Journal
CELL
Volume 184, Issue 25, Pages 6119-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2021.11.017
Keywords
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Funding
- Lustgarten Foundation Dedicated Laboratory
- Dana-Farber Cancer Institute Hale Center for Pancreatic Cancer Research
- Doris Duke Charitable Foundation
- Pancreatic Cancer Action Network
- NIH-NCI [K08 CA218420-02, P50 CA127003, U01 CA176058, U01 CA224146, U01 CA210171, U01 28020510, 1U2CCA23319501, U54 CA217377, U01 CA250549]
- Stand Up To Cancer
- Noble Effort Fund
- Wexler Family Fund
- Promises for Purple
- Hope Funds for Cancer Research Postdoctoral Fellowship
- Harvard Cata-lyst/The Harvard Clinical and Translational Science Center [UL1 TR002541]
- Koch Institute for Integrative Cancer Research at MIT
- Dana-Farber/Harvard Cancer Center Bridge Project
- Dana-Farber Cancer Institute Gloria Spivak Faculty Advancement Fund
- Hopper-Belmont Foundation Inspiration Award
- Marcotte Center for Cancer Research
- Finnish Cultural Foundation
- Orion Research Foundation sr
- Damon Runyon Cancer Research Founda-tion
- NIH K99 Award [CA241072-01]
- Koch Institute Cancer Core Grant [NIH P30 CA14051]
- Broman Family Fund for Pancreatic Cancer Research
- Ludwig Center for Molecular Oncology at MIT
- Searle Scholars Program
- Beckman Young Investi-gator Program
- Sloan Fellowship in Chemistry
- Pew-Stewart Scholars Program for Cancer Research
- National Cancer Institute's Office of Cancer Genomics Cancer Target Discovery and Development (CTD<^>2) initiative
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Prognostically relevant RNA expression states exist in pancreatic ductal adenocarcinoma (PDAC), with strong culture-specific biases in cancer cell transcriptional state representation and non-genetic modulation of cell state strongly influencing drug responses. This study provides a 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.
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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