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.
