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Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. ​

Literature Information ​

DOI10.1084/jem.20162024
PMID28232471
JournalThe Journal of experimental medicine
Publication Year2017
Times Cited1384
Keywordscancer-associated fibroblasts, pancreatic cancer, tumor biology
Literature TypeJournal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural
ISSN0022-1007
Pages579-596
Issue214(3)
AuthorsDaniel 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

TL;DR ​

This study uncovers the heterogeneity of cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinoma (PDA), identifying distinct subpopulations that differ in their expression of α-smooth muscle actin and cytokine secretion. These findings enhance our understanding of the tumor microenvironment and may inform future therapeutic strategies targeting specific CAF subtypes to improve treatment outcomes in PDA.

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cancer-associated fibroblasts · pancreatic cancer · tumor biology

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.

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Primary Questions Addressed ​

  1. How do the distinct populations of CAFs influence the progression of pancreatic ductal adenocarcinoma?
  2. What are the specific roles of IL6 and other inflammatory mediators secreted by the CAF subpopulation distant from neoplastic cells?
  3. How does the presence of α-smooth muscle actin (αSMA) in CAFs correlate with their functional roles in tumor microenvironment?
  4. What therapeutic strategies could be developed to target the different subpopulations of CAFs in pancreatic cancer?
  5. How might the heterogeneity of CAFs impact the response to existing pancreatic cancer treatments?

Key Findings ​

Research Background and Objective ​

Pancreatic ductal adenocarcinoma (PDA) is characterized by a dense desmoplastic stroma primarily composed of cancer-associated fibroblasts (CAFs), which are derived from pancreatic stellate cells (PSCs). This study aims to explore the heterogeneity of CAFs in PDA, specifically investigating whether distinct subpopulations of CAFs exist with unique functions and phenotypes.

Main Methods/Materials/Experimental Design ​

The researchers utilized a novel three-dimensional co-culture system combining mouse PSCs and pancreatic cancer organoids to simulate the tumor microenvironment. Key methods included:

  • Isolation of PSCs: Quiescent PSCs were isolated from mouse pancreata and characterized for their ability to differentiate into myofibroblastic CAFs.
  • Co-culture System: PSCs were co-cultured with GFP-labeled pancreatic organoids in a reduced media to prevent fibroblast inhibition.
  • Immunofluorescence and In Situ Hybridization: Used to assess α-smooth muscle actin (αSMA) and inflammatory cytokine expression in CAFs.
  • Secretome Analysis: The secreted factors from co-cultures were analyzed to identify cytokines and their roles in tumor progression.
  • Flow Cytometry: Employed to distinguish between different CAF subpopulations based on αSMA and IL-6 expression.

The following flowchart summarizes the experimental design:

Mermaid diagram

Key Results and Findings ​

  1. Heterogeneous CAF Populations: The study identified two distinct subpopulations of CAFs:

    • Myofibroblastic CAFs (myCAFs): Characterized by high αSMA expression and located near neoplastic cells.
    • Inflammatory CAFs (iCAFs): Characterized by low αSMA and high IL-6 expression, located further from the tumor.

  2. Functional Characteristics:

    • MyCAFs were primarily involved in producing desmoplastic stroma, while iCAFs secreted inflammatory cytokines, including IL-6, which promoted cancer progression.
    • The co-culture system revealed that PSCs could switch between these phenotypes depending on their proximity to tumor cells and the signals received.

  3. Cytokine Production: Elevated levels of IL-6, IL-11, and leukemia inhibitory factor (LIF) were observed in co-cultures, indicating a paracrine signaling mechanism driving CAF activation and function.

Main Conclusion/Significance/Innovation ​

This study provides direct evidence for the existence of heterogeneous CAF populations in pancreatic cancer, challenging the traditional view of CAFs as a uniform entity. The identification of myCAFs and iCAFs with distinct spatial distributions and functional roles underscores the complexity of the tumor microenvironment and highlights potential targets for therapeutic intervention.

Research Limitations and Future Directions ​

  • Limitations: The study primarily utilized mouse models, which may not fully recapitulate human disease complexity. Additionally, the specific mechanisms governing the transition between CAF subtypes remain to be elucidated.
  • Future Directions: Further research should focus on characterizing additional CAF subtypes, their specific roles in tumor biology, and how these findings can be translated into effective therapies for PDA patients. Investigating the potential for targeting specific CAF populations could lead to improved therapeutic strategies.

References ​

  1. Clinical significance of interleukin-6 (IL-6) gene polymorphism and IL-6 serum level in pancreatic adenocarcinoma and chronic pancreatitis. - Renata Talar-Wojnarowska;Anita Gasiorowska;Beata Smolarz;Hanna Romanowicz-Makowska;Andrzej Kulig;Ewa Malecka-Panas - Digestive diseases and sciences (2009)
  2. Tumor-Induced IL-6 Reprograms Host Metabolism to Suppress Anti-tumor Immunity. - Thomas R Flint;Tobias Janowitz;Claire M Connell;Edward W Roberts;Alice E Denton;Anthony P Coll;Duncan I Jodrell;Douglas T Fearon - Cell metabolism (2016)
  3. Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogenesis. - Hua Tian;Christopher A Callahan;Kelly J DuPree;Walter C Darbonne;Christina P Ahn;Suzie J Scales;Frederic J de Sauvage - Proceedings of the National Academy of Sciences of the United States of America (2009)
  4. The senescence-associated secretory phenotype: the dark side of tumor suppression. - Jean-Philippe Coppé;Pierre-Yves Desprez;Ana Krtolica;Judith Campisi - Annual review of pathology (2010)
  5. Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. - Cristovão M Sousa;Douglas E Biancur;Xiaoxu Wang;Christopher J Halbrook;Mara H Sherman;Li Zhang;Daniel Kremer;Rosa F Hwang;Agnes K Witkiewicz;Haoqiang Ying;John M Asara;Ronald M Evans;Lewis C Cantley;Costas A Lyssiotis;Alec C Kimmelman - Nature (2016)
  6. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. - Berna C Özdemir;Tsvetelina Pentcheva-Hoang;Julienne L Carstens;Xiaofeng Zheng;Chia-Chin Wu;Tyler R Simpson;Hanane Laklai;Hikaru Sugimoto;Christoph Kahlert;Sergey V Novitskiy;Ana De Jesus-Acosta;Padmanee Sharma;Pedram Heidari;Umar Mahmood;Lynda Chin;Harold L Moses;Valerie M Weaver;Anirban Maitra;James P Allison;Valerie S LeBleu;Raghu Kalluri - Cancer cell (2014)
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  8. Pancreatic stellate cell secreted IL-6 stimulates STAT3 dependent invasiveness of pancreatic intraepithelial neoplasia and cancer cells. - Nagaraj S Nagathihalli;Jason A Castellanos;Michael N VanSaun;Xizi Dai;Mahogany Ambrose;Qiaozhi Guo;Yanhua Xiong;Nipun B Merchant - Oncotarget (2016)
  9. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. - Ravid Straussman;Teppei Morikawa;Kevin Shee;Michal Barzily-Rokni;Zhi Rong Qian;Jinyan Du;Ashli Davis;Margaret M Mongare;Joshua Gould;Dennie T Frederick;Zachary A Cooper;Paul B Chapman;David B Solit;Antoni Ribas;Roger S Lo;Keith T Flaherty;Shuji Ogino;Jennifer A Wargo;Todd R Golub - Nature (2012)
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Literatures Citing This Work ​

  1. Mathematical model of chronic pancreatitis. - Wenrui Hao;Hannah M Komar;Phil A Hart;Darwin L Conwell;Gregory B Lesinski;Avner Friedman - Proceedings of the National Academy of Sciences of the United States of America (2017)
  2. IL6 Receptor Blockade Enhances Chemotherapy Efficacy in Pancreatic Ductal Adenocarcinoma. - Kristen B Long;Graham Tooker;Evan Tooker;Santiago Lombo Luque;Jae W Lee;Xiaoqing Pan;Gregory L Beatty - Molecular cancer therapeutics (2017)
  3. The Role of Fibroblasts in Pancreatic Cancer: Extracellular Matrix Versus Paracrine Factors. - Louisa Bolm;Simon Cigolla;Uwe A Wittel;Ulrich T Hopt;Tobias Keck;Dirk Rades;Peter Bronsert;Ulrich Friedrich Wellner - Translational oncology (2017)
  4. Tumor engraftment in patient-derived xenografts of pancreatic ductal adenocarcinoma is associated with adverse clinicopathological features and poor survival. - Ilaria Pergolini;Vicente Morales-Oyarvide;Mari Mino-Kenudson;Kim C Honselmann;Matthew W Rosenbaum;Sabikun Nahar;Marina Kem;Cristina R Ferrone;Keith D Lillemoe;Nabeel Bardeesy;David P Ryan;Sarah P Thayer;Andrew L Warshaw;Carlos Fernández-Del Castillo;Andrew S Liss - PloS one (2017)
  5. Therapeutic Targeting of TAZ and YAP by Dimethyl Fumarate in Systemic Sclerosis Fibrosis. - Tetsuo Toyama;Agnieszka P Looney;Brendon M Baker;Lukasz Stawski;Paul Haines;Robert Simms;Aleksander D Szymaniak;Xaralabos Varelas;Maria Trojanowska - The Journal of investigative dermatology (2018)
  6. Requisite role of vasohibin-2 in spontaneous gastric cancer formation and accumulation of cancer-associated fibroblasts. - Yasuhiro Suzuki;Shuji Kitahara;Takuya Suematsu;Masanobu Oshima;Yasufumi Sato - Cancer science (2017)
  7. Tissue Force Programs Cell Fate and Tumor Aggression. - Jason J Northey;Laralynne Przybyla;Valerie M Weaver - Cancer discovery (2017)
  8. GPR68, a proton-sensing GPCR, mediates interaction of cancer-associated fibroblasts and cancer cells. - Shu Z Wiley;Krishna Sriram;Wenjing Liang;Sarah E Chang;Randall French;Thalia McCann;Jason Sicklick;Hiroshi Nishihara;Andrew M Lowy;Paul A Insel - FASEB journal : official publication of the Federation of American Societies for Experimental Biology (2018)
  9. Validation and comparison of the molecular classifications of pancreatic carcinomas. - David J Birnbaum;Pascal Finetti;Daniel Birnbaum;Emilie Mamessier;François Bertucci - Molecular cancer (2017)
  10. Role of pericytes in the retina. - G S P Santos;P H D M Prazeres;A Mintz;A Birbrair - Eye (London, England) (2018)

... (1374 more literatures)

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