Methodological Advancements for Investigating Intra-tumoral Heterogeneity in Breast Cancer at the Bench and Bedside

Abstract

There is a major need to overcome therapeutic resistance and metastasis that eventually arises in many breast cancer patients. Therapy resistant and metastatic tumors are increasingly recognized to possess intra-tumoral heterogeneity (ITH), a diversity of cells within an individual tumor. First hypothesized in the 1970s, the possibility that this complex ITH may endow tumors with adaptability and evolvability to metastasize and evade therapies is now supported by multiple lines of evidence. Our understanding of ITH has been driven by recent methodological advances including next-generation sequencing, computational modeling, lineage tracing, single-cell technologies, and multiplexed in situ approaches. These have been applied across a range of specimens, including patient tumor biopsies, liquid biopsies, cultured cell lines, and mouse models. In this review, we discuss these approaches and how they have deepened our understanding of the mechanistic origins of ITH amongst tumor cells, including stem cell-like differentiation hierarchies and Darwinian evolution, and the functional role for ITH in breast cancer progression. While ITH presents a challenge for combating tumor evolution, in-depth analyses of ITH in clinical biopsies and laboratory models hold promise to elucidate therapeutic strategies that should ultimately improve outcomes for breast cancer patients.

Spatial Proteomics for the Molecular Characterization of Breast Cancer

“…Single cell omics, in contrast to bulk omics, targets extraction of DNA, RNA, proteins, and metabolites from individual cells within a tissue or cell culture to measure differences between cells and visualize discrete populations of cells based on their physiological condition. For detection and characterization of tumor heterogeneity, single-cell omics methods represent a promising approach [ 52 ].…”

Experimental and spontaneous metastasis assays can result in divergence in clonal architecture

“…The mortality rate of TNBC is linked with the distant spread of the disease that forms lethal metastases in vital organs 2 . Despite the dire need to better understand the advanced setting of the disease, study of the metastatic cascade is challenging 3 . Cancer cell fitness can be investigated in 2D or 3D cultures, but these models often lack the complex interaction with cells from the tumour microenvironment 4 .…”

Unraveling the Breast: Advances in Mammary Biology and Cancer Methods

“…Accordingly, the number of articles on intratumor heterogeneity has increased from tens to hundreds per year since 2010. To highlight this issue, the review by Baek and colleagues [17] compares the ability of different methods to capture breast tumor heterogeneity and discusses the promise and utility of liquid biopsy. They also address 1 3 key findings regarding clonal evolution and therapeutic resistance from studies of breast tumor heterogeneity, and provide a helpful perspective for this growing and evolving field.…”