Open AccessTetraspanin 6 is a regulator of carcinogenesis in colorectal cancer
Author(s) -
Regina Andrijes,
Rahul Hejmadi,
Matthew Pugh,
Sundaresan Rajesh,
Vera Novitskaya,
Maha Ibrahim,
Michael Overduin,
Chris Tselepis,
Gary Middleton,
Balázs Győrffy,
Andrew D Beggs,
Fedor Berditchevski
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2011411118
Subject(s) - tetraspanin , colorectal cancer , cetuximab , epidermal growth factor receptor , kras , cancer research , biology , carcinogenesis , signal transduction , regulator , epidermal growth factor , cancer , medicine , receptor , gene , microbiology and biotechnology , genetics , cell
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 Apc min/+ 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.