| Literature DB >> 35902743 |
William L Hwang1,2,3, Karthik A Jagadeesh1,2, Jimmy A Guo1,2,4,5,6, Hannah I Hoffman1,2,3,7, Payman Yadollahpour1,2, Jason W Reeves8, Rahul Mohan2, Eugene Drokhlyansky2, Nicholas Van Wittenberghe2, Orr Ashenberg2, Samouil L Farhi2, Denis Schapiro2,9,10, Prajan Divakar8, Eric Miller8, Daniel R Zollinger8, George Eng3,11, Jason M Schenkel3,12, Jennifer Su1,2,3, Carina Shiau1,2, Patrick Yu2, William A Freed-Pastor3,5, Domenic Abbondanza2, Arnav Mehta2,5,13, Joshua Gould2, Conner Lambden2, Caroline B M Porter2, Alexander Tsankov2, Danielle Dionne2, Julia Waldman2, Michael S Cuoco2, Lan Nguyen2, Toni Delorey2, Devan Phillips2,14, Jaimie L Barth11, Marina Kem11, Clifton Rodrigues15, Debora Ciprani15, Jorge Roldan15, Piotr Zelga15, Vjola Jorgji11, Jonathan H Chen2,11, Zackery Ely3, Daniel Zhao16, Kit Fuhrman8, Robin Fropf8, Joseph M Beechem8, Jay S Loeffler1, David P Ryan13, Colin D Weekes13, Cristina R Ferrone15, Motaz Qadan15, Martin J Aryee2,11, Rakesh K Jain1,17, Donna S Neuberg18, Jennifer Y Wo1, Theodore S Hong1, Ramnik Xavier2, Andrew J Aguirre2,5, Orit Rozenblatt-Rosen2,14, Mari Mino-Kenudson11, Carlos Fernandez-Del Castillo15, Andrew S Liss15, David T Ting13, Tyler Jacks19, Aviv Regev20,21.
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal and treatment-refractory cancer. Molecular stratification in pancreatic cancer remains rudimentary and does not yet inform clinical management or therapeutic development. Here, we construct a high-resolution molecular landscape of the cellular subtypes and spatial communities that compose PDAC using single-nucleus RNA sequencing and whole-transcriptome digital spatial profiling (DSP) of 43 primary PDAC tumor specimens that either received neoadjuvant therapy or were treatment naive. We uncovered recurrent expression programs across malignant cells and fibroblasts, including a newly identified neural-like progenitor malignant cell program that was enriched after chemotherapy and radiotherapy and associated with poor prognosis in independent cohorts. Integrating spatial and cellular profiles revealed three multicellular communities with distinct contributions from malignant, fibroblast and immune subtypes: classical, squamoid-basaloid and treatment enriched. Our refined molecular and cellular taxonomy can provide a framework for stratification in clinical trials and serve as a roadmap for therapeutic targeting of specific cellular phenotypes and multicellular interactions.Entities:
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Year: 2022 PMID： 35902743 DOI： 10.1038/s41588-022-01134-8
Source DB: PubMed Journal: Nat Genet ISSN： 1061-4036 Impact factor: 41.307