Tetraspanin 6 is a regulator of carcinogenesis in colorectal cancer

Regina Andrijes, Rahul K Hejmadi, Matthew Pugh, Sundaresan Rajesh, Vera Novitskaya, Maha Ibrahim, Michael Overduin, Chris Tselepis, Gary W Middleton, Balázs Győrffy, Andrew D Beggs, Fedor Berditchevski

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Abstract

Early stages of colorectal cancer (CRC) development are characterized by a complex rewiring of transcriptional networks resulting in changes in the expression of multiple genes. Here, we demonstrate that the deletion of a poorly studied tetraspanin protein Tspan6 in Apcmin/+ mice, a well-established model for premalignant CRC, resulted in increased incidence of adenoma formation and tumor size. We demonstrate that the effect of Tspan6 deletion results in the activation of EGF-dependent signaling pathways through increased production of the transmembrane form of TGF-α (tmTGF-α) associated with extracellular vesicles. This pathway is modulated by an adaptor protein syntenin-1, which physically links Tspan6 and tmTGF-α. In support of this, the expression of Tspan6 is frequently decreased or lost in CRC, and this correlates with poor survival. Furthermore, the analysis of samples from the epidermal growth factor receptor (EGFR)-targeting clinical trial (COIN trial) has shown that the expression of Tspan6 in CRC correlated with better patient responses to EGFR-targeted therapy involving Cetuximab. Importantly, Tspan6-positive patients with tumors in the proximal colon (right-sided) and those with KRAS mutations had a better response to Cetuximab than the patients that expressed low Tspan6 levels. These results identify Tspan6 as a regulator of CRC development and a potential predictive marker for EGFR-targeted therapies in CRC beyond RAS pathway mutations.

Original languageEnglish
Article numbere2011411118
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number39
Early online date14 Sep 2021
DOIs
Publication statusPublished - 28 Sep 2021

Bibliographical note

Funding Information:
ACKNOWLEDGMENTS. The work was supported by the Medical Research Council (MRC) research studentship to F.B., C.T., and A.D.B. (Ref No. 1575158). We are grateful for the use of tissue samples and data from the COIN trial funded by the MRC and Cancer Research United Kingdom (CRUK) (Grant C1210/A4850). The Stratification in Colorectal Cancer (S-CORT) consortium was supported by the CRUK and MRC Stratified Medicine Award for the S-CORT project (Ref. MR/M016587/1). A.D.B. is currently supported by a CRUK Advanced Clinician Scientist Award (Ref. C31641/A23923). We are grateful for Mr. Steven Hayward for technical assistance.

Keywords

  • Animals
  • Antineoplastic Agents, Immunological/pharmacology
  • Apoptosis
  • Biomarkers, Tumor/genetics
  • Cell Proliferation
  • Cetuximab/pharmacology
  • Colorectal Neoplasms/drug therapy
  • ErbB Receptors/antagonists & inhibitors
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Prognosis
  • Survival Rate
  • Tetraspanins/genetics
  • Tumor Cells, Cultured

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