Cell signaling intra-tumor heterogeneity as a driver of TNBC tumor quiescence

Cancer dormancy, a major driver of chemotherapeutic resistance, remains a poorly understood process and the molecular mechanisms and cellular signals underlying this reversible growth arrest are unknown. Triple Negative Breast Cancer (TNBC) is an aggressive subtype with poor prognosis and high recurrence rates attributed to the presence of a subpopulation of cells with enhanced drug tolerance properties. On the basis of our preliminary results, we hypothesize that Wnt signaling activation (Wnt-high) induces a “slow- cycling/quasi-quiescent” state in breast cancer cell lines, a mechanism which is highly dependent on the degree of pathway activation. This suggests a balance between proliferation and dormancy that is dynamically regulated through “dosage-dependent” activation of Wnt signaling pathway. Furthermore, in vitro generated data identified: upregulated expression of stemness markers, enhanced chemotherapy resistance and, in vitro tumor initiating capacity among the Wnt-high population. Using cell-derived xenografts, patient-derived xenografts (PDX) and patient datasets, we aim to understand the mechanisms underlying the Wnt- dependent slow-proliferative stem-like phenotype in vivo through the identification of Wnt-population specific transcriptomic signatures. In addition, we aim to establish a novel Wnt-induced 3D-in vitro quiescence model derived from PDX models for development of improved treatment regimens.