PT  - JOURNAL ARTICLE
AU  - Pasquale Laise
AU  - Mikko Turunen
AU  - H. Carlo Maurer
AU  - Alvaro G. Curiel
AU  - Ela Elyada
AU  - Bernhard Schmierer
AU  - Lorenzo Tomassoni
AU  - Jeremy Worley
AU  - Mariano J. Alvarez
AU  - Jordan Kesner
AU  - Xiangtian Tan
AU  - Somnath Tagore
AU  - Alexander L. E. Wang
AU  - Sabrina Ge
AU  - Alina Cornelia Iuga
AU  - Aaron Griffin
AU  - Winston Wong
AU  - Gulam Manji
AU  - Faiyaz Notta
AU  - David A. Tuveson
AU  - Kenneth P. Olive
AU  - Andrea Califano
TI  - Pancreatic Ductal Adenocarcinoma Comprises Coexisting Regulatory States with both Common and Distinct Dependencies
AID  - 10.1101/2020.10.27.357269
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.10.27.357269
4099  - http://biorxiv.org/content/early/2020/10/27/2020.10.27.357269.short
4100  - http://biorxiv.org/content/early/2020/10/27/2020.10.27.357269.full
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.