Microenvironment drives cell state, plasticity, and drug response in pancreatic cancer.

Prognostically relevant RNA expression states exist in pancreatic ductal adenocarcinoma (PDAC), but our understanding of their drivers, stability, and relationship to therapeutic response is limited. To examine these attributes systematically, we profiled metastatic biopsies and matched organoid models at single-cell resolution. In vivo, we identify a new intermediate PDAC transcriptional cell state and uncover distinct site- and state-specific tumor microenvironments (TMEs). Benchmarking models against this reference map, we reveal strong culture-specific biases in cancer cell transcriptional state representation driven by altered TME signals. We restore expression state heterogeneity by adding back in vivo-relevant factors and show plasticity in culture models. Further, we prove that non-genetic modulation of cell state can strongly influence drug responses, uncovering state-specific vulnerabilities. This work provides a broadly applicable framework for aligning cell states across in vivo and ex vivo settings, identifying drivers of transcriptional plasticity and manipulating cell state to target associated vulnerabilities.

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Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests B.M.W. reports research support from Celgene and Eli Lilly and consulting for BioLineRx, Celgene, G1 Therapeutics, and GRAIL. W.C.H. is a consultant for Thermo Fisher, Solasta Ventures, MPM Capital, Tyra Biosciences, iTeos, Frontier Medicines, Function Oncology, KSQ Therapeutics, Jubilant Therapeutics, RAPPTA Therapeutics, and Paraxel. A.K.S. reports compensation for consulting and/or SAB membership from Merck, Honeycomb Biotechnologies, Cellarity, Repertoire Immune Medicines, Ochre Bio, Third Rock Ventures, Hovione, Relation Therapeutics, FL82, and Dahlia Biosciences. A.J.A. has consulted for Oncorus, Arrakis Therapeutics, and Merck & Co. and has research funding from Mirati Therapeutics, Syros, Deerfield, and Novo Ventures that are unrelated to this project. S.R.M. is a founder of Travera. S.R. has equity in Amgen. J.M.C. has received research funding from Merck, Tesaro, AstraZeneca, Bayer, and Esperas Pharma; has served as a consultant to Bristol Myers Squibb; and has received travel funding from Bristol Myers Squibb. A.R. is an employee of AstraZeneca and an equity holder in Celsius Therapeutics and NucleAI. Y.Y.L. reports equity from g.Root Biomedical Services. A.D. Cherniack reports research support from Bayer. R.J.S reports research support from Merck and consulting and/or SAB membership for Bristol Myers Squibb, Merck, Novartis, and Pfizer. G.I.S. reports sponsored research support from Eli Lilly, Merck KGaA/EMD-Serono, Merck, and Sierra Oncology and has served on advisory boards for Pfizer, Eli Lilly, G1 Therapeutics, Roche, Merck KGaA/EMD-Serono, Sierra Oncology, Bicycle Therapeutics, Fusion Pharmaceuticals, Cybrexa Therapeutics, Astex, Almac, Ipsen, Bayer, Angiex, Daiichi Sankyo, Seattle Genetics, Boehringer Ingelheim, ImmunoMet, Asana, Artios, Atrin, Concarlo Holdings, Syros, Zentalis, CytomX Therapeutics, Blueprint Medicines, and Kymera Therapeutics. T.J. is a member of the Board of Directors of Amgen and Thermo Fisher Scientific; a co-Founder of Dragonfly Therapeutics and T2 Biosystems; serves on the Scientific Advisory Board of Dragonfly Therapeutics, SQZ Biotech, and Skyhawk Therapeutics; and is the President of Break Through Cancer. None of these affiliations represent a conflict of interest with respect to the design or execution of this study or interpretation of data presented in this manuscript. T.J.’s laboratory currently also receives funding from the Johnson & Johnson Lung Cancer Initiative and The Lustgarten Foundation for Pancreatic Cancer Research, but this funding did not support the research described in this manuscript. K.N. reports research support from Revolution Medicines, Evergrande Group, Pharmavite, and Janssen; is a member of SABs for SeaGen, BiomX, and Bicara Therapeutics; and has consulted for X-Biotix Therapeutics and Redesign Health. A.K.S., P.S.W., A.W.N., S.R., W.C.H., A.J.A., B.W.M., and J.G.R. have filed a patent (Publication number WO/2021/081491; International application number PCT/US2020/057342) related to this work.