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

Srivatsan Raghavan; Peter S Winter; Andrew W Navia; Hannah L Williams; Alan DenAdel; Kristen E Lowder; Jennyfer Galvez-Reyes; Radha L Kalekar; Nolawit Mulugeta; Kevin S Kapner; Manisha S Raghavan; Ashir A Borah; Nuo Liu; Sara A Väyrynen; Andressa Dias Costa; Raymond W S Ng; Junning Wang; Emma K Hill; Dorisanne Y Ragon; Lauren K Brais; Alex M Jaeger; Liam F Spurr; Yvonne Y Li; Andrew D Cherniack; Matthew A Booker; Elizabeth F Cohen; Michael Y Tolstorukov; Isaac Wakiro; Asaf Rotem; Bruce E Johnson; James M McFarland; Ewa T Sicinska; Tyler E Jacks; Ryan J Sullivan; Geoffrey I Shapiro; Thomas E Clancy; Kimberly Perez; Douglas A Rubinson; Kimmie Ng; James M Cleary; Lorin Crawford; Scott R Manalis; Jonathan A Nowak; Brian M Wolpin; William C Hahn; Andrew J Aguirre; Alex K Shalek

doi:10.1016/j.cell.2021.11.017

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

Cell. 2021 Dec 9;184(25):6119-6137.e26. doi: 10.1016/j.cell.2021.11.017.

Authors

Srivatsan Raghavan¹, Peter S Winter², Andrew W Navia³, Hannah L Williams⁴, Alan DenAdel⁵, Kristen E Lowder⁶, Jennyfer Galvez-Reyes⁷, Radha L Kalekar⁶, Nolawit Mulugeta⁷, Kevin S Kapner⁶, Manisha S Raghavan⁶, Ashir A Borah⁸, Nuo Liu⁷, Sara A Väyrynen⁴, Andressa Dias Costa⁴, Raymond W S Ng⁶, Junning Wang⁹, Emma K Hill⁹, Dorisanne Y Ragon⁹, Lauren K Brais⁹, Alex M Jaeger¹⁰, Liam F Spurr⁶, Yvonne Y Li⁶, Andrew D Cherniack¹¹, Matthew A Booker¹², Elizabeth F Cohen¹², Michael Y Tolstorukov¹², Isaac Wakiro⁹, Asaf Rotem¹³, Bruce E Johnson¹⁴, James M McFarland⁸, Ewa T Sicinska¹⁵, Tyler E Jacks¹⁰, Ryan J Sullivan¹⁶, Geoffrey I Shapiro¹⁷, Thomas E Clancy¹⁸, Kimberly Perez¹⁷, Douglas A Rubinson¹⁷, Kimmie Ng¹⁷, James M Cleary¹⁷, Lorin Crawford¹⁹, Scott R Manalis²⁰, Jonathan A Nowak²¹, Brian M Wolpin¹⁷, William C Hahn¹, Andrew J Aguirre²², Alex K Shalek²³

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02115, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
² Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: [email protected].
³ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁴ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02115, USA.
⁵ Center for Computational Molecular Biology, Brown University, Providence, RI 02912, USA; Division of Applied Mathematics, Brown University, Providence, RI 02912, USA.
⁶ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁷ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁸ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
¹⁰ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
¹¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02115, USA.
¹² Department of Informatics and Analytics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
¹³ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
¹⁴ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02115, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
¹⁵ Harvard Medical School, Boston, MA 02115, USA; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
¹⁶ Harvard Medical School, Boston, MA 02115, USA; Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA.
¹⁷ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02115, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
¹⁸ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02115, USA; Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA.
¹⁹ Center for Computational Molecular Biology, Brown University, Providence, RI 02912, USA; Department of Biostatistics, Brown University, Providence, RI 02912, USA; Microsoft Research New England, Cambridge, MA 02142, USA.
²⁰ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
²¹ Harvard Medical School, Boston, MA 02115, USA; Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
²² Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02115, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. Electronic address: [email protected].
²³ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02115, USA; Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA. Electronic address: [email protected].

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.

Keywords: liver metastases; pancreatic cancer; patient-derived organoid models; plasticity; single-cell RNA-sequencing; transcriptional states; tumor heterogeneity; tumor microenvironment.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Biomarkers, Tumor / metabolism*
Carcinoma, Pancreatic Ductal / metabolism*
Cell Line, Tumor
Female
Gene Expression Regulation, Neoplastic
Humans
Male
Middle Aged
Pancreatic Neoplasms / metabolism*
Single-Cell Analysis
Tumor Microenvironment*

Substances

Biomarkers, Tumor

Abstract

Publication types

MeSH terms

Substances

Grants and funding