Hierarchical tumor heterogeneity mediated by cell contact between distinct genetic subclones

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.

Automated summary

Intratumor heterogeneity plays a crucial role in determining the poor outcomes of many cancers, including breast cancer. This study reveals that oncogenic PIK3CA mutant cells can induce the proliferation of quiescent HER2 mutant cells through a cell contact-mediated mechanism, leading to HER2 cells becoming the major subclone over PIK3CA counterparts. The findings highlight the nonrandom subclonal architecture of heterogenous tumors and may provide insights into tumor evolution for future personalized medicine strategies.