Bone Marrow Stromal Cells Regulate Functional States of ER+ Breast Cancer Cells
BME PhD Defense: Johanna Buschhaus
WHEN: May 25, 2022 1:00 pm-2:00 pmADD TO CALENDAR
Even with targeted therapies, patients with the most common subtype of breast cancer, estrogen-receptor-positive (ER+) disease, face an ongoing, progressively increasing risk of metastases. ER+ breast cancer predominantly metastasizes to bone marrow (~70% of patients with advanced disease). Current hormone therapies frequently suppress, but fail to eliminate, both proliferating and quiescent breast cancer cells in bone marrow. While drug resistance may arise from cancer-cell intrinsic mechanisms, studies implicate interactions between ER+ breast cancer cells and bone marrow mesenchymal stromal cells (MSCs) as a pivotal cause of resistance to hormone therapies and transitions to CSC states. This dissertation focuses on elucidating targetable mechanisms for MSC-induced increases in cancer cell plasticity and resistance to antiestrogenic therapy.
This work began showing that direct co-culture with MSCs induces resistance to antiestrogenic therapy in ER+ breast cancer cells, in part through increases in intracellular iron. Combining iron chelators or novel lysosomal iron-targeting compounds with clinical antiestrogenic therapy reduced resistance of cancer cells to therapy. Next, we showed that co-culture with MSCs increased oxidative metabolism, intracellular ATP, glucose, and metabolic plasticity in ER+ breast cancer cells treated with antiestrogenic therapy, including under conditions of nutrient stress. We successfully limited metabolic plasticity, heterogeneous treatment responses, and drug resistance by inhibiting monocarboxylate transporters. Finally, we utilized a physiologically-relevant 3D co-culture model with MSCs that successfully recapitulated slow proliferation, signaling, and metabolic profiles of disseminated ER+ breast cancer cells. Simultaneous treatment with inhibitors of Akt and thioredoxin reductase effectively reduced cancer burden versus antiestrogenic therapy in both in vitro and in vivo models. By exploiting adaptations of ER+ breast cancer cells to the stromal microenvironment, we identified multiple clinically-actionable approaches to overcome stromal-mediated drug resistance, paving the way toward more effective treatments against bone marrow metastases.
Date: Wednesday May 25, 2022
Time: 1:00 PM
Chair: Dr. Gary Luker