胶原蛋白可促进肥胖三阴性乳腺癌转移

　　细胞外基质是肿瘤微环境的主要组成部分，可促进肿瘤局部浸润和远处转移。不过，究竟是细胞外基质的什么成分促进了肿瘤的局部浸润和远处转移？

　　2020年10月21日，美国科学促进会《科学》旗下《科学进展》在线发表美国塔夫茨大学的研究报告，通过分析去除细胞后的细胞外基质支架，发现其中一种胶原蛋白是肥胖患者三阴性乳腺癌细胞浸润和远处转移的驱动因素。

　　该研究首先对全组织细胞外基质的作用进行分析，找出与肿瘤细胞转移相关的病变状态，并确定驱动这些作用的细胞外基质蛋白质和信号传导通路。

　　结果发现，来自带瘤肥胖小鼠乳腺的去细胞后细胞外基质可驱动人类三阴性乳腺癌细胞（MDA-MB-231）浸润。

　　根据肥胖小鼠和肥胖患者的乳腺细胞外基质蛋白质组学分析，确定全长胶原蛋白VI是三阴性乳腺癌细胞浸润的驱动蛋白，而且人类三阴性乳腺癌患者肿瘤基质的全长胶原蛋白VI水平与患者体重指数成正比。

　　根据机制分析，胶原蛋白VI主要通过神经胶质抗原蛋白聚糖NG2与表皮生长因子EGFR相互影响和促有丝分裂原活化蛋白激酶MAPK信号传导，促进三阴性乳腺癌细胞浸润，而NG2抗体＋EGFR抑制剂拉帕替尼或MAPK抑制剂曲莫替尼可阻断胶原蛋白VI的作用。

　　因此，该研究结果表明，从组织获得的去细胞后细胞外基质支架可确定细胞外基质的新功能，并为三阴性乳腺癌细胞外基质靶向治疗奠定基础。

Sci Adv. 2020 Oct 21;6(43):eabc3175.

Decellularized extracellular matrix scaffolds identify full-length collagen VI as a driver of breast cancer cell invasion in obesity and metastasis.

Andrew L. Wishart, Sydney J. Conner, Justinne R. Guarin, Jackson P. Fatherree, Yifan Peng, Rachel A. Mcginn, Rebecca Crews, Stephen P. Naber, Martin Hunter, Andrew S. Greenberg, Madeleine J. Oudin.

Tufts University, Medford, MA, USA; Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, USA; Tufts Medical Center, Boston, MA, USA; Tufts University School of Medicine, Boston, MA, USA.

The extracellular matrix (ECM), a major component of the tumor microenvironment, promotes local invasion to drive metastasis. Here, we describe a method to study whole-tissue ECM effects from disease states associated with metastasis on tumor cell phenotypes and identify the individual ECM proteins and signaling pathways that are driving these effects. We show that decellularized ECM from tumor-bearing and obese mammary glands drives TNBC cell invasion. Proteomics of the ECM from the obese mammary gland led us to identify full-length collagen VI as a novel driver of TNBC cell invasion whose abundance in tumor stroma increases with body mass index in human TNBC patients. Last, we describe the mechanism by which collagen VI contributes to TNBC cell invasion via NG2-EGFR cross-talk and MAPK signaling. Overall, these studies demonstrate the value of decellularized ECM scaffolds obtained from tissues to identify novel functions of the ECM.

DOI: 10.1126/sciadv.abc3175