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Tetraspanin 6 is a regulator of carcinogenesis in colorectal cancer.

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 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.

SUBMITTER: Andrijes R

PROVIDER: S-EPMC8488650 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Tetraspanin 6 is a regulator of carcinogenesis in colorectal cancer.

Andrijes Regina R Hejmadi Rahul K RK Pugh Matthew M Rajesh Sundaresan S Novitskaya Vera V Ibrahim Maha M Overduin Michael M Tselepis Chris C Middleton Gary W GW Győrffy Balázs B Beggs Andrew D AD Berditchevski Fedor F

Proceedings of the National Academy of Sciences of the United States of America 20210901 39

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<sup>min/+</sup> 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-dependen ...[more]

PMID: 34521767

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Tetraspanin 6 is a regulator of carcinogenesis in colorectal cancer.

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Tetraspanin 6 is a regulator of carcinogenesis in colorectal cancer.

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