Cancer-associated fibroblasts and extracellular matrix remodeling in pediatric neuroblastoma

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PROJECT SUMMARY Extracellular matrix (ECM) remodeling is a critical process within the solid tumor microenvironment. Cancer- associated fibroblasts (CAFs) are the primary producers of matrix proteins and remodeling enzymes that cross- link and degrade matrix proteins. CAFs are enigmatic in that they can promote or impede tumor growth, suggesting heterogeneity that is not completely understood. How CAF heterogeneity evolves over tumor progression and how this evolution impacts ECM remodeling within solid tumors remain an outstanding question in cancer biology. Recent studies have focused on CAF function in models of adult cancer, but little attention has been directed toward understanding CAF heterogeneity and ECM remodeling in childhood cancers, which are etiologically different diseases. Neuroblastoma (NB) is a childhood cancer of neuroendocrine cells that accounts for 15% of pediatric cancer deaths. The 5-year overall survival rate for high-risk NB remains at 50%, highlighting the need for a deeper understanding of the molecular and immunological mechanisms driving tumorigenesis in this subset of patients. Like other solid tumors, the NB tumor microenvironment includes malignant cells, CAFs, and immune cells. Our laboratory studies NB using a penetrant, spontaneous model of high-risk NB (TH-MYCN, AlkF1178L/+) in immunocompetent mice, allowing in vivo investigation of the tumor immune microenvironment from tumorigenesis to progressive disease. Using this model, we previously demonstrated the pro-tumorigenic role of macrophages and CD4+ T cells by showing that their depletion significantly reduced the formation of tumors and extended survival. My preliminary experiments utilizing 10X Chromium gene expression analysis of stromal cells from nascent and mature tumors identified two distinct subsets of CAFs characterized by alpha smooth muscle actin (Acta2) and Wilms tumor 1 (Wt1) expression. Interestingly, only Wt1 CAFs expressed chemokines and cytokines involved in recruitment of myeloid and T cells. Wt1 CAFs were enriched in the early tumor microenvironment and expressed genes encoding ADAMTS enzymes involved in degradation of the proteoglycan versican. Our preliminary findings indicate that Wt1 CAFs may be a crucial early recruiter of pro-tumorigenic immune cells in our model of neuroblastoma. The studies proposed will assess how CAF heterogeneity affects ECM remodeling over neuroblastoma progression, examine tumor-CAF and CAF-immune signaling, and test the effect of perturbing ECM deposition and degradation on tumor formation and progression. Together, these studies will generate new and exciting information about the tumor microenvironment and potential vulnerabilities to exploit in pediatric solid tumors.