RT Journal Article
SR Electronic
T1 Pancreatic Ductal Adenocarcinoma Comprises Coexisting Regulatory States with both Common and Distinct Dependencies
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.10.27.357269
DO 10.1101/2020.10.27.357269
A1 Pasquale Laise
A1 Mikko Turunen
A1 H. Carlo Maurer
A1 Alvaro G. Curiel
A1 Ela Elyada
A1 Bernhard Schmierer
A1 Lorenzo Tomassoni
A1 Jeremy Worley
A1 Mariano J. Alvarez
A1 Jordan Kesner
A1 Xiangtian Tan
A1 Somnath Tagore
A1 Alexander L. E. Wang
A1 Sabrina Ge
A1 Alina Cornelia Iuga
A1 Aaron Griffin
A1 Winston Wong
A1 Gulam Manji
A1 Faiyaz Notta
A1 David A. Tuveson
A1 Kenneth P. Olive
A1 Andrea Califano
YR 2020
UL http://biorxiv.org/content/early/2020/10/27/2020.10.27.357269.abstract
AB 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 StatementP.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.