Author ORCID Identifier

0000-0003-4779-8470

Date of Graduation

5-2025

Document Type

Dissertation (PhD)

Program Affiliation

Cancer Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

George Calin

Committee Member

Sendurai Mani

Committee Member

Jeffery Rosen

Committee Member

Don Gibbons

Committee Member

Pamela Wenzel

Abstract

Triple-negative breast cancer (TNBC) is a highly metastatic breast cancer subtype. The epithelial-to-mesenchymal transition (EMT) of cancer cells is a key feature of the metastatic cascade and is not a binary process but often generates malignant cells with both epithelial (E) and mesenchymal (M) traits known as hybrid EM cells. Recent studies highlight the enhanced metastatic potential of the hybrid EM cells. However, molecular insights and targetable vulnerabilities within hybrid EM remain elusive. We discovered that hybrid EM murine tumors are enriched in CD38, an immunesuppressive molecule associated with worse clinical outcomes in liquid malignancies but relatively understudied in solid tumors such as breast cancers. Hence, we sought to investigate the role of CD38 in hybrid EM-driven metastasis using pre-clinical models of TNBC. We observed that altering tumor cell CD38 expression impacts the migratory, invasive, and metastatic capabilities of hybrid EM cells. Abrogation of CD38 expression triggers an immunostimulatory response thereby preventing the assembly of an immunesuppressive microenvironment in hybrid EM tumors. Moreover, TNBC patient samples harbored tumoral CD38 expression that positively correlated with PD-L1+ immune cell subsets. Furthermore, co-targeting CD38 and PD-L1 potentiates a stronger anti-tumor immune response with delayed tumor growth in hybrid EM murine models. Thus, our research exposes CD38 as a specific survival strategy utilized by hybrid EM tumors to suppress immune cells and sustain metastasis with strong implications in other carcinomas that have hybrid EM properties.

Keywords

Breast Cancer, Tumor Immune Microenvironment, Epithelial Mesenchymal Transition, Plasticity, Hybrid EM, CD38, Therapeutics, Immunotherapy

Download

Share

COinS