Tetraspanin 6 is a regulator of carcinogenesis in colorectal cancer


Posted: 2021-09-15 19:00:00
Proc Natl Acad Sci U S A . 2021 Sep 28;118(39):e2011411118. doi: 10.1073/pnas.2011411118. Regina Andrijes 1 , Rahul K Hejmadi 2 , Matthew Pugh 1 , Sundaresan Rajesh 1 , Vera Novitskaya 1 , Maha Ibrahim 1 3 , Michael Overduin 1 , Chris Tselepis 1 , Gary W Middleton 1 , Balázs Győrffy 4 5 6 , Andrew D Beggs 1 , Fedor Berditchevski 7 Affiliations Expand Affiliations 1 Institute of Cancer and Genomic Sciences, The University of Birmingham, Birmingham B15 2TT, United Kingdom. 2 University Hospitals Birmingham National Health Service Foundation Trust, Birmingham B15 2TH, United Kingdom. 3 South Egypt Cancer Institute, Assiut University, Assiut 71515, Egypt. 4 Department of Bioinformatics, Semmelweis University, 1094 Budapest, Hungary. 5 2nd Department of Paediatrics, Semmelweis University, 1094 Budapest, Hungary. 6 TTK Cancer Biomarker Research Group, 1117 Budapest, Hungary. 7 Institute of Cancer and Genomic Sciences, The University of Birmingham, Birmingham B15 2TT, United Kingdom; f.berditchevski@bham.ac.uk. Item in Clipboard Regina Andrijes et al. Proc Natl Acad Sci U S A. 2021. Show details Display options Display options Format Proc Natl Acad Sci U S A . 2021 Sep 28;118(39):e2011411118. doi: 10.1073/pnas.2011411118. Authors Regina Andrijes 1 , Rahul K Hejmadi 2 , Matthew Pugh 1 , Sundaresan Rajesh 1 , Vera Novitskaya 1 , Maha Ibrahim 1 3 , Michael Overduin 1 , Chris Tselepis 1 , Gary W Middleton 1 , Balázs Győrffy 4 5 6 , Andrew D Beggs 1 , Fedor Berditchevski 7 Affiliations 1 Institute of Cancer and Genomic Sciences, The University of Birmingham, Birmingham B15 2TT, United Kingdom. 2 University Hospitals Birmingham National Health Service Foundation Trust, Birmingham B15 2TH, United Kingdom. 3 South Egypt Cancer Institute, Assiut University, Assiut 71515, Egypt. 4 Department of Bioinformatics, Semmelweis University, 1094 Budapest, Hungary. 5 2nd Department of Paediatrics, Semmelweis University, 1094 Budapest, Hungary. 6 TTK Cancer Biomarker Research Group, 1117 Budapest, Hungary. 7 Institute of Cancer and Genomic Sciences, The University of Birmingham, Birmingham B15 2TT, United Kingdom; f.berditchevski@bham.ac.uk. Item in Clipboard CiteDisplay options Display options Format 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. Keywords: APCmin; EGFR; TGF alpha; colorectal cancer; tetraspanin. Copyright © 2021 the Author(s). Published by PNAS. Conflict of interest statement The authors declare no competing interest. References Kaprio T., Hagström J., Andersson L. C., Haglund C.. Tetraspanin CD63 independently predicts poor prognosis in colorectal cancer. Histol. Histopathol.. 2020;35:887–892. Liu J., Chen C., Li G., Chen D., Zhou Q.. Upregulation of TSPAN12 is associated with the colorectal cancer growth and metastasis. Am. J. Transl. Res.. 2017;9:812–822. Greco C., et al. E-cadherin/p120-catenin and tetraspanin Co-029 cooperate for cell motility control in human colon carcinoma. Cancer Res.. 2010;70:7674–7683. Romanska H. M., Berditchevski F.. Tetraspanins in human epithelial malignancies. J. Pathol.. 2011;223:4–14. Xu L., et al. Transcriptome analysis of human colorectal cancer biopsies reveals extensive expression correlations among genes related to cell proliferation, lipid metabolism, immune response and collagen catabolism. Oncotarget. 2017;8:74703–74719. Show all 28 references [x] Cite Copy Format: Send To [x]

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バイオクイックニュース日本語版:エクソソーム特集

バイオクイックニュース日本語版
9月 18, 2019 バイオアソシエイツ

創傷治療治験中のペプチド変異体が、心臓発作の『バイスタンダー効果』による損傷を防御する可能性。研究グループはエクソソームによる防御ペプチドの送達を検討中。

健康な心筋組織を保護することで損傷を減らす心臓発作の直後に服用できる薬があると想像して欲しい。 心臓発作が起きた場合、心臓の専門医は、「時は筋肉なり」と言うと、バージニア工科大学カリリオン心臓医療センター・フラリン生物医学研究所のディレクターであるRobert Gourdie博士(写真)は語った。 血流によって酸素が供給されないと、心臓細胞はすぐに死ぬ。…

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