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Transcriptional subtype-specific microenvironmental crosstalk and tumor cell plasticity in metastatic pancreatic cancer

Srivatsan Raghavan, Peter S. Winter, Andrew W. Navia, Hannah L. Williams, Alan DenAdel, Radha L. Kalekar, Jennyfer Galvez-Reyes, Kristen E. Lowder, Nolawit Mulugeta, Manisha S. Raghavan, Ashir A. Borah, Sara A. Väyrynen, Andressa Dias Costa, Raymond W.S. Ng, Junning Wang, Emma Reilly, Dorisanne Y. Ragon, Lauren K. Brais, Alex M. Jaeger, Liam F. Spurr, Yvonne Y. Li, Andrew D. Cherniack, Isaac Wakiro, Asaf Rotem, Bruce E. Johnson, James M. McFarland, Ewa T. Sicinska, Tyler E. Jacks, 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: https://doi.org/10.1101/2020.08.25.256214
Srivatsan Raghavan
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
2Broad Institute of MIT and Harvard, Cambridge, MA
3Harvard Medical School, Boston, MA
4Department of Medicine, Brigham and Women’s Hospital, Boston, MA
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Peter S. Winter
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
2Broad Institute of MIT and Harvard, Cambridge, MA
5Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA
6Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA
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  • For correspondence: pswinter@mit.edu andrew_aguirre@dfci.harvard.edu shalek@mit.edu
Andrew W. Navia
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
2Broad Institute of MIT and Harvard, Cambridge, MA
5Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA
6Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA
7Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA
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Hannah L. Williams
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
3Harvard Medical School, Boston, MA
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Alan DenAdel
8Center for Computational Molecular Biology, Brown University, Providence, RI
9Division of Applied Mathematics, Brown University, Providence, RI
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Radha L. Kalekar
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
2Broad Institute of MIT and Harvard, Cambridge, MA
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Jennyfer Galvez-Reyes
2Broad Institute of MIT and Harvard, Cambridge, MA
5Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA
6Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA
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Kristen E. Lowder
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
2Broad Institute of MIT and Harvard, Cambridge, MA
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Nolawit Mulugeta
2Broad Institute of MIT and Harvard, Cambridge, MA
5Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA
6Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA
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Manisha S. Raghavan
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
2Broad Institute of MIT and Harvard, Cambridge, MA
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Ashir A. Borah
2Broad Institute of MIT and Harvard, Cambridge, MA
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Sara A. Väyrynen
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
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Andressa Dias Costa
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
3Harvard Medical School, Boston, MA
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Raymond W.S. Ng
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
2Broad Institute of MIT and Harvard, Cambridge, MA
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Junning Wang
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
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Emma Reilly
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
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Dorisanne Y. Ragon
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
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Lauren K. Brais
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
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Alex M. Jaeger
6Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA
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Liam F. Spurr
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
2Broad Institute of MIT and Harvard, Cambridge, MA
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Yvonne Y. Li
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
2Broad Institute of MIT and Harvard, Cambridge, MA
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Andrew D. Cherniack
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
2Broad Institute of MIT and Harvard, Cambridge, MA
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Isaac Wakiro
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
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Asaf Rotem
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
2Broad Institute of MIT and Harvard, Cambridge, MA
10Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA
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Bruce E. Johnson
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
3Harvard Medical School, Boston, MA
4Department of Medicine, Brigham and Women’s Hospital, Boston, MA
10Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA
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James M. McFarland
2Broad Institute of MIT and Harvard, Cambridge, MA
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Ewa T. Sicinska
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
3Harvard Medical School, Boston, MA
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Tyler E. Jacks
6Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA
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Thomas E. Clancy
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
3Harvard Medical School, Boston, MA
11Department of Surgery, Brigham and Women’s Hospital, Boston, MA
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Kimberly Perez
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
3Harvard Medical School, Boston, MA
4Department of Medicine, Brigham and Women’s Hospital, Boston, MA
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Douglas A. Rubinson
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
3Harvard Medical School, Boston, MA
4Department of Medicine, Brigham and Women’s Hospital, Boston, MA
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Kimmie Ng
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
3Harvard Medical School, Boston, MA
4Department of Medicine, Brigham and Women’s Hospital, Boston, MA
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James M. Cleary
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
3Harvard Medical School, Boston, MA
4Department of Medicine, Brigham and Women’s Hospital, Boston, MA
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Lorin Crawford
8Center for Computational Molecular Biology, Brown University, Providence, RI
12Department of Biostatistics, Brown University, Providence, RI
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Scott R. Manalis
6Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA
13Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA
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Jonathan A. Nowak
3Harvard Medical School, Boston, MA
14Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA
15Department of Pathology, Brigham and Women’s Hospital, Boston, MA
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Brian M. Wolpin
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
3Harvard Medical School, Boston, MA
4Department of Medicine, Brigham and Women’s Hospital, Boston, MA
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William C. Hahn
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
2Broad Institute of MIT and Harvard, Cambridge, MA
3Harvard Medical School, Boston, MA
4Department of Medicine, Brigham and Women’s Hospital, Boston, MA
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Andrew J. Aguirre
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
2Broad Institute of MIT and Harvard, Cambridge, MA
3Harvard Medical School, Boston, MA
4Department of Medicine, Brigham and Women’s Hospital, Boston, MA
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  • For correspondence: pswinter@mit.edu andrew_aguirre@dfci.harvard.edu shalek@mit.edu
Alex K. Shalek
2Broad Institute of MIT and Harvard, Cambridge, MA
3Harvard Medical School, Boston, MA
5Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA
7Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA
16Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA
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  • For correspondence: pswinter@mit.edu andrew_aguirre@dfci.harvard.edu shalek@mit.edu
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ABSTRACT

In pancreatic ductal adenocarcinoma (PDAC), the basal-like and classical transcriptional subtypes are associated with differential chemotherapy sensitivity and patient survival. These phenotypes have been defined using bulk transcriptional profiling, which can mask underlying cellular heterogeneity and the biologic mechanisms that distinguish these subtypes. Furthermore, few studies have interrogated metastases, which are the cause of mortality in most patients with this highly lethal disease. Using single-cell RNA-sequencing of metastatic needle biopsies and matched organoid models, we demonstrate intra-tumoral subtype heterogeneity at the single-cell level and define a continuum for the basal-like and classical phenotypes that includes hybrid cells that co-express features of both states. Basal-like tumors show enrichment of mesenchymal and stem-like programs, and demonstrate immune exclusion and tumor cell crosstalk with specific macrophage subsets. Conversely, classical tumors harbor greater immune infiltration and a relatively pro-angiogenic microenvironment. Matched organoid models exhibit a strong bias against the growth of basal-like cells in standard organoid media, but modification of culture conditions can rescue the basal-like phenotype. This study reframes the transcriptional taxonomy of PDAC, demonstrates how divergent transcriptional subtypes associate with unique tumor microenvironments, and highlights the importance of evaluating both genotype and transcriptional phenotype to establish high-fidelity patient-derived cancer models.

Competing Interest Statement

B.M.W. reports research support from Celgene, Eli Lilly and consulting for BioLineRx, Celgene, G1 Therapeutics, GRAIL. W.C.H. is a consultant for Thermo Fisher, Solasta Ventures, MPM Capital, Tyra Biosciences, iTeos, Frontier Medicines, and Paraxel. W.C.H. is a founder and a member of the scientific advisory board (SAB) for KSQ Therapeutics. A.K.S. reports compensation for consulting and/or SAB membership from Merck, Honeycomb Biotechnologies, Cellarity, Cogen Therapeutics, Orche Bio, and Dahlia Biosciences. A.J.A. has consulted for Oncorus, Inc., Arrakis Therapeutics, and Merck & Co., Inc, and has research funding from Mirati Therapeutics, Deerfield, Inc. and Novo Ventures that are unrelated to this project. S.R.M. is a founder of Travera. J.M.C. has received research funding from Merck, Tesaro, Astrazeneca, and Esperas Pharma, has served as a consultant to Bristol Myers Squib, and has received travel funding from Bristol Myers Squib. A.R. is a consultant to eGenesis, a member of the SAB for NucleAI, and an equity holder in Celsius Therapeutics. Y.Y.L. reports equity from g.Root Biomedical Services. A.D.C. reports research support from Bayer. K.N. reports research support from Revolution Medicines, Evergrande Group, Genentech, Gilead Sciences, Celgene, Trovagene, Pharmavite, and Tarrex Biopharma, is a member of SABs for Bayer, Seattle Genetics, and Array Biopharma, and has consulted for X-Biotix Therapeutics.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Transcriptional subtype-specific microenvironmental crosstalk and tumor cell plasticity in metastatic pancreatic cancer
Srivatsan Raghavan, Peter S. Winter, Andrew W. Navia, Hannah L. Williams, Alan DenAdel, Radha L. Kalekar, Jennyfer Galvez-Reyes, Kristen E. Lowder, Nolawit Mulugeta, Manisha S. Raghavan, Ashir A. Borah, Sara A. Väyrynen, Andressa Dias Costa, Raymond W.S. Ng, Junning Wang, Emma Reilly, Dorisanne Y. Ragon, Lauren K. Brais, Alex M. Jaeger, Liam F. Spurr, Yvonne Y. Li, Andrew D. Cherniack, Isaac Wakiro, Asaf Rotem, Bruce E. Johnson, James M. McFarland, Ewa T. Sicinska, Tyler E. Jacks, 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
bioRxiv 2020.08.25.256214; doi: https://doi.org/10.1101/2020.08.25.256214
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Transcriptional subtype-specific microenvironmental crosstalk and tumor cell plasticity in metastatic pancreatic cancer
Srivatsan Raghavan, Peter S. Winter, Andrew W. Navia, Hannah L. Williams, Alan DenAdel, Radha L. Kalekar, Jennyfer Galvez-Reyes, Kristen E. Lowder, Nolawit Mulugeta, Manisha S. Raghavan, Ashir A. Borah, Sara A. Väyrynen, Andressa Dias Costa, Raymond W.S. Ng, Junning Wang, Emma Reilly, Dorisanne Y. Ragon, Lauren K. Brais, Alex M. Jaeger, Liam F. Spurr, Yvonne Y. Li, Andrew D. Cherniack, Isaac Wakiro, Asaf Rotem, Bruce E. Johnson, James M. McFarland, Ewa T. Sicinska, Tyler E. Jacks, 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
bioRxiv 2020.08.25.256214; doi: https://doi.org/10.1101/2020.08.25.256214

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