Author ORCID Identifier

https://orcid.org/0000-0002-4880-5110

Date of Award

Spring 2023

Document Type

Thesis (Ph.D.)

Department or Program

Molecular and Systems Biology

First Advisor

Diwakar R. Pattabiraman

Second Advisor

Yashi Ahmed

Third Advisor

Steven N. Fiering

Abstract

Intra-tumoral heterogeneity and the presence of a phenotypically diverse cell population within a single tumor represents a major hurdle in the understanding of tumor progression and dynamics, and complicates the effective diagnosis and management of this disease. One of the ways by which tumors gain intra-tumoral variation is through the acquisition of phenotypic or lineage plasticity, whereby tumor cells evolve away from the lineage of origin and gain altered profiles. These alterations may impart specific survival benefits to different subpopulations of cells, enabling them to proliferate faster, migrate away from the site of the primary tumor or evade drug-induced elimination, amongst others. Phenotypic plasticity and alterations of transcriptional profiles can be driven by either extrinsic signals or intrinsic cell autonomous mechanisms. Work presented in this thesis across three chapters has uncovered several molecular drivers altering cell-state plasticity in breast cancer, and their resulting effects on tumor development and progression. Lineage plasticity, driven by the transcription factor SOX10, allows breast tumors of the luminal lineage expressing lower Estrogen Receptor (ER) levels to gain basal-like characteristics, resulting in the evolution of these luminal-like tumors into a more basal-like subtype. Activation of Protein Kinase A (PKA) curtails cellular plasticity in a mouse mammary tumor model, preventing epithelial-mesenchymal transition (EMT) and metastasis, ultimately improving prognosis and survival. Eribulin treatment induces transcriptional reprogramming of breast tumor cell lines, forcing them to undergo mesenchymal-epithelial transition (MET). Together, these findings help to elucidate how cellular plasticity contributes to intra-tumoral heterogeneity of breast tumors, and how phenotypic diversity influences the progression, metastasis, and chemotherapy response of breast cancer. While these results have identified specific agents that act to promote phenotypic plasticity, the exact mechanisms by which they act, and the steps necessary for lineage evolution to occur are only partially understood. This work provides a foundation for further inquiry into the mechanisms driving phenotypic plasticity and resulting tumor heterogeneity, with the ultimate goal of developing better strategies to overcome this disease.

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