Single-nucleus and spatial transcriptome profiling of pancreatic cancer identifies multicellular dynamics associated with neoadjuvant treatment.
IF: 41.307
Cited by: 59


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.


Gene Expression
Spatial Transcriptomics

MeSH terms

Biomarkers, Tumor
Carcinoma, Pancreatic Ductal
Gene Expression Profiling
Neoadjuvant Therapy
Pancreatic Neoplasms
Pancreatic Neoplasms


Hwang, William L
Jagadeesh, Karthik A
Guo, Jimmy A
Hoffman, Hannah I
Yadollahpour, Payman
Reeves, Jason W
Mohan, Rahul
Drokhlyansky, Eugene
Van Wittenberghe, Nicholas
Ashenberg, Orr
Farhi, Samouil L
Schapiro, Denis
Divakar, Prajan
Miller, Eric
Zollinger, Daniel R
Eng, George
Schenkel, Jason M
Su, Jennifer
Shiau, Carina
Yu, Patrick
Freed-Pastor, William A
Abbondanza, Domenic
Mehta, Arnav
Gould, Joshua
Lambden, Conner
Porter, Caroline B M
Tsankov, Alexander
Dionne, Danielle
Waldman, Julia
Cuoco, Michael S
Nguyen, Lan
Delorey, Toni
Phillips, Devan
Barth, Jaimie L
Kem, Marina
Rodrigues, Clifton
Ciprani, Debora
Roldan, Jorge
Zelga, Piotr
Jorgji, Vjola
Chen, Jonathan H
Ely, Zackery
Zhao, Daniel
Fuhrman, Kit
Fropf, Robin
Beechem, Joseph M
Loeffler, Jay S
Ryan, David P
Weekes, Colin D
Ferrone, Cristina R
Qadan, Motaz
Aryee, Martin J
Jain, Rakesh K
Neuberg, Donna S
Wo, Jennifer Y
Hong, Theodore S
Xavier, Ramnik
Aguirre, Andrew J
Rozenblatt-Rosen, Orit
Mino-Kenudson, Mari
Castillo, Carlos Fernandez-Del
Liss, Andrew S
Ting, David T
Jacks, Tyler
Regev, Aviv