title: Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer.
abstract: Pancreatic stellate cells (PSCs) differentiate into cancer-associated fibroblasts (CAFs) that produce desmoplastic stroma, thereby modulating disease progression and therapeutic response in pancreatic ductal adenocarcinoma (PDA). However, it is unknown whether CAFs uniformly carry out these tasks or if subtypes of CAFs with distinct phenotypes in PDA exist. We identified a CAF subpopulation with elevated expression of α-smooth muscle actin (αSMA) located immediately adjacent to neoplastic cells in mouse and human PDA tissue. We recapitulated this finding in co-cultures of murine PSCs and PDA organoids, and demonstrated that organoid-activated CAFs produced desmoplastic stroma. The co-cultures showed cooperative interactions and revealed another distinct subpopulation of CAFs, located more distantly from neoplastic cells, which lacked elevated αSMA expression and instead secreted IL6 and additional inflammatory mediators. These findings were corroborated in mouse and human PDA tissue, providing direct evidence for CAF heterogeneity in PDA tumor biology with implications for disease etiology and therapeutic development.
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.|Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724.|Department of Surgical and Perioperative Sciences, Surgery, Umeå University, 901 85 Umeå, Sweden.
authors.forename: Daniel
authors.identifier: 0000-0002-5847-2778
authors.initials: D
authors.lastname: Öhlund
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.|Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724.
authors.forename: Abram
authors.initials: A
authors.lastname: Handly-Santana
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.|Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724.
authors.forename: Giulia
authors.initials: G
authors.lastname: Biffi
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.|Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724.
authors.forename: Ela
authors.initials: E
authors.lastname: Elyada
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.|APC Microbiome Institute and School of Microbiology, University College Cork, Cork, Ireland.
authors.forename: Ana S
authors.identifier: 0000-0001-8997-2639
authors.initials: AS
authors.lastname: Almeida
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.|Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724.|Department of Oncology, Clinica Universidad de Navarra, CIMA, IDISNA, Pamplona 31008, Spain.
authors.forename: Mariano
authors.initials: M
authors.lastname: Ponz-Sarvise
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.|Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724.|ARC-Net centre for applied research on cancer, University and Hospital Trust of Verona, 37134 Verona, Italy.|Department of Diagnostic and Public Health, University and Hospital Trust of Verona, 37134 Verona, Italy.
authors.forename: Vincenzo
authors.identifier: 0000-0002-6340-8009
authors.initials: V
authors.lastname: Corbo
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.|Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724.|Graduate Program in Molecular and Cellular Biology, Stony Brook University, Stony Brook, NY 11794.
authors.forename: Tobiloba E
authors.identifier: 0000-0002-6916-3380
authors.initials: TE
authors.lastname: Oni
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
authors.forename: Stephen A
authors.identifier: 0000-0002-2489-2424
authors.initials: SA
authors.lastname: Hearn
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.|Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724.
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Lee
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.|Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724.
authors.forename: Iok In Christine
authors.initials: II
authors.lastname: Chio
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.|Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724.
authors.forename: Chang-Il
authors.identifier: 0000-0002-5710-7672
authors.initials: CI
authors.lastname: Hwang
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.|Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724.
authors.forename: Hervé
authors.initials: H
authors.lastname: Tiriac
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.|Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724.
authors.forename: Lindsey A
authors.identifier: 0000-0002-3098-2231
authors.initials: LA
authors.lastname: Baker
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.|Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724.
authors.forename: Dannielle D
authors.identifier: 0000-0003-1876-7675
authors.initials: DD
authors.lastname: Engle
authors.affiliation: University of Cambridge, Cancer Research UK, Cambridge Institute, Cambridge, UK.
authors.forename: Christine
authors.initials: C
authors.lastname: Feig
authors.affiliation: University of Cambridge, Cancer Research UK, Cambridge Institute, Cambridge, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: Kultti
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
authors.forename: Mikala
authors.identifier: 0000-0002-3371-1445
authors.initials: M
authors.lastname: Egeblad
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
authors.forename: Douglas T
authors.identifier: 0000-0003-0612-0495
authors.initials: DT
authors.lastname: Fearon
authors.affiliation: Hofstra Northwell School of Medicine, Hempstead, NY 11550.
authors.forename: James M
authors.initials: JM
authors.lastname: Crawford
authors.affiliation: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), University Medical Centre Utrecht and CancerGenomics.nl, 3584 CT Utrecht, Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Clevers
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.|Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724.
authors.forename: Youngkyu
authors.initials: Y
authors.lastname: Park
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.|Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724.
authors.forename: David A
authors.identifier: 0000-0002-8017-2712
authors.initials: DA
authors.lastname: Tuveson
mesh_terms: D000199:Actins / Q000032:analysis; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D005347:Fibroblasts / Q000502:physiology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D058628:Myofibroblasts / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: C558396:Acta2 protein, mouse; D000199:Actins; D016207:Cytokines; D050796:STAT3 Transcription Factor