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Pancreatic Ductal Adenocarcinoma Comprises Coexisting Regulatory States with both Common and Distinct Dependencies

View ORCID ProfilePasquale Laise, View ORCID ProfileMikko Turunen, View ORCID ProfileH. Carlo Maurer, Alvaro G. Curiel, Ela Elyada, View ORCID ProfileBernhard Schmierer, Lorenzo Tomassoni, View ORCID ProfileJeremy Worley, View ORCID ProfileMariano J. Alvarez, Jordan Kesner, Xiangtian Tan, Somnath Tagore, Alexander L. E. Wang, Sabrina Ge, Alina Cornelia Iuga, Aaron Griffin, Winston Wong, Gulam Manji, View ORCID ProfileFaiyaz Notta, David A. Tuveson, View ORCID ProfileKenneth P. Olive, View ORCID ProfileAndrea Califano
doi: https://doi.org/10.1101/2020.10.27.357269
Pasquale Laise
1Department of Systems Biology, Columbia University, New York, NY, US
2DarwinHealth Inc., New York, NY US
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Mikko Turunen
1Department of Systems Biology, Columbia University, New York, NY, US
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H. Carlo Maurer
3Klinikum rechts der Isar, II, Medizinische Klinik, Technische Universität München, 81675, Munich, Germany
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Alvaro G. Curiel
4Division of Digestive and Liver Diseases, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
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Ela Elyada
5Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, US
6Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York
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Bernhard Schmierer
7Karolinska Institutet, Stockholm, Sweden
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Lorenzo Tomassoni
1Department of Systems Biology, Columbia University, New York, NY, US
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Jeremy Worley
1Department of Systems Biology, Columbia University, New York, NY, US
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Mariano J. Alvarez
1Department of Systems Biology, Columbia University, New York, NY, US
2DarwinHealth Inc., New York, NY US
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Jordan Kesner
1Department of Systems Biology, Columbia University, New York, NY, US
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Xiangtian Tan
1Department of Systems Biology, Columbia University, New York, NY, US
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Somnath Tagore
1Department of Systems Biology, Columbia University, New York, NY, US
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Alexander L. E. Wang
1Department of Systems Biology, Columbia University, New York, NY, US
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Sabrina Ge
8Princess Margaret Cancer Centre, Toronto, Ontario, Canada
9Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
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Alina Cornelia Iuga
10Department of Pathology and Laboratory Medicine, Univ. of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Aaron Griffin
1Department of Systems Biology, Columbia University, New York, NY, US
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Winston Wong
11Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
12Division of Hematology and Oncology, Columbia University Irving Medical Center and New York Presbyterian Hospital Herbert Irving Pavilion, New York, NY, USA
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Gulam Manji
11Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
12Division of Hematology and Oncology, Columbia University Irving Medical Center and New York Presbyterian Hospital Herbert Irving Pavilion, New York, NY, USA
13Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
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Faiyaz Notta
8Princess Margaret Cancer Centre, Toronto, Ontario, Canada
9Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
14PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada
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David A. Tuveson
5Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, US
6Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York
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Kenneth P. Olive
4Division of Digestive and Liver Diseases, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
11Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
13Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
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  • For correspondence: kenolive@columbia.edu ac2248@cumc.columbia.edu
Andrea Califano
1Department of Systems Biology, Columbia University, New York, NY, US
13Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
16Department of Biomedical Informatics, Columbia University, New York, NY, USA
17Department of Biochemistry and Molecular Biophysics, Columbia University, New York
18J.P. Sulzberger Columbia Genome Center, New York, New York, USA
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  • For correspondence: kenolive@columbia.edu ac2248@cumc.columbia.edu
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Summary

Despite extensive efforts to characterize the transcriptional landscape of pancreatic ductal adenocarcinoma (PDA), reproducible assessment of subtypes with actionable dependencies remains challenging. Systematic, network-based analysis of regulatory protein activity stratified PDA tumours into novel functional subtypes that were highly conserved across multiple cohorts, including at the single cell level and in laser capture microdissected (LCM) samples. Identified subtypes were characterized by activation of master regulator proteins representing either gastrointestinal lineage markers or transcriptional effectors of morphogen pathways. Single cell analysis confirmed the existence of Lineage and Morphogenic states but also revealed a dominant population of more differentiated Oncogenic Precursor (OP) cells, present in all sampled patients, yet not apparent from bulk tumor analysis. Master regulators were validated by pooled, CRISPR/Cas9 screens, demonstrating both subtype-specific and universal dependencies. Conversely, ectopic expression of Lineage MRs, such as OVOL2, was sufficient to reprogram Morphogenic cells, thus providing a roadmap for the future targeting of patient-specific dependencies in PDA.

Competing Interest Statement

P.L. is Director of Single-Cell Systems Biology at DarwinHealth, Inc., a company that has licensed some of the algorithms used in this manuscript from Columbia University. M.J.A. is CSO and equity holder of DarwinHealth, Inc. Columbia University is also an equity holder in DarwinHealth Inc. A.C. is founder, equity holder, consultant, and director of DarwinHealth Inc.

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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Posted October 27, 2020.
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Pancreatic Ductal Adenocarcinoma Comprises Coexisting Regulatory States with both Common and Distinct Dependencies
Pasquale Laise, Mikko Turunen, H. Carlo Maurer, Alvaro G. Curiel, Ela Elyada, Bernhard Schmierer, Lorenzo Tomassoni, Jeremy Worley, Mariano J. Alvarez, Jordan Kesner, Xiangtian Tan, Somnath Tagore, Alexander L. E. Wang, Sabrina Ge, Alina Cornelia Iuga, Aaron Griffin, Winston Wong, Gulam Manji, Faiyaz Notta, David A. Tuveson, Kenneth P. Olive, Andrea Califano
bioRxiv 2020.10.27.357269; doi: https://doi.org/10.1101/2020.10.27.357269
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Pancreatic Ductal Adenocarcinoma Comprises Coexisting Regulatory States with both Common and Distinct Dependencies
Pasquale Laise, Mikko Turunen, H. Carlo Maurer, Alvaro G. Curiel, Ela Elyada, Bernhard Schmierer, Lorenzo Tomassoni, Jeremy Worley, Mariano J. Alvarez, Jordan Kesner, Xiangtian Tan, Somnath Tagore, Alexander L. E. Wang, Sabrina Ge, Alina Cornelia Iuga, Aaron Griffin, Winston Wong, Gulam Manji, Faiyaz Notta, David A. Tuveson, Kenneth P. Olive, Andrea Califano
bioRxiv 2020.10.27.357269; doi: https://doi.org/10.1101/2020.10.27.357269

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