Wang Xuya, Mooradian Arshag D, Erdmann-Gilmore Petra, Zhang Qiang, Viner Rosa, Davies Sherri R, Huang Kuan-Lin, Bomgarden Ryan, Van Tine Brian A, Shao Jieya, Ding Li, Li Shunqiang, Ellis Matthew J, Rogers John C, Townsend R Reid, Fenyö David, Held Jason M
Institute for Systems Genetics, New York University School of Medicine, New York, NY 10016, USA.
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
Sci Signal. 2017 Aug 8;10(491):eaam8065. doi: 10.1126/scisignal.aam8065.
Cancer forms specialized microenvironmental niches that promote local invasion and colonization. Engrafted patient-derived xenografts (PDXs) locally invade and colonize naïve stroma in mice while enabling unambiguous molecular discrimination of human proteins in the tumor from mouse proteins in the microenvironment. To characterize how patient breast tumors form a niche and educate naïve stroma, subcutaneous breast cancer PDXs were globally profiled by species-specific quantitative proteomics. Regulation of PDX stromal proteins by breast tumors was extensive, with 35% of the stromal proteome altered by tumors consistently across different animals and passages. Differentially regulated proteins in the stroma clustered into six signatures, which included both known and previously unappreciated contributors to tumor invasion and colonization. Stromal proteomes were coordinately regulated; however, the sets of proteins altered by each tumor were highly distinct. Integrated analysis of tumor and stromal proteins, a comparison made possible in these xenograft models, indicated that the known hallmarks of cancer contribute pleiotropically to establishing and maintaining the microenvironmental niche of the tumor. Education of the stroma by the tumor is therefore an intrinsic property of breast tumors that is highly individualized, yet proceeds by consistent, nonrandom, and defined tumor-promoting molecular alterations.
癌症形成促进局部侵袭和定植的特殊微环境生态位。移植的患者来源异种移植瘤（PDXs）在小鼠体内局部侵袭并定植于幼稚基质，同时能够明确区分肿瘤中人类蛋白质与微环境中小鼠蛋白质。为了表征患者乳腺肿瘤如何形成生态位并塑造幼稚基质，通过物种特异性定量蛋白质组学对皮下乳腺癌PDXs进行了全面分析。乳腺肿瘤对PDX基质蛋白的调控广泛，在不同动物和传代过程中，35%的基质蛋白质组被肿瘤持续改变。基质中差异调节的蛋白质聚集成六个特征，其中包括肿瘤侵袭和定植的已知和先前未被认识的促成因素。基质蛋白质组受到协同调节；然而，每个肿瘤改变的蛋白质组高度不同。肿瘤和基质蛋白质的综合分析（在这些异种移植模型中得以实现）表明，癌症的已知特征对建立和维持肿瘤的微环境生态位具有多效性作用。因此，肿瘤对基质的塑造是乳腺肿瘤的一种内在特性，具有高度个体化，但通过一致、非随机且明确的促肿瘤分子改变来进行。
