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The Origin and Contribution of Cancer-Associated Fibroblasts in Colorectal Carcinogenesis
  • Hiroki Kobayashi, Adelaide Medical School
  • Krystyna A. Gieniec, Adelaide Medical School
  • Tamsin R.M. Lannagan, Adelaide Medical School
  • Tongtong Wang, Adelaide Medical School
  • Naoya Asai, Fujita Health University Graduate School of Medicine
  • Yasuyuki Mizutani, Nagoya University Graduate School of Medicine
  • Tadashi Iida, Nagoya University Graduate School of Medicine
  • Ryota Ando, Nagoya University Graduate School of Medicine
  • Elaine M. Thomas, Adelaide Medical School
  • Akihiro Sakai, Nagoya University Graduate School of Medicine
  • Nobumi Suzuki, Adelaide Medical School
  • Mari Ichinose, Adelaide Medical School
  • Josephine A. Wright, South Australian Health and Medical Research Institute
  • Laura Vrbanac, Adelaide Medical School
  • Jia Q. Ng, Adelaide Medical School
  • Jarrad Goyne, Adelaide Medical School
  • Georgette Radford, Adelaide Medical School
  • Matthew J. Lawrence, Royal Adelaide Hospital
  • Tarik Sammour, Adelaide Medical School
  • Yoku Hayakawa, Graduate School of Medicine
  • Sonja Klebe, Flinders Medical Centre
  • Alice E. Shin, Schulich School of Medicine & Dentistry
  • Samuel Asfaha, Western University
  • Mark L. Bettington, KELVIN GROVE
  • Florian Rieder, Cleveland Clinic Foundation
  • Nicholas Arpaia, Vagelos College of Physicians and Surgeons
  • Tal Danino, Columbia University
  • Lisa M. Butler, Adelaide Medical School
  • Alastair D. Burt, Adelaide Medical School
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Background & Aims: Cancer-associated fibroblasts (CAFs) play an important role in colorectal cancer (CRC) progression and predict poor prognosis in CRC patients. However, the cellular origins of CAFs remain unknown, making it challenging to therapeutically target these cells. Here, we aimed to identify the origins and contribution of colorectal CAFs associated with poor prognosis. Methods: To elucidate CAF origins, we used a colitis-associated CRC mouse model in 5 different fate-mapping mouse lines with 5-bromodeoxyuridine dosing. RNA sequencing of fluorescence-activated cell sorting–purified CRC CAFs was performed to identify a potential therapeutic target in CAFs. To examine the prognostic significance of the stromal target, CRC patient RNA sequencing data and tissue microarray were used. CRC organoids were injected into the colons of knockout mice to assess the mechanism by which the stromal gene contributes to colorectal tumorigenesis. Results: Our lineage-tracing studies revealed that in CRC, many ACTA2+ CAFs emerge through proliferation from intestinal pericryptal leptin receptor (Lepr)+ cells. These Lepr-lineage CAFs, in turn, express melanoma cell adhesion molecule (MCAM), a CRC stroma-specific marker that we identified with the use of RNA sequencing. High MCAM expression induced by transforming growth factor β was inversely associated with patient survival in human CRC. In mice, stromal Mcam knockout attenuated orthotopically injected colorectal tumoroid growth and improved survival through decreased tumor-associated macrophage recruitment. Mechanistically, fibroblast MCAM interacted with interleukin-1 receptor 1 to augment nuclear factor κB–IL34/CCL8 signaling that promotes macrophage chemotaxis. Conclusions: In colorectal carcinogenesis, pericryptal Lepr-lineage cells proliferate to generate MCAM+ CAFs that shape the tumor-promoting immune microenvironment. Preventing the expansion/differentiation of Lepr-lineage CAFs or inhibiting MCAM activity could be effective therapeutic approaches for CRC.

Citation Information
Hiroki Kobayashi, Krystyna A. Gieniec, Tamsin R.M. Lannagan, Tongtong Wang, et al.. "The Origin and Contribution of Cancer-Associated Fibroblasts in Colorectal Carcinogenesis" Gastroenterology Vol. 162 Iss. 3 (2022) p. 890 - 906
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