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 Laise, Pasquale
A1 Turunen, Mikko
A1 Maurer, H. Carlo
A1 Curiel, Alvaro G.
A1 Elyada, Ela
A1 Schmierer, Bernhard
A1 Tomassoni, Lorenzo
A1 Worley, Jeremy
A1 Alvarez, Mariano J.
A1 Kesner, Jordan
A1 Tan, Xiangtian
A1 Tagore, Somnath
A1 Wang, Alexander L. E.
A1 Ge, Sabrina
A1 Iuga, Alina Cornelia
A1 Griffin, Aaron
A1 Wong, Winston
A1 Manji, Gulam
A1 Notta, Faiyaz
A1 Tuveson, David A.
A1 Olive, Kenneth P.
A1 Califano, Andrea
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.