Characterizing Novel Tumor-Microenvironment Interactions in Gli2-Enriched Cancers

Abstract

While cancer treatments have made great strides, aberrant activation of key signaling pathways presents an opportunity for improved therapeutic targeting. Overactivation of the Hedgehog developmental signaling pathway supports tumorigenesis and tumor progression. Using in vitro, in vivo, and computational approaches, the work presented in this dissertation demonstrates novel roles for Hedgehog signaling in modulating how tumor cells interact with their microenvironment in Glioma-associated Oncogene Homolog 2 (Gli2)-enriched cancers. First, we reveal the Hedgehog signaling component Gli2 as a mediator of cytokine expression and secretion by bone metastatic breast cancer cells and show that pharmacologic inhibition of tumor cell Gli2 induces differentiation of myeloid cells toward a pro-inflammatory phenotype. Second, we demonstrate that Gli2 overexpression in dedifferentiated liposarcoma cells induces parallel secretory changes, resulting in a preponderance of M2-like macrophages in an orthotopic tumor model. Additionally, Gli2 overexpression results in a shift toward an osteoblastic gene signature in vitro and phenotypic plasticity of tumor cells in vivo. Finally, this dissertation proposes computational modeling as a strategy to predict experimental outcomes in murine models of bone metastatic cancer, particularly focusing on Gli2-induced processes. In summary, the work presented herein reveals that Hedgehog signaling, and Gli2 more specifically, modifies tumor-microenvironment interactions. We therefore propose Hedgehog inhibition as a strategy for inducing anti-tumor immunity with potential opportunities for combination therapies.