Multifaceted roles of FMRP in the tumor microenvironment: From cancer cell-intrinsic functions to immunosuppressive fibroblasts

The RNA-binding protein Fragile X Messenger Ribonucleoprotein (FMRP), long studied for its role in synaptic plasticity and neurodevelopment, has more recently emerged as an unexpected regulator of tumor biology. Beyond its neuronal functions, mounting evidence indicates that FMRP is aberrantly induced in malignant contexts, where it orchestrates transcriptional and translational programs that sustain tumor progression and immune evasion. Yet, its roles across distinct cellular compartments of the tumor microenvironment have remained poorly defined, leaving a critical gap in our understanding of how this neuronal protein is repurposed in cancer. Building on previous work from the Hanahan lab showing that FMRP is upregulated in cancer cells, this thesis identifies its induction in cancer-associated fibroblasts (CAFs), where it functions as a key stromal regulator of tumor progression and immunosuppression. Using orthotopic and genetically engineered mouse models, combined with transcriptomic and functional analyses, I dissect the dual and context-dependent roles of FMRP across the tumor microenvironment. In the first part of the thesis, I showed that FMRP expression is induced upon activation of naive fibroblasts into a cancer-associated fibroblast (CAF) state within tumors. Using orthotopic pancreatic and mammary tumor models, I demonstrated that stromal FMRP enforces tumor progression and immune exclusion, remodels the extracellular matrix, and polarizes macrophages toward immunosuppressive phenotypes. Functional and transcriptional analyses established FMRP as an active determinant of CAF activation rather than a passive marker, in part by regulating FAP expression and key iCAF and myCAF effector pathways. High stromal FMRP activity further correlated with poor immune infiltration and poor prognosis in human breast cancer, highlighting its translational relevance. In the second part of the thesis, I investigated the cancer cell-intrinsic role of FMRP by deleting the Fmr1 gene in two genetically engineered mouse models: the RIP1-Tag2 model of pancreatic neuroendocrine tumors and the MMTV-PyMT model of breast cancer. Temporally controlled Fmr1 deletion revealed that FMRP is involved in tumorigenesis as well as maintenance of established disease. Across both models, FMRP sustained an immunosuppressive and pro-angiogenic tumor microenvironment, with its loss driving broad immune reprogramming toward effector T-cell activation, reduced suppressive myeloid states, and impaired angiogenesis. Beyond this shared role, FMRP also maintained tumor-type-specific programs: reinforcing an aberrant β-cell-like endocrine phenotype and systemic hypoglycemia in RIP1-Tag2 tumors, and enabling metastatic outgrowth in MMTV-PyMT tumors by sustaining an immune-permissive niche. Deletion of FMRP consistently suppressed tumor progression, normalized systemic physiology, and significantly extended survival, including in advanced-stage tumors. Collectively, this thesis e