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Microenvironment drives cell state, plasticity, and drug response in pancreatic cancer
Name
1-s2.0-S0092867421013325-main.pdf
Description
Published version
Size
25.22 MB
Format
Adobe PDF
Checksum (MD5)
3239a61e465fc422dfc2e58f4b7d35fb
Date Issued
December 2021
Journal
Cell
Publisher
Elsevier BV
Citation
2021. "Microenvironment drives cell state, plasticity, and drug response in pancreatic cancer." Cell, 184 (25).
Version
Final published version
Abstract
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.
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
Persistent DSpace Link
DOI of Published Version
10.1016/j.cell.2021.11.017
