Despite the successful progress in the treatment of primary breast cancers resulting in a decrease in cancer mortality rates, metastasis remains the principle cause of death among women afflicted with the disease. Primary tumors consist of heterogeneous populations of cells co-existing as an ecosystem, which evolve over the course of tumor progression to enable certain cells to locally invade and disseminate from the primary site and eventually colonize within a distant organ. At present, it remains unclear how diverse cell populations interact and behave in complex cellular landscapes within tumors and over the course of metastatic progression. My preliminary data demonstrate that noncanonical ?-catenin-independent Wnt signaling through the atypical receptor Ror2 inhibits canonical ?-catenin-dependent Wnt signaling in vivo. Moreover, these different modes of Wnt signaling demarcate distinct tumor cell subpopulations in vivo and mediate key aspects of tumor progression and metastasis. While current data implicate a hyperactive canonical Wnt state within basal-like breast cancers, which exhibit poor prognosis, it is unclear how canonical and noncanonical Wnt pathways cooperate within complex cellular landscapes. Within this proposal, I will utilize a transplantable syngeneic TP53 null genetically engineered mouse model (GEMM) of breast cancer, which by gene expression profiling collectively exhibit characteristics that mirror human breast cancer subtypes, and then extend these studies to human-in-mouse patient derived xenograft (PDX) models. In addition, this proposal leverages unique approaches to actively monitor Wnt pathway changes in vivo using sophisticated Wnt pathway reporters. My preliminary data demonstrate that depletion of Ror2 within multiple TP53 null basal-like models alters the canonical Wnt signaling landscape in vivo, accompanied by changes in cellular adhesion and migration of tumor cells. Further, I have identified a spatiotemporal change in Wnt pathway activation between micro- to macro-metastatic colonization within the lung. It is my central hypothesis that the noncanonical and canonical Wnt pathways are highly integrated within the tumor landscape and coordinately regulate the plasticity of heterogeneous populations of tumor cells within Triple Negative Breast Cancers (TNBCs) to drive tumor progression and metastasis. To test this hypothesis, I will investigate how Ror2-mediated noncanonical Wnt signaling and canonical Wnt signaling direct states of adhesion and migration, respectively, within the primary and metastatic sites. Furthermore, I will determine how context-dependent changes in the mode of Wnt signaling direct the transition from micro- to macro-metastatic colonization within the lung. Together, these studies will identify novel insights into the balance and spatiotemporal regulation of Wnt pathway dynamics in metastatic progression of breast cancer and have the potential to recognize Ror2 as a therapeutic target of macro-metastatic disease.
Despite successful progress in the treatment of primary breast cancers, metastatic breast cancers still account for nearly 40,000 deaths per year among women afflicted with the disease. Our preliminary data suggest that Wnt signaling pathways play a critical role in breast cancer heterogeneity and metastasis. This proposal will determine how canonical and noncanonical Wnt pathways are integrated to regulate cell plasticity in triple negative breast cancers to drive tumor progression and metastasis.
| Roarty, K; Pfefferle, A D; Creighton, C J et al. (2017) Ror2-mediated alternative Wnt signaling regulates cell fate and adhesion during mammary tumor progression. Oncogene 36:5958-5968 |
