2. Academic Validation
  3. TGM2-mediated serotonylation in tumor endothelial cells promotes angiogenesis and tumor growth in colorectal cancer

TGM2-mediated serotonylation in tumor endothelial cells promotes angiogenesis and tumor growth in colorectal cancer

  • Cancer Lett. 2026 May 1:645:218396. doi: 10.1016/j.canlet.2026.218396.
Tianlong Ling 1,  Wei Zhang 2,  Haiyan Cai 3,  Tran Trung Kien 4,  Tingting Yan 5,  Jilin Wang 6,  Jianjun Chen 7
Affiliations

Affiliations

  • 1 Department of Gastrointestinal Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
  • 2 Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
  • 3 Department of Gastroenterology, Songjiang District Sijing Hospital of Western Medicine, Songjiang District, Shanghai, China.
  • 4 Oncology Department, University Medical Shing Mark Hospital, 1054 Highway 51, Long Binh Tan Ward, Bien Hoa City, Dong Nai, Viet Nam.
  • 5 Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China. Electronic address: [email protected].
  • 6 Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China. Electronic address: [email protected].
  • 7 Department of Gastrointestinal Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China. Electronic address: [email protected].
PMID: 41780842 DOI: 10.1016/j.canlet.2026.218396
Abstract

Angiogenesis fuels colorectal Cancer (CRC) growth and metastasis by supplying oxygen and nutrients to expanding tumors. Here, we define a TGM2-mediated serotonylation axis in tumor endothelial cells as a driver of angiogenesis and a key mediator of epigenetic reprogramming within the tumor microenvironment. Across CRC single-cell datasets, TGM2 is broadly expressed in endothelial cells, and endothelial TGM2 correlates with the H3Q5Ser MARK. Endothelial-specific deletion of Tgm2 in mice markedly suppresses angiogenesis and slows allograft tumor growth. In human umbilical vein endothelial cells, TGM2 knockdown diminishes H3Q5Ser, proliferation, migration, and tube formation, which can be rescued with nuclear-localized wild-type TGM2 but not a transamidase-inactive mutant. Mechanistically, TGM2-catalyzed serotonylation promotes LDHA transcription via H3Q5Ser at the LDHA promoter, thereby upregulating glycolysis. Hypoxia induces TGM2 expression via HIF-1α signaling. Moreover, endothelial cells lack canonical serotonin transporters and serotonin biosynthesis, and exosome-mediated transfer of 5-HT provides a source that fuels endothelial serotonylation. Clinically, high endothelial TGM2 and H3Q5Ser levels predict poorer prognosis. Collectively, the TGM2-serotonylation axis in endothelial cells represents a promising therapeutic target to disrupt tumor angiogenesis and CRC progression, with potential to synergize with immunotherapy by normalizing tumor vasculature and enhancing anti-tumor immunity.

Keywords

Serotonylation; Transglutaminases; Tumor angiogenesis; Tumor-associated endothelial cells.

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  • HY-12337
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