The Origin and Contribution of Cancer-Associated Fibroblasts in Colorectal Carcinogenesis

Hiroki Kobayashi; Krystyna A Gieniec; Tamsin R M Lannagan; Tongtong Wang; Naoya Asai; Yasuyuki Mizutani; Tadashi Iida; Ryota Ando; Elaine M Thomas; Akihiro Sakai; Nobumi Suzuki; Mari Ichinose; Josephine A Wright; Laura Vrbanac; Jia Q Ng; Jarrad Goyne; Georgette Radford; Matthew J Lawrence; Tarik Sammour; Yoku Hayakawa; Sonja Klebe; Alice E Shin; Samuel Asfaha; Mark L Bettington; Florian Rieder; Nicholas Arpaia; Tal Danino; Lisa M Butler; Alastair D Burt; Simon J Leedham; Anil K Rustgi; Siddhartha Mukherjee; Masahide Takahashi; Timothy C Wang; Atsushi Enomoto; Susan L Woods; Daniel L Worthley

doi:10.1053/j.gastro.2021.11.037

The Origin and Contribution of Cancer-Associated Fibroblasts in Colorectal Carcinogenesis

Gastroenterology. 2022 Mar;162(3):890-906. doi: 10.1053/j.gastro.2021.11.037. Epub 2021 Dec 6.

Authors

Hiroki Kobayashi¹, Krystyna A Gieniec², Tamsin R M Lannagan², Tongtong Wang², Naoya Asai³, Yasuyuki Mizutani⁴, Tadashi Iida⁴, Ryota Ando⁵, Elaine M Thomas², Akihiro Sakai⁵, Nobumi Suzuki⁶, Mari Ichinose², Josephine A Wright⁷, Laura Vrbanac², Jia Q Ng², Jarrad Goyne², Georgette Radford², Matthew J Lawrence⁸, Tarik Sammour⁹, Yoku Hayakawa¹⁰, Sonja Klebe¹¹, Alice E Shin¹², Samuel Asfaha¹³, Mark L Bettington¹⁴, Florian Rieder¹⁵, Nicholas Arpaia¹⁶, Tal Danino¹⁷, Lisa M Butler², Alastair D Burt¹⁸, Simon J Leedham¹⁹, Anil K Rustgi²⁰, Siddhartha Mukherjee²¹, Masahide Takahashi²², Timothy C Wang²¹, Atsushi Enomoto²³, Susan L Woods²⁴, Daniel L Worthley²⁵

Affiliations

¹ Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia; South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia; Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan; Division of Molecular Pathology, Center for Neurological Disease and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
² Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia; South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia.
³ Department of Molecular Pathology, Graduate School of Medicine, Fujita Health University, Toyoake, Aichi, Japan.
⁴ Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan; Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
⁵ Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
⁶ Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia; South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia; Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
⁷ South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia.
⁸ Colorectal Unit, Department of Surgery, Royal Adelaide Hospital, Adelaide, South Australia, Australia.
⁹ Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia; South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia; Colorectal Unit, Department of Surgery, Royal Adelaide Hospital, Adelaide, South Australia, Australia.
¹⁰ Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
¹¹ Department of Anatomical Pathology, Flinders Medical Centre, Bedford Park, Adelaide, South Australia, Australia.
¹² Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
¹³ Department of Medicine, University of Western Ontario, London, Ontario, Canada.
¹⁴ Envoi Specialist Pathologists, Kelvin Grove, Queensland, Australia; Faculty of Medicine, University of Queensland, Herston, Queensland, Australia; QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
¹⁵ Department of Gastroenterology, Hepatology, and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA; Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA.
¹⁶ Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York, USA.
¹⁷ Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York, USA; Department of Biomedical Engineering, Columbia University, New York, New York, USA.
¹⁸ Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia; Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
¹⁹ Intestinal Stem Cell Biology Lab, Wellcome Trust Centre Human Genetics, University of Oxford, Oxford, United Kingdom.
²⁰ Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York, USA.
²¹ Department of Medicine and Irving Cancer Research Center, Columbia University, New York, New York, USA.
²² Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan; Division of Molecular Pathology, Center for Neurological Disease and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan; International Center for Cell and Gene Therapy, Fujita Health University, Toyoake, Aichi, Japan.
²³ Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan. Electronic address: [email protected].
²⁴ Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia; South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia. Electronic address: [email protected].
²⁵ South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia; GastroIntestinal Endoscopy, Lutwyche, Queensland, Australia. Electronic address: [email protected].

Abstract

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.

Keywords: Alpha-Smooth Muscle Actin (αSMA); CD146; Colorectal Cancer; Tumor Microenvironment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Actins / genetics
Actins / metabolism
Adult
Aged
Aged, 80 and over
Animals
CD146 Antigen / genetics
CD146 Antigen / metabolism
Cancer-Associated Fibroblasts / pathology*
Cancer-Associated Fibroblasts / physiology*
Carcinogenesis / genetics
Carcinogenesis / metabolism
Carcinogenesis / pathology*
Cell Differentiation
Cell Lineage*
Cell Proliferation
Colorectal Neoplasms / metabolism
Colorectal Neoplasms / pathology*
Disease Models, Animal
Female
Humans
Intestinal Mucosa / pathology
Ki-67 Antigen / metabolism
Male
Mesenchymal Stem Cells / physiology*
Mice
Mice, Transgenic
Middle Aged
Organoids / pathology
Organoids / physiology
Prognosis
Receptors, Leptin / genetics
Receptors, Leptin / metabolism
Sequence Analysis, RNA
Survival Rate
Tumor Microenvironment

Substances

ACTA2 protein, human
Acta2 protein, mouse
Actins
CD146 Antigen
Ki-67 Antigen
LEPR protein, human
MCAM protein, human
Mcam protein, mouse
Receptors, Leptin
leptin receptor, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding