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 mod...

Full description

Saved in:
Bibliographic Details
Published in:Cell 2021-12, Vol.184 (25), p.6119-6137.e26
Main Authors: Raghavan, Srivatsan, Winter, Peter S., Navia, Andrew W., Williams, Hannah L., DenAdel, Alan, Lowder, Kristen E., Galvez-Reyes, Jennyfer, Kalekar, Radha L., Mulugeta, Nolawit, Kapner, Kevin S., Raghavan, Manisha S., Borah, Ashir A., Liu, Nuo, Väyrynen, Sara A., Costa, Andressa Dias, Ng, Raymond W.S., Wang, Junning, Hill, Emma K., Ragon, Dorisanne Y., Brais, Lauren K., Jaeger, Alex M., Spurr, Liam F., Li, Yvonne Y., Cherniack, Andrew D., Booker, Matthew A., Cohen, Elizabeth F., Tolstorukov, Michael Y., Wakiro, Isaac, Rotem, Asaf, Johnson, Bruce E., McFarland, James M., Sicinska, Ewa T., Jacks, Tyler E., Sullivan, Ryan J., Shapiro, Geoffrey I., Clancy, Thomas E., Perez, Kimberly, Rubinson, Douglas A., Ng, Kimmie, Cleary, James M., Crawford, Lorin, Manalis, Scott R., Nowak, Jonathan A., Wolpin, Brian M., Hahn, William C., Aguirre, Andrew J., Shalek, Alex K.
Format: Article
Language:English
Subjects:
Adult
Aged
Biomarkers, Tumor - metabolism
Carcinoma, Pancreatic Ductal - metabolism
Cell Line, Tumor
Female
Gene Expression Regulation, Neoplastic
Humans
liver metastases
Male
Middle Aged
pancreatic cancer
Pancreatic Neoplasms - metabolism
patient-derived organoid models
plasticity
Single-Cell Analysis
single-cell RNA-sequencing
transcriptional states
tumor heterogeneity
Tumor Microenvironment
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. [Display omitted] •scRNA-seq of metastatic pancreatic cancer and matched organoid models•Ex vivo to in vivo comparisons reveal loss of cell state heterogeneity in models•Cell state is shaped by the microenvironment in vivo and can be controlled ex vivo•Cell state drives drug response Systematic profiling of metastatic pancreatic cancer biopsies and matched organoid models provides a view of cellular states, their regulation by the tumor microenvironment, and the ability to modulate these states to impact drug responses.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2021.11.017