Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer

Daniel Öhlund; Abram Handly-Santana; Giulia Biffi; Ela Elyada; Ana S Almeida; Mariano Ponz-Sarvise; Vincenzo Corbo; Tobiloba E Oni; Stephen A Hearn; Eun Jung Lee; Iok In Christine Chio; Chang-Il Hwang; Hervé Tiriac; Lindsey A Baker; Dannielle D Engle; Christine Feig; Anne Kultti; Mikala Egeblad; Douglas T Fearon; James M Crawford; Hans Clevers; Youngkyu Park; David A Tuveson

doi:10.1084/jem.20162024

Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer

Daniel Öhlund, Abram Handly-Santana, Giulia Biffi, Ela Elyada, Ana S Almeida, Mariano Ponz-Sarvise, Vincenzo Corbo, Tobiloba E Oni, Stephen A Hearn, Eun Jung Lee, Iok In Christine Chio, Chang-Il Hwang, Hervé Tiriac, Lindsey A Baker, Dannielle D Engle, Christine Feig, Anne Kultti, Mikala Egeblad, Douglas T Fearon, James M CrawfordHans Clevers, Youngkyu Park, David A Tuveson

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

1615 Citations (Scopus)

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.

Original language	English
Pages (from-to)	579-596
Number of pages	18
Journal	Journal of Experimental Medicine
Volume	214
Issue number	3
DOIs	https://doi.org/10.1084/jem.20162024
Publication status	Published - 06 Mar 2017

Keywords

Actins
Animals
Carcinoma, Pancreatic Ductal
Cells, Cultured
Cytokines
Fibroblasts
Humans
Mice
Mice, Inbred C57BL
Myofibroblasts
Pancreatic Neoplasms
STAT3 Transcription Factor
Journal Article

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10.1084/jem.20162024

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Öhlund, D., Handly-Santana, A., Biffi, G., Elyada, E., Almeida, A. S., Ponz-Sarvise, M., Corbo, V., Oni, T. E., Hearn, S. A., Lee, E. J., Chio, I. I. C., Hwang, C.-I., Tiriac, H., Baker, L. A., Engle, D. D., Feig, C., Kultti, A., Egeblad, M., Fearon, D. T., ... Tuveson, D. A. (2017). Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. Journal of Experimental Medicine, 214(3), 579-596. https://doi.org/10.1084/jem.20162024

@article{5c35c0036f174c49972951e2a031bc3e,

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.",

keywords = "Actins, Animals, Carcinoma, Pancreatic Ductal, Cells, Cultured, Cytokines, Fibroblasts, Humans, Mice, Mice, Inbred C57BL, Myofibroblasts, Pancreatic Neoplasms, STAT3 Transcription Factor, Journal Article",

author = "Daniel {\"O}hlund and Abram Handly-Santana and Giulia Biffi and Ela Elyada and Almeida, {Ana S} and Mariano Ponz-Sarvise and Vincenzo Corbo and Oni, {Tobiloba E} and Hearn, {Stephen A} and Lee, {Eun Jung} and Chio, {Iok In Christine} and Chang-Il Hwang and Herv{\'e} Tiriac and Baker, {Lindsey A} and Engle, {Dannielle D} and Christine Feig and Anne Kultti and Mikala Egeblad and Fearon, {Douglas T} and Crawford, {James M} and Hans Clevers and Youngkyu Park and Tuveson, {David A}",

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year = "2017",

month = mar,

day = "6",

doi = "10.1084/jem.20162024",

language = "English",

volume = "214",

pages = "579--596",

journal = "Journal of Experimental Medicine",

issn = "0022-1007",

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Öhlund, D, Handly-Santana, A, Biffi, G, Elyada, E, Almeida, AS, Ponz-Sarvise, M, Corbo, V, Oni, TE, Hearn, SA, Lee, EJ, Chio, IIC, Hwang, C-I, Tiriac, H, Baker, LA, Engle, DD, Feig, C, Kultti, A, Egeblad, M, Fearon, DT, Crawford, JM, Clevers, H, Park, Y & Tuveson, DA 2017, 'Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer', Journal of Experimental Medicine, vol. 214, no. 3, pp. 579-596. https://doi.org/10.1084/jem.20162024

TY - JOUR

T1 - Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer

AU - Öhlund, Daniel

AU - Handly-Santana, Abram

AU - Biffi, Giulia

AU - Elyada, Ela

AU - Almeida, Ana S

AU - Ponz-Sarvise, Mariano

AU - Corbo, Vincenzo

AU - Oni, Tobiloba E

AU - Hearn, Stephen A

AU - Lee, Eun Jung

AU - Chio, Iok In Christine

AU - Hwang, Chang-Il

AU - Tiriac, Hervé

AU - Baker, Lindsey A

AU - Engle, Dannielle D

AU - Feig, Christine

AU - Kultti, Anne

AU - Egeblad, Mikala

AU - Fearon, Douglas T

AU - Crawford, James M

AU - Clevers, Hans

AU - Park, Youngkyu

AU - Tuveson, David A

PY - 2017/3/6

Y1 - 2017/3/6

N2 - 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.

AB - 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.

KW - Actins

KW - Animals

KW - Carcinoma, Pancreatic Ductal

KW - Cells, Cultured

KW - Cytokines

KW - Fibroblasts

KW - Humans

KW - Mice

KW - Mice, Inbred C57BL

KW - Myofibroblasts

KW - Pancreatic Neoplasms

KW - STAT3 Transcription Factor

KW - Journal Article

U2 - 10.1084/jem.20162024

DO - 10.1084/jem.20162024

M3 - Article

C2 - 28232471

SN - 0022-1007

VL - 214

SP - 579

EP - 596

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

IS - 3

ER -

Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer

Abstract

Keywords

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