An engineered pancreatic cancer model with intra-tumoral heterogeneity of driver mutations

Hye-ran Moon; Altug Ozcelikkale; Yi Yang; Bennett D. Elzey; Stephen F. Konieczny; Bumsoo Han

doi:10.1039/D0LC00707B

An engineered pancreatic cancer model with intra-tumoral heterogeneity of driver mutations†

Hye-ran Moon,‡^a Altug Ozcelikkale,‡^ab Yi Yang,^c Bennett D. Elzey,^de Stephen F. Konieczny

^ce and Bumsoo Han

*^aef

Author affiliations

* Corresponding authors

^a School of Mechanical Engineering, Purdue University, West Lafayette, IN, USA
E-mail: bumsoo@purdue.edu

^b Department of Mechanical Engineering, Middle East Technical University, Ankara, Turkey

^c Department of Biological Science, Purdue University, West Lafayette, IN, USA

^d Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, USA

^e Purdue Center for Cancer Research, Purdue University, West Lafayette, IN, USA

^f Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, USA

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a complex disease with significant intra-tumoral heterogeneity (ITH). Currently, no reliable PDAC tumor model is available that can present ITH profiles in a controlled manner. We develop an in vitro microfluidic tumor model mimicking the heterogeneous accumulation of key driver mutations of human PDAC using cancer cells derived from genetically engineered mouse models. These murine pancreatic cancer cell lines have KPC (Kras and Trp53 mutations) and KIC genotypes (Kras mutation and Cdkn2a deletion). Also, the KIC genotypes have two distinct phenotypes – mesenchymal or epithelial. The tumor model mimics the ITH of human PDAC to study the effects of ITH on the gemcitabine response. The results show gemcitabine resistance induced by ITH. Remarkably, it shows that cancer cell–cell interactions induce the gemcitabine resistance potentially through epithelial–mesenchymal-transition. The tumor model can provide a useful testbed to study interaction mechanisms between heterogeneous cancer cell subpopulations.

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DOI: https://doi.org/10.1039/D0LC00707B
Article type: Paper
Submitted: 10 Jul 2020
Accepted: 02 Sep 2020
First published: 02 Sep 2020

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Lab Chip, 2020,20, 3720-3732

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An engineered pancreatic cancer model with intra-tumoral heterogeneity of driver mutations

H. Moon, A. Ozcelikkale, Y. Yang, B. D. Elzey, S. F. Konieczny and B. Han, Lab Chip, 2020, 20, 3720 DOI: 10.1039/D0LC00707B

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An engineered pancreatic cancer model with intra-tumoral heterogeneity of driver mutations†

Abstract

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An engineered pancreatic cancer model with intra-tumoral heterogeneity of driver mutations

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