Unravelling complex associations of genetic variation and tumor microenvironments for clonal expansion in breast cancer with metastasis

Breast cancer (BrCa) is highly heterogeneous, with multiple distinct subtypes associated with variable clinical outcomes and high intra-tumor clonal diversity. This clonal diversity is caused by genomic instability, microenvironmental factors, and tumor cell plasticity. Intra-tumor clonal diversity has been linked to poor clinical outcomes including aggressive, recurrent, and treatment resistant tumors and progression to metastases. Somatic mutations that induce transcriptomic alterations and genomic instability, in combination with the harsh tumor microenvironment, shape the heterogeneity and expansion of intra-tumor clones. We identified RHAMM, which has pro-inflammatory functions in response-to-injury processes, as a contributor to BrCA cell heterogeneity. RHAMM is expressed in tumor and host cells and Rhamm-loss in these cell compartments strongly reduces clonal heterogeneity detected by single nucleotide variants used as endogenous barcodes. Our evidence predicts that a RHAMM-ve microenvironment exerts selective pressure permitting the emergence of dominant clones in lung metastases that carry specific oncogenic mutations. Our goal is to probe the interplay between clonal heterogeneity and the tumor microenvironment in the emergence of dominant intra-tumor clones. Next-generation DNA sequencing technologies now offer a two-pronged approach to the analysis of genetic heterogeneity. Long-read genome sequencing enables discovery of large structural variants and short-read, deep sequencing achieves highly accurate detection of ultra-rare single nucleotide variants. The interplay of clonal dynamics and the tumour microenvironments in the development of heterogeneous BrCa tumours can be teased apart to better understand the causative processes underlying the metastatic and treatment-resistant nature of these tumours, with discovery of potential genetic determinants relevant to cancer management.