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 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.

Exosome biogenesis: machinery, regulation, and therapeutic implications in cancer

“…Andrijes et al found that TSPN6 and its adaptor Syntenin-1 negatively mediated the exosomal secretion of the transmembrane form of TGF-α and inhibited Fig. 5 Categories of mechanisms mediating the dysregulation of exosome biogenesis in cancer carcinogenesis in colorectal cancer [149]. For the ESCRT independent pathway, both caveolin-1, flotillins, and Rab31 are ubiquitously overexpressed in cancer and promote cancer progression and chemoresistance by their function in controlling exosomes secretion [45,50,150].…”

TSPAN6 is a suppressor of Ras-driven cancer

“…Moreover, TSPAN6 can bind to the EGFR suggesting that it directly negatively regulates EGFR phosphorylation and signaling. Indeed a recent study has shown that TSPAN6 controls the production of the extracellular vesicles containing the transmembrane form of TGF-alpha, a EGFR ligand, and thereby downregulates EGFR signaling [ 42 ]. In this newly described mechanism, TSPAN6 is physically linked to TNF-alpha via the adapter protein syntenin-1, and upon TSPAN6 downregulation increased production of extracellular tm-TGF-alpha occurs leading to increased EGFR signaling [ 42 ].…”

“…Indeed a recent study has shown that TSPAN6 controls the production of the extracellular vesicles containing the transmembrane form of TGF-alpha, a EGFR ligand, and thereby downregulates EGFR signaling [ 42 ]. In this newly described mechanism, TSPAN6 is physically linked to TNF-alpha via the adapter protein syntenin-1, and upon TSPAN6 downregulation increased production of extracellular tm-TGF-alpha occurs leading to increased EGFR signaling [ 42 ]. Although our findings show that TSPAN6 knockdown phenocopies DLG1 and SCRIB knockdown, and our analysis in Drosophila has linked Tsp29Fb to Scrib/Dlg1 regulation/function [ 14 ], and that Scrib/Dlg1 are known to regulate Ras signaling in Drosophila and mammalian cells [ 11 , 30 , 43 , 44 ], since TSPAN6 does not bind to DLG1 or SCRIB, it is likely that these proteins regulate EGFR-RAS signaling by parallel pathways, with TSPAN6 functioning at the level of the EGFR by binding to it and inhibiting its activation, and SCRIB/DLG1 directly binding to and negatively regulating ERK activation [ 43 ].…”

“…In addition to lung and pancreatic cancer, mining of various databases, including TCGA, revealed mutations, deletions, and copy number variations of TSPAN6 in multiple human cancers (not shown). A recent study has revealed that TSPAN6 also plays a tumor suppressor role in colorectal cancer [ 42 ], but whether TSPAN6 has a tumor suppressor role in additional cancer types, apart from pancreatic, lung and colorectal, needs to be explored in future experiments.…”

The versatile roles of testrapanins in cancer from intracellular signaling to cell–cell communication: cell membrane proteins without ligands

“…The expression of TSPAN6 is frequently decreased or even lost in colorectal cancer tissues, and correlates with favorable survival. TSPAN6 deletion facilitates colorectal cancer development and 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 [ 83 ]. Liang G. and colleagues found that TSPAN12 could inhibit tumor growth of non-small lung cancer cells [ 77 ].…”