Reference SummaryAndrijes R, Proc Natl Acad Sci U S A 2021 Sep 28;118(39):
Title |
Tetraspanin 6 is a regulator of carcinogenesis in colorectal cancer. |
Authors |
Andrijes R; Hejmadi RK; Pugh M; Rajesh S; Novitskaya V; Ibrahim M; Overduin M; Tselepis C; Middleton GW; Gyorffy B; Beggs AD; Berditchevski F |
Journal |
Proc Natl Acad Sci U S A |
Volume |
118 |
Issue |
39 |
Year |
2021 |
Pages |
|
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-alpha (tmTGF-alpha) associated with extracellular vesicles. This pathway is modulated by an adaptor protein syntenin-1, which physically links Tspan6 and tmTGF-alpha. 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. |
Links |
J:311175 – MGI References 34521767 – National Library of Medicine/PubMed |
Strain | Model Name | Treatment Agent(s) | Organ Affected | Frequency | Model Details |
---|---|---|---|---|---|
C57BL/6J-ApcMin/+ | Intestine - Large Intestine - Colon adenoma | Intestine - Large Intestine - Colon |
0 |
||
C57BL/6J-ApcMin/+ Tspan6tm2Vlcg | Intestine - Large Intestine - Colon adenoma | Intestine - Large Intestine - Colon |
39.13 |
||
C57BL/6J-ApcMin/+ | Intestine - Large Intestine - Colon dysplasia - high grade | Intestine - Large Intestine - Colon |
0 |
||
C57BL/6J-ApcMin/+ Tspan6tm2Vlcg | Intestine - Large Intestine - Colon dysplasia - high grade | Intestine - Large Intestine - Colon |
39.13 |
||
C57BL/6J-ApcMin/+ | Intestine - Large Intestine - Colon dysplasia - low grade | Intestine - Large Intestine - Colon |
15.79 |
||
C57BL/6J-ApcMin/+ Tspan6tm2Vlcg | Intestine - Large Intestine - Colon dysplasia - low grade | Intestine - Large Intestine - Colon |
65.22 |
||
C57BL/6J-ApcMin/+ | Intestine - Large Intestine - Colon polyp | Intestine - Large Intestine - Colon |
very low |
||
C57BL/6J-ApcMin/+ | Intestine - Large Intestine polyp | Intestine - Large Intestine |
very low |
||
C57BL/6J-ApcMin/+ | Intestine - Small Intestine adenoma | Intestine - Small Intestine |
5.26 - 94.74 |
||
C57BL/6J-ApcMin/+ Tspan6tm2Vlcg | Intestine - Small Intestine adenoma | Intestine - Small Intestine |
43.48 - 86.96 |
||
C57BL/6J-ApcMin/+ | Intestine - Small Intestine dysplasia - high grade | Intestine - Small Intestine |
5.26 |
||
C57BL/6J-ApcMin/+ Tspan6tm2Vlcg | Intestine - Small Intestine dysplasia - high grade | Intestine - Small Intestine |
43.48 |
||
C57BL/6J-ApcMin/+ | Intestine - Small Intestine dysplasia - low grade | Intestine - Small Intestine |
94.74 |
||
C57BL/6J-ApcMin/+ Tspan6tm2Vlcg | Intestine - Small Intestine dysplasia - low grade | Intestine - Small Intestine |
86.96 |
||
C57BL/6J-ApcMin/+ | Intestine - Small Intestine lesion | Intestine - Small Intestine |
observed |
||
C57BL/6J-ApcMin/+ Tspan6tm2Vlcg | Intestine - Small Intestine lesion | Intestine - Small Intestine |
0 |
||
C57BL/6J-ApcMin/+ | Intestine - Small Intestine lesion - malignant | Intestine - Small Intestine |
0 |
||
C57BL/6J-ApcMin/+ Tspan6tm2Vlcg | Intestine - Small Intestine lesion - malignant | Intestine - Small Intestine |
observed |
||
C57BL/6J-ApcMin/+ | Intestine - Small Intestine polyp | Intestine - Small Intestine |
observed |
||
C57BL/6J-ApcMin/+ | Intestine lesion | Intestine |
observed |
||
C57BL/6J-ApcMin/+ Tspan6tm2Vlcg | Intestine lesion | Intestine |
observed |
||
C57BL/6J-ApcMin/+ | Intestine polyp | Intestine |
observed - 100 |
||
C57BL/6J-ApcMin/+ Tspan6tm2Vlcg | Intestine polyp | Intestine |
observed - 100 |
||
C57BL/6J-ApcMin/+ | Intestine tumor | Intestine |
observed |
||
C57BL/6J-ApcMin/+ Tspan6tm2Vlcg | Intestine tumor | Intestine |
observed |