Two main issues confound the treatment of breast cancers, as well as other carcinomas. Firstly, most deaths from carcinomas (~90%) result from metastatic spread of the disease to distant sites rather than from the primary tumors. Secondly, the development of therapeutic resistance to initially treated tumors results in the relapse of cancers into more aggressive forms. Both of these properties of aggressive carcinomas can be traced to intrinsic intratumoral heterogeneity, which can arise through various mechanisms. Our laboratory studies various forms of tumor heterogeneity with the goal of understanding its origins and developing novel ways of combating it.
- Epithelial-Mesenchymal Heterogeneity
The epithelial-to-mesenchymal transition (EMT) represents a program that leads to the generation of cells at various states along the epithelial-mesenchymal spectrum in carcinomas. During passage through an EMT, epithelial cells lose their characteristics of cell-cell adhesion, lack of motility, and apical-basal polarity, and instead acquire mesenchymal properties that confer on them migratory and invasive powers. The EMT is known to confer tumor cells with increased resistance to various chemotherapeutic drugs. We study the contributions of epithelial-mesenchymal heterogeneity to metastasis and therapy resistance using a combination of mouse and human models.
- Lineage HeterogeneityCancer's life is a recapitulation of the body's life, its existence a pathological mirror of our own – Siddhartha Mukherjee in “Emperor of all maladies”
The study of developmental lineages in the mammary gland have long informed our understanding of breast cancer and enabled its classification into subtypes. The contributions of luminal and basal lineages to intratumoral heterogeneity and tumor metastasis are poorly understood. We approach the study of lineage heterogeneity with Cre-Lox lineage tracing to study contributions to tumor progression at single-cell resolution.
Specific Research Directions
- Understanding the intermediate/hybrid EMT state, the transcriptional programs and chromatin landscape that maintains it, and identifying therapeutic vulnerabilities
- Developing approaches to quantifying intratumoral heterogeneity in patient tumors as a means to informing prognosis and therapeutic decision-making
- Studying the mechanisms of eribulin-induced alterations to breast cancer cell state (Supported by Eisai Inc.)
- Uncovering the contributions of luminal and basal developmental lineages to intratumoral heterogeneity in breast cancers
- Uncovering the role of Protein Kinase A in inducing a mesenchymal-epithelial transition (MET) and tumor differentiation through a detailed study of its substrates.