Title: Targeting Breast Cancer Stem Cells Challenges and Opportunities
Host: Olga Razorenova
Abstract: Breast cancer stem cells maintain plasticity allowing them to transition between epithelial (E)) and mesenchymal (M)states states. M- and E-BCSCs rely on distinct metabolic pathways and display markedly different sensitivities to inhibitors of glycolysis and redox metabolism. Metabolic/oxidative stress generated by 2DG/H2O2 or hypoxia promotes the transition of ROSlo M-BCSCs to a ROShi E-state. This transition is reversed by N-acetyl cysteine and mediated by activation of the AMPK-HIF1α axis. Moreover, E-BCSCs exhibit robust NRF2-mediated antioxidant responses, rendering them vulnerable to ROS-induced differentiation and cytotoxicity following suppression of NRF2 or downstream thioredoxin (TXN) and glutathione (GSH) antioxidant pathways. Co-inhibition of glycolysis and TXN/GSH pathways suppresses tumor growth, tumor-initiating potential and metastasis by eliminating both M- and E-BCSCs. Exploiting metabolic vulnerabilities of distinct BCSC states provides a novel therapeutic approach targeting this critical tumor cell population.
We have also examined interactions between bcsc and immune cells within the tumor microenvironment Utilizing syngeneic mouse models, we demonstrate both positive and negative regulators of the CSC phenotype. Myeloid derived suppressor cells directly stimulate CSC self-renewal pathways via activation of Notch and STAT3 signaling potentiating tumor metastasis. BCSC may also avoid immune surveillance via upregulation of T cell inhibitory pathways including PDL-1. To overcome these immunosuppressive barriers, we are developing CSC vaccine strategies involving CSC pulsed dendritic cells (DC’s) or CSC shared antigens. In several syngeneic mouse tumor models dendritic cells pulsed with ALDH+ CSC enriched cell lysates are significantly more effective than ALDH- or bulk tumor cell derived vaccines at blocking subsequent tumor development.
Together, these results suggest that the metabolic and immunogenic vulnerabilities of bcsc’s can be targeted for therapeutic gain.
Bio: Dr. Wicha received his M.D. degree from Stanford University School of Medicine in 1974, trained in Internal medicine at the University of Chicago and in Medical Oncology at the NIH. His scientific career has focused on the biology and treatment of breast cancer. He has been a major leader in the science of cancer stem cells. His group was part of the team that first identified breast cancer stem cells, the first such cells identified in solid tumors. His laboratory has identified a number of cancer stem cell markers and developed in vitro and mouse models to isolate and characterize these cells, models which have been widely utilized in the field. His group has subsequently elucidated a number of intrinsic and extrinsic pathways which regulate stem cell self-renewal and cell fate decisions. This work has directly led to development of several clinical trials aimed at targeting breast cancer stem cells. Dr. Wicha is also the founding director of the University of Michigan Rogel Cancer Center, a position he held for 27 years. Under his leadership, the University of Michigan Rogel Cancer Center established itself as one of the nation’s premier cancer centers. In 2015, Dr. Wicha stepped down as the Cancer Center Director enabling him to devote his full efforts to cancer stem cell research. He now holds the Madeline and Sidney Forbes Professor of Oncology Chair, and serves as Director of the Forbes Institute for Cancer Discovery. He was also recently appointed by President Obama to the National Cancer Advisory Board (NCAB). This board advises the NCI Director and Secretary of Health on matters related to cancer research and health policy.