Laise, Pasquale, Turunen, Mikko, Maurer, Hans Carlo, Garcia, Alvaro Curiel, Elyada, Ela, Schmierer, Bernhard, Tomassoni, Lorenzo, Worley, Jeremy, Alvarez, Mariano J, Kesner, Jordan, Tan, Xiangtian, Tagore, Somnath, Fernandez, Ester Calvo, Wong, Kelly, Wang, Alexander LE, Ge, Sabrina, Iuga, Alina C, Griffin, Aaron T, Wong, Winston, Manji, Gulam A, Notta, Faiyaz, Tuveson, David A, Olive, Kenneth PP, Califano, Andrea (2022) Pancreatic cancer comprises co-existing transcriptional states regulated by distinct master regulator programs. In: AACR Special Conference on Pancreatic Cancer, 2022 Sep 13-16, Boston, MA.
Abstract
Despite extensive efforts, reproducible assessment of pancreatic ductal adenocarcinoma (PDA) heterogeneity and plasticity at the single cell level remains elusive. Systematic, network-based analysis of single cell RNA-seq profiles showed that most PDA tumors comprise three coexisting lineages whose aberrant transcriptional state is mechanistically controlled by distinct regulatory programs. These lineages were characterized by the aberrant activation of either gastrointestinal lineage markers (GLS), transcriptional effectors of morphogen pathways (MOS) and acinar to ductal metaplasia markers (ALS). Each lineage was characterized by cells in two different cell states determined by the differential activation of MEK signaling (M+/M-) and high cellular plasticity. These states were confirmed in multiple cohorts, cell lines, PDX models and harmonized with bulk profile analyses. Master regulators (MRs) of GLS and MOS state were predictive of patient’s survival in bulk profiles. Cross-state plasticity was confirmed by lineage tracing assays, while pooled CRISPR/Cas9 assays confirmed the essentiality of identified MR proteins. Finally, mechanistic MR-mediated cell state control was confirmed by MR expression-mediated reprogramming of MOS cells to a GLS state. Our work provided a mechanistic model of pancreatic cancer heterogeneity and testable hypothesis to target cell state-specific pancreatic cancer dependencies.
| Item Type: | Conference or Workshop Item (Speech) |
|---|---|
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > transcription diseases & disorders > cancer > cancer types > pancreatic cancer |
| CSHL Authors: | |
| Communities: | CSHL labs > Tuveson lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 2022 |
| Date Deposited: | 29 Sep 2023 17:48 |
| Last Modified: | 29 Sep 2023 17:48 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/41070 |
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