibit primary resistance to current ICIs, suggesting substantial molecular

EGFR inhibitors have shown poor efficacy in head and neck squamous cell carcinoma (HNSCC) with demonstrated involvement of the insulin-like growth factor-1 receptor (IGF1R) in resistance to EGFR inhibition. IGF1R activates the PI3K–Akt pathway, which phosphorylates proline-rich Akt substrate of 40 kDa (PRAS40) to cease mTOR inhibition resulting in increased mTOR signaling. Proliferation assays separated

Ovarian cancer is an aggressive disease that affects about 300,000 patients worldwide, with a yearly death count of about 185,000. Following surgery, treatment involves adjuvant or neoadjuvant administration of taxane with platinum compounds cisplatin or carboplatin, which alkylate DNA through the same chemical intermediates. However, although platinum-based therapy can cure patients in a number of

Recent studies have demonstrated that lysine acetylation of histones is crucial for nucleotide excision repair (NER) by relaxing the chromatin structure, which facilitates the recruitment of repair factors. However, few studies have focused on the contribution of histone deacetylases (HDAC) to NER. Here, we found that histone H3 Lys14 (H3K14) was deacetylated by HDAC3 after UV irradiation. Depletion

DNA replication stress (DRS) is a predominant cause of genome instability, a driver of tumorigenesis and malignant progression. Nucleoside analogue-type chemotherapeutic drugs introduce DNA damage and exacerbate DRS in tumor cells. However, the mechanisms underlying the antitumor effect of these drugs are not fully understood. Here, we show that the fluorinated thymidine analogue trifluridine (FTD)

There is accumulating evidence for a link between circadian clock disruption and cancer progression. In this study, the circadian clock was investigated in cervical and esophageal cancers, to determine whether it is disrupted in these cancer types. Oncomine datamining revealed downregulation of multiple members of the circadian clock gene family in cancer patient tissue compared with matched normal

Telomere shortening has been demonstrated in benign prostatic hypertrophy (BPH), which is associated with prostate epithelial cell senescence. Telomere shortening is the most frequently observed genetic alteration in prostatic intraepithelial neoplasia, and is associated with poor clinical outcomes in prostate cancer. Gene expression database analysis revealed decreased TRF2 expression during malignant

gBRCA1/2 mutations increase the incidence of breast cancer by interrupting the homologous recombination repair (HRR) pathway. Although gBRCA1 and gBRCA2 breast cancer have similar clinical profiles, different molecular characteristics have been observed. In this study, we conducted comprehensive genomic analyses and compared gBRCA1/2 breast cancer. Sanger sequencing to identify gBRCA1/2 mutations was

Leiomyosarcoma (LMS) is a mesenchymal neoplasm with complex copy-number alterations and characteristic loss of tumor suppressor genes without known recurrent activating mutations. Clinical management of advanced LMS relies on chemotherapy and complementary palliative approaches, and research efforts to date have had limited success identifying clinically actionable biomarkers or targeted therapeutic

The majority of patients with prostate cancer treated with docetaxel develop resistance to it. To better understand the mechanism behind the acquisition of resistance, we conducted single-cell RNA-sequencing (scRNA-seq) of docetaxel-sensitive and -resistant variants of DU145 and PC3 prostate cancer cell lines. Overall, sensitive and resistant cells clustered separately. Differential gene expression

Breast cancer metastasis is a leading cause of cancer-related death of women in the United States. A hurdle in advancing metastasis-targeted intervention is the phenotypic heterogeneity between primary and secondary lesions. To identify metastasis-specific gene expression profiles we performed RNA-sequencing of breast cancer mouse models; analyzing metastases from models of various drivers and routes

The mechanism of cancer induction involves an aberrant expression of oncogenes whose functions can be controlled by RNAi with miRNA. Even foreign bacterial RNA may interfere with the expression of oncogenes. Here we show that bacterial plasmid mucAB and its Escherichia coli genomic homolog umuDC, carrying homologies that match the mouse anti-miR-145, sequestered the miR-145 function in mouse BALB 3T3

Epithelial–mesenchymal transition (EMT) programs play essential functions in normal morphogenesis and organogenesis, including that occurring during mammary gland development and glandular regeneration. Historically, EMT programs were believed to reflect a loss of epithelial gene expression signatures and morphologies that give way to those associated with mesenchymal cells and their enhanced migratory

### [Endo et al. Page 1402][1] Colorectal cancer patients with defective mismatch repair and high microsatellite instability (dMMR/MSI-H) tend to be more likely to benefit from immune checkpoint inhibitors (ICI), a finding that led to the recent FDA approval of the anti-PD-1 monoclonal antibody,

Collective invasion can be led by breast cancer cells expressing basal epithelial markers, typified by keratin-14 (KRT14). We analyzed gene expression data from The Cancer Genome Atlas and demonstrated a significant correlation between a KRT14+ invasion signature and a stromal mediated extracellular matrix (ECM) organization module. We then developed a novel co-culture model of tumor organoids with

Recent studies indicate that adipose tissue in obesity promotes breast cancer progression by secreting pro-tumorigenic chemokines, growth factors and fatty acids. However, the detailed mechanisms by which hypertrophic adipose tissue influences breast cancer cells are still not well understood. Here we show that co-culture with adipose tissue from high-fat diet induced obese C57BL/6 mice alters transcriptome

The ATP6V1G1 subunit (V1G1) of the vacuolar proton ATPase (V-ATPase) pump is crucial for glioma stem cells (GSC) maintenance and in vivo tumorigenicity. Moreover, V-ATPase reprograms the tumor microenvironment through acidification and release of extracellular vesicles (EV). Therefore, we investigated the role of V1G1 in GSC small EVs and their effects on primary brain cultures. To this end, small

The NF-E2-related factor 2 (referred to as NRF2) transcription factor binds antioxidant responsive elements within the promoters of cytoprotective genes to induce their expression. Next-generation sequencing studies in lung cancer have shown a significant number of activating mutations within the NRF2 signaling pathway. Mutations in components of the SWI/SNF chromatin-remodeling complex, a general

Gastric cancer remains the third leading cause of cancer-related death, and tumor metastasis is the main risk factor for poor prognosis of patients with gastric cancer. Transcription factor EB (TFEB) is a MiT family member and has been found to drive tumorigenesis in a number of tissues, whereas few studies were focused on investigating its prometastasis role and mechanism in gastric cancer. Here,

Multiple human polyomaviruses (HPyV) can infect the skin, but only Merkel cell polyomavirus (MCPyV) has been implicated in the development of a cancer, Merkel cell carcinoma (MCC). While expression of HPyV6, HPyV7, and MCPyV small T antigens (sT), all induced a senescence-associated secretory phenotype (SASP), MCPyV sT uniquely activated noncanonical NFκB (ncNFκB), instead of canonical NFκB signaling

Abstract: Bone marrow fibrosis (BMF) is a rare complication in acute leukemia. In pediatrics, it predominantly occurs in acute megakaryoblastic leukemia (AMKL) and here especially in patients with trisomy 21, called myeloid leukemia in Down syndrome (ML-DS). Defects in mesenchymal stromal cells (MSCs) and cytokines specifically released by the myeloid blasts are thought to be the main drivers of fibrosis

Constitutive NRF2 activation by disrupted KEAP1-NRF2 interaction has been reported in a variety of human cancers. However, studies focusing on NRF2-driven KEAP1 expression under human cancer contexts are still uncommon. We examined mRNA expression correlation between NRF2 and KEAP1 in multiple human cancers. We measured KEAP1 mRNA and protein alterations in response to the activation or silencing of

The thyroid hormone receptor beta (TRβ), a key regulator of cellular growth and differentiation, is frequently dysregulated in cancers. Diminished expression of TRβ is noted in thyroid, breast, and other solid tumors and is correlated with more aggressive disease. Restoration of TRβ levels decreased tumor growth supporting the concept that TRβ could function as a tumor suppressor. Yet, the TRβ tumor

Mechanisms regulating nuclear organization control fundamental cellular processes, including the cell and chromatin organization. Their disorganization, including aberrant nuclear architecture, has been often implicated in cellular transformation. Here, we identify Lamin A, among proteins essential for nuclear architecture, as SPANX (sperm protein associated with the nucleus on the X chromosome), a

Intratumoral tumor-specific activated CD8+ T cells with functions in antitumor immune surveillance predict metastasis and clinical outcome in human colorectal cancer. Intratumoral CD8+ T cells also affect treatment with immune checkpoint inhibitors. Interestingly, inhibition of Aurora kinase A (Aurora-A) by its selective inhibitor alisertib obviously induced infiltration of CD8+ T cells. However, the

Epigenetic changes are one underlying cause for cancer development and often due to dysregulation of enzymes modifying DNA or histones. Most Jumonji C domain-containing (JMJD) proteins are histone lysine demethylases (KDM) and therefore epigenetic regulators. One JMJD subfamily consists of JMJD1A/KDM3A, JMJD1B/KDM3B, and JMJD1C/KDM3C that are roughly 50% identical at the amino acid level. All three

The R-spondin family plays important roles in embryonic development, including in humans. However, information on the relationship between R-spondin2 and hepatocellular carcinoma (HCC) is lacking. This study aimed was to explore the mechanisms of R-spondin2 action in the progression of HCC. By analyzing R-spondin2 expression levels in HCC tissues by IHC and database, we identified that HCC tissues

We generated eight multiple myeloma cell lines resistant to bortezomib; five acquired PSMB5 mutations. In 1,500 patients such mutations were rare clinically. To better understand disruption of proteasomes on multiple myeloma viability and drug sensitivity, we systematically deleted the major proteasome catalytic subunits. Multiple myeloma cells without PSMB5 were viable. Drug-resistant, PSMB5-mutated

Soft-tissue sarcomas (STS) are rare malignancies showing lineage differentiation toward diverse mesenchymal tissues. Half of all high-grade STSs develop lung metastasis with a median survival of 15 months. Here, we used a genetically engineered mouse model that mimics undifferentiated pleomorphic sarcoma (UPS) to study the molecular mechanisms driving metastasis. High-grade sarcomas were generated

Numerous noncoding transcripts have been reported to correlate with cancer development and progression. Nevertheless, there remains a paucity of long noncoding RNAs (lncRNA) with well-elucidated functional roles. Here, we leverage the International Cancer Genome Consortium-Early Onset Prostate Cancer transcriptome and identify the previously uncharacterized lncRNA LINC00920 to be upregulated in prostate

The Hippo pathway effector Yes-associated protein (YAP) is localized to the nucleus and transcriptionally active in a number of tumor types, including a majority of human cholangiocarcinomas. YAP activity has been linked to chemotherapy resistance and has been shown to rescue KRAS and BRAF inhibition in RAS/RAF-driven cancers; however, the underlying mechanisms of YAP-mediated chemoresistance have

O-GlcNAc transferase (OGT) is a nutrient-sensitive glycosyltransferase that is overexpressed in prostate cancer, the most common cancer in males. We recently developed a specific and potent inhibitor targeting this enzyme, and here, we report a synthetic lethality screen using this compound. Our screen identified pan-cyclin-dependent kinase (CDK) inhibitor AT7519 as lethal in combination with OGT inhibition

Melanoma is one of the severe skin cancers, accounting for three fourths of all deaths caused by skin cancers and gathering attention from researchers. Previous studies have elucidated that long non-coding RNAs (lncRNAs) engage actively in tissue physiology and disease development, especially in tumorigenesis. LncRNA LHFPL3 antisense RNA 1 (LHFPL3-AS1) has rarely been mentioned in researches regarding

Diffuse intrinsic pontine glioma (DIPG) is a poor-prognosis pediatric brain tumor with a median survival of less than one year. No effective therapy is currently available, and no therapeutic advances have been made in several decades. We have previously identified BMI-1 as a potential therapeutic target in DIPG and have shown that BMI-1 is highly expressed in DIPG tumors regardless of histone 3 subtype

Triple-negative breast cancer (TNBC) has the worst prognosis of all breast cancers, and lacks effective targeted treatment strategies. Previously, we identified 33 transcription factors highly expressed in TNBC. Here, we focused on six sex determining region Y-related HMG-box (SOX) transcription factors (SOX4, 6, 8, 9, 10, and 11) highly expressed in TNBCs. Our siRNA screening assay demonstrated that

EphA2 receptor tyrosine kinase (RTK) is often expressed at high levels in cancer and has been shown to regulate tumor growth and metastasis across multiple tumor types, including non–small cell lung cancer. A number of signaling pathways downstream of EphA2 RTK have been identified; however, mechanisms of EphA2 proximal downstream signals are less well characterized. In this study, we used a yeast-two-hybrid

PTEN loss-of-function contributes to hyperactivation of the PI3K pathway and to drug resistance in breast cancer. Unchecked PI3K pathway signaling increases activation of the mechanistic target of rapamycin complex 1 (mTORC1), which promotes tumorigenicity. Several studies have suggested that vacuolar (H+)–ATPase (V–ATPase) complex activity is regulated by PI3K signaling. In this study, we showed that

Children suffering from neurologic cancers undergoing chemotherapy and radiotherapy are at high risk of reduced neurocognitive abilities likely via damage to proliferating neural stem cells (NSC). Therefore, strategies to protect NSCs are needed. We argue that induced cell-cycle arrest/quiescence in NSCs during cancer treatment can represent such a strategy. Here, we show that hyperpolarization-activated

HSP90 is a molecular chaperone required for stabilization and activation of hundreds of client proteins, including many known oncoproteins. AUY922 (luminespib), a new-generation HSP90 inhibitor, exhibits potent preclinical efficacy against several cancer types including prostate cancer. However, clinical use of HSP90 inhibitors for prostate cancer has been limited by toxicity and treatment resistance

Effective treatment of advanced prostate cancer persists as a significant clinical need as only 30% of patients with distant disease survive to 5 years after diagnosis. Targeting signaling and tumor cell–immune cell interactions in the tumor microenvironment has led to the development of powerful immunotherapeutic agents, however, the prostate tumor milieu remains impermeable to these strategies highlighting

Vesicular stomatitis virus (VSV) expressing IFNβ induces apoptosis in multiple tumor models while maintaining an excellent safety profile. VSV-IFNβ is oncoselective due to permissive replication in cells with an altered IFN pathway. The human VSV-IFNβ (hIFNβ) vector is currently used in clinical trials as a standalone therapy; however, we hypothesized that oncolytic virotherapy might be more effective

Glioblastoma (GBM) is the most lethal primary brain tumor and has a complex molecular profile. Hypoxia plays a critical role during tumor progression and in the tumor microenvironment (TME). Exosomes released by tumor cells contain informative nucleic acids, proteins, and lipids involved in the interaction between cancer and stromal cells, thus leading to TME remodeling. Accumulating evidence indicates

Treatment of ovarian cancer is limited by extensive metastasis and yet it remains poorly understood. We have studied the critical step of metastatic colonization in the context of the productive interactions with the metastatic microenvironment with a goal of identifying key regulators. By combining miRNA expression analysis using an organotypic 3D culture model of early ovarian cancer metastasis with