1. Hierarchical tumor heterogeneity mediated by cell contact between distinct genetic subclones
- Author
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Paula J. Hurley, Brad A. Davidson, Daniel J. Zabransky, Swathi Karthikeyan, Ian Waters, Morgan V. Pantone, Melinda E. Sanders, Karen Cravero, Hong Yuen Wong, Kelly Kyker-Snowman, Berry Button, Violeta Sanchez, Riley E. Bergman, D. Marc Rosen, Sarah C. Reed, Ben Ho Park, Joshua Donaldson, David Chu, Sarah Croessmann, Lauren Dennison, Paula I. Gonzalez-Ericsson, and Dong Ho Shin
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Class I Phosphatidylinositol 3-Kinases ,Receptor, ErbB-2 ,Cell ,Mutant ,Breast Neoplasms ,Cell Communication ,Gene Knockout Techniques ,03 medical and health sciences ,0302 clinical medicine ,Gene Frequency ,Cell Line, Tumor ,Molecular genetics ,medicine ,Humans ,neoplasms ,biology ,Mechanism (biology) ,General Medicine ,Immunohistochemistry ,Phenotype ,Coculture Techniques ,In vitro ,Fibronectins ,Gene Expression Regulation, Neoplastic ,Fibronectin ,Cell Transformation, Neoplastic ,030104 developmental biology ,medicine.anatomical_structure ,Cell culture ,030220 oncology & carcinogenesis ,Mutation ,MCF-7 Cells ,Cancer research ,biology.protein ,Female ,Research Article - Abstract
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.
- Published
- 2021
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