Uncovering Targetable Mechanisms Underlying Intratumor Heterogeneity in Prostate Cancer

Intratumor heterogeneity encompasses both cellular and clonal diversity, each contributing to cancer progression and therapy resistance. At the cellular level, using lineage tracing and single-cell transcriptomics in genetically engineered mouse models, we uncovered a luminal intermediate state marked by Wnt/p63 signaling that contributes to the maintenance of long-term prostate homeostasis and greatly expands in aging and cancer. At the clonal level, aggressive tumor models displayed competition between dominant and minor clones within a disorganized microenvironment. Minor clones exhibited IFNγ-response signatures and expression of the T cell- activating chemokines Cxcl9 and Cxcl11, features correlated with recurrence-free survival in prostate cancer patients. Immunomodulation of the IFNγ pathway rescued minor clones from elimination, highlighting the immune selective pressures as key regulators of clonal dynamics. Together, these findings reveal how aging, lineage plasticity, and immune selection converge to shape tumor evolution and identify Wnt/p63 and IFNγ-driven pathways as potential therapeutic targets. 

Flaminia Talos, MD, PhD is an Associate Professor in the Departments of Urology and Pathology at the Renaissance School of Medicine at Stony Brook University. She is also a member of Stony Brook Cancer Center and an affiliated faculty member of the Laufer Center for Physical and Quantitative Biology. Dr. Talos received her MD from the "Iuliu Hatieganu" University of Medicine and Pharmacy in Romania and her PhD in Molecular and Cellular Biology from Stony Brook University. Her postdoctoral training included work at Stony Brook University and Columbia University. Dr. Talos's group investigates the cellular origins and mechanisms driving intratumor heterogeneity and clonal diversification, particularly in prostate and bladder cancers. Her lab currently focuses on clonal and cellular dynamics in normal prostate homeostasis and aging, identification of novel biomarkers/mechanisms of drug resistance, and immunomodulatory interventions on the tumor clonal landscape.