研究人员报道了一个通过多维蛋白-蛋白相互作用图阐明肿瘤遗传复杂性的框架，并将其应用于加强人们对头颈部鳞状细胞癌的理解。这个网络发现了来自癌症和非癌症细胞状态的771个相互作用，包括WT和突变的蛋白异构体。对富含癌症的相互作用进行优先排序，结果揭示了以前未被发现的成纤维细胞生长因子受体酪氨酸激酶3与Daple（一种鸟嘌呤核苷酸交换因子）的关联，导致Gαi和p21激活的蛋白激酶1/2激活，进而促进癌细胞迁移。
此外，研究人员观察到人表皮生长因子受体3（HER3）受体酪氨酸激酶和PIK3CA（磷脂酰肌醇3-激酶的α催化亚单位）之间突变丰富的相互作用，可以为体内对HER3抑制的反应提供信息。研究人员预计，这一框架的应用对于将基因改变转化为对许多疾病领域的理解具有价值。
附：英文原文
Title: A protein network map of head and neck cancer reveals PIK3CA mutant drug sensitivity
Author: Danielle L. Swaney, Dana J. Ramms, Zhiyong Wang, Jisoo Park, Yusuke Goto, Margaret Soucheray, Neil Bhola, Kyumin Kim, Fan Zheng, Yan Zeng, Michael McGregor, Kari A. Herrington, Rachel O’Keefe, Nan Jin, Nathan K. VanLandingham, Helene Foussard, John Von Dollen, Mehdi Bouhaddou, David Jimenez-Morales, Kirsten Obernier, Jason F. Kreisberg, Minkyu Kim, Daniel E. Johnson, Natalia Jura, Jennifer R. Grandis, J. Silvio Gutkind, Trey Ideker, Nevan J. Krogan
Issue&Volume: 2021-10-01
Abstract: We outline a framework for elucidating tumor genetic complexity through multidimensional protein-protein interaction maps and apply it to enhancing our understanding of head and neck squamous cell carcinoma. This network uncovers 771 interactions from cancer and noncancerous cell states, including WT and mutant protein isoforms. Prioritization of cancer-enriched interactions reveals a previously unidentified association of the fibroblast growth factor receptor tyrosine kinase 3 with Daple, a guanine-nucleotide exchange factor, resulting in activation of Gαi- and p21-activated protein kinase 1/2 to promote cancer cell migration. Additionally, we observe mutation-enriched interactions between the human epidermal growth factor receptor 3 (HER3) receptor tyrosine kinase and PIK3CA (the alpha catalytic subunit of phosphatidylinositol 3-kinase) that can inform the response to HER3 inhibition in vivo. We anticipate that the application of this framework will be valuable for translating genetic alterations into a molecular and clinical understanding of the underlying biology of many disease areas.
DOI: abf2911
Source: https://www.science.org/doi/10.1126/science.abf2911