The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Division of Hematology, Oncology, Department of Medicine, Vanderbilt Ingram Cancer Center.
J Clin Invest. 2021 Mar 15;131(6). doi: 10.1172/JCI143557.
Intratumor heterogeneity is an important mediator of poor outcomes in many cancers, including breast cancer. Genetic subclones frequently contribute to this heterogeneity; however, their growth dynamics and interactions remain poorly understood. PIK3CA and HER2 alterations are known to coexist in breast and other cancers. Herein, we present data that describe the ability of oncogenic PIK3CA mutant cells to induce the proliferation of quiescent HER2 mutant cells through a cell contact-mediated mechanism. Interestingly, the HER2 cells proliferated to become the major subclone over PIK3CA counterparts both in vitro and in vivo. Furthermore, this phenotype was observed in both hormone receptor-positive and -negative cell lines, and was dependent on the expression of fibronectin from mutant PIK3CA cells. Analysis of human tumors demonstrated similar HER2:PIK3CA clonal dynamics and fibronectin expression. Our study provides insight into nonrandom subclonal architecture of heterogenous tumors, which may aid the understanding of tumor evolution and inform future strategies for personalized medicine.
肿瘤内异质性是包括乳腺癌在内的许多癌症不良预后的重要介导因素。遗传亚克隆经常促成这种异质性；然而，它们的生长动态和相互作用仍然知之甚少。PIK3CA 和 HER2 改变已知在乳腺癌和其他癌症中共存。在此，我们提供的数据描述了致癌 PIK3CA 突变细胞通过细胞接触介导的机制诱导静止 HER2 突变细胞增殖的能力。有趣的是，在体外和体内，HER2 细胞增殖成为主要的亚克隆，超过了 PIK3CA 对应物。此外，这种表型在激素受体阳性和阴性细胞系中均观察到，并且依赖于来自突变 PIK3CA 细胞的纤维连接蛋白的表达。对人类肿瘤的分析表明了类似的 HER2：PIK3CA 克隆动力学和纤维连接蛋白表达。我们的研究提供了对异质肿瘤非随机亚克隆结构的深入了解，这可能有助于理解肿瘤进化，并为个性化医疗提供未来策略的信息。
