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

文献信息 ​

DOI10.1084/jem.20162024
PMID28232471
期刊The Journal of experimental medicine
发表年份2017
被引次数1384
关键词癌相关成纤维细胞, 胰腺癌, 异质性, 炎症介质
文献类型Journal 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
页码579-596
期号214(3)
作者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

一句话小结 ​

本研究揭示胰腺导管腺癌中存在不同表型的癌相关成纤维细胞（CAFs）亚群，特别是一种高α-平滑肌肌动蛋白表达的CAFs亚群与肿瘤细胞紧邻，能够产生纤维化基质，而另一种离肿瘤细胞较远的CAFs则分泌IL6等炎症介质。这些发现为理解CAFs在胰腺癌中的异质性及其在疾病进程和治疗反应中的作用提供了重要依据。

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癌相关成纤维细胞 · 胰腺癌 · 异质性 · 炎症介质

摘要 ​

胰腺星形细胞（PSCs）分化为癌相关成纤维细胞（CAFs），这些细胞产生纤维化基质，从而调节胰腺导管腺癌（PDA）的疾病进程和治疗反应。然而，目前尚不清楚CAFs是否统一地执行这些任务，或者在PDA中是否存在具有不同表型的CAFs亚型。我们在小鼠和人类PDA组织中识别出一种CAFs亚群，其α-平滑肌肌动蛋白（αSMA）表达水平升高，且位于肿瘤细胞的紧邻处。我们在小鼠PSCs与PDA类器官的共培养中重复了这一发现，并证明激活的类器官CAFs能够产生纤维化基质。共培养显示出合作性相互作用，并揭示了另一种CAFs亚群，位于离肿瘤细胞更远处，该亚群缺乏升高的αSMA表达，而是分泌IL6及其他炎症介质。这些发现在人类和小鼠PDA组织中得到了证实，为PDA肿瘤生物学中的CAFs异质性提供了直接证据，并对疾病病因和治疗开发具有重要意义。

英文摘要 ​

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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主要研究问题 ​

  1. 在胰腺癌中，炎症成纤维细胞和肌成纤维细胞的不同亚群如何影响肿瘤的免疫微环境？
  2. 不同亚群的癌症相关成纤维细胞（CAFs）在胰腺导管腺癌的治疗反应中扮演了怎样的角色？
  3. 如何通过靶向特定亚群的CAFs来改善胰腺癌的治疗效果？
  4. 在其他类型的癌症中，是否也存在类似的CAFs亚群异质性现象，若有，其机制是否相似？
  5. 在未来的研究中，如何进一步探讨CAFs亚群与胰腺癌细胞之间的相互作用？

核心洞察 ​

研究背景和目的 ​

胰腺导管腺癌（PDA）是最具侵袭性的癌症之一，患者的中位生存期约为6个月，5年生存率低于8%。目前对晚期PDA的治疗效果有限，迫切需要新的治疗策略。研究表明，肿瘤相关成纤维细胞（CAFs）在PDA的发生和发展中发挥重要作用，但对CAFs的异质性及其功能尚未充分了解。本研究旨在探讨PDA中CAFs的不同亚群及其在肿瘤微环境中的作用。

主要方法/材料/实验设计 ​

研究采用了一种新型的三维共培养系统，结合小鼠胰腺星形细胞（PSCs）和胰腺肿瘤类器官，旨在模拟体内CAFs与癌细胞的相互作用。

Mermaid diagram
  1. PSCs的分离：从小鼠胰腺中分离出PSCs，通过酶解和密度梯度离心进行纯化。
  2. 共培养系统：将PSCs与GFP标记的肿瘤类器官共培养，观察其形态学变化和表型特征。
  3. 表型分析：使用免疫荧光和流式细胞术分析CAFs中αSMA和IL-6的表达。
  4. 分泌组分析：评估共培养条件下分泌的细胞因子，重点关注IL-6、IL-11和LIF的变化。
  5. 信号通路激活评估：通过Western blot分析STAT3的磷酸化状态。

关键结果和发现 ​

  1. CAFs的异质性：研究发现PDA中存在两种不同亚群的CAFs：

    • 肌成纤维CAF（myCAFs）：位于肿瘤细胞附近，表现出高水平的αSMA和低水平的IL-6。
    • 炎性CAF（iCAFs）：位于肿瘤细胞远端，表现出低水平的αSMA和高水平的IL-6及其他炎性细胞因子。

  2. 共培养的互作：PSCs在与肿瘤类器官共培养后，表现出CAF表型的激活，且分泌的细胞因子促进了肿瘤细胞的增殖。

  3. 信号通路激活：IL-6通过激活STAT3信号通路，促进了肿瘤细胞的生存和增殖。

主要结论/意义/创新性 ​

本研究首次系统性地表征了PDA中CAFs的异质性，识别了myCAFs和iCAFs两种功能不同的CAF亚群。这些发现不仅为理解PDA的肿瘤微环境提供了新视角，也为开发针对特定CAF亚群的靶向治疗策略奠定了基础。

研究局限性和未来方向 ​

  1. 局限性：本研究主要基于小鼠模型和体外实验，临床转化仍需进一步验证。
  2. 未来方向：未来的研究应集中于探索CAFs在PDA中的具体功能机制，以及开发针对不同CAF亚群的治疗策略，以改善PDA患者的预后。

参考文献 ​

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  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)
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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)
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引用本文的文献 ​

  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 更多 篇文献)

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