TY - JOUR
T1 - The Origin and Contribution of Cancer-Associated Fibroblasts in Colorectal Carcinogenesis
AU - Kobayashi, Hiroki
AU - Gieniec, Krystyna A.
AU - Lannagan, Tamsin R.M.
AU - Wang, Tongtong
AU - Asai, Naoya
AU - Mizutani, Yasuyuki
AU - Iida, Tadashi
AU - Ando, Ryota
AU - Thomas, Elaine M.
AU - Sakai, Akihiro
AU - Suzuki, Nobumi
AU - Ichinose, Mari
AU - Wright, Josephine A.
AU - Vrbanac, Laura
AU - Ng, Jia Q.
AU - Goyne, Jarrad
AU - Radford, Georgette
AU - Lawrence, Matthew J.
AU - Sammour, Tarik
AU - Hayakawa, Yoku
AU - Klebe, Sonja
AU - Shin, Alice E.
AU - Asfaha, Samuel
AU - Bettington, Mark L.
AU - Rieder, Florian
AU - Arpaia, Nicholas
AU - Danino, Tal
AU - Butler, Lisa M.
AU - Burt, Alastair D.
AU - Leedham, Simon J.
AU - Rustgi, Anil K.
AU - Mukherjee, Siddhartha
AU - Takahashi, Masahide
AU - Wang, Timothy C.
AU - Enomoto, Atsushi
AU - Woods, Susan L.
AU - Worthley, Daniel L.
N1 - Publisher Copyright:
© 2022 AGA Institute
PY - 2022/3
Y1 - 2022/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85122332361&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85122332361&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2021.11.037
DO - 10.1053/j.gastro.2021.11.037
M3 - Article
C2 - 34883119
AN - SCOPUS:85122332361
SN - 0016-5085
VL - 162
SP - 890
EP - 906
JO - Gastroenterology
JF - Gastroenterology
IS - 3
ER -
