Staufen1 in melanoma progression and immune surveillance

Resumen

Cutaneous melanoma is the most aggressive and lethal form of skin cancer. This tumor is characterized by an intrinsic metastatic potential associated in part with large transcriptional changes. In addition, melanoma is the tumor with the highest mutational burden, a feature contributing to a high neoantigen load that conceptually should favor the action of immunomodulatory agents. Indeed, immune checkpoint (ICBs) are benefitting a large set of melanoma patients. Nevertheless, a significant fraction of patients shows minimal or no response to ICBs and mechanisms underlying this response are unclear. This PhD thesis was set to identify new drivers of melanoma, with the unexpected finding of the dsRNA binding protein STAUFEN1 (STAU1) as a new modulator of melanoma progression and immune evasion. We selected to study RBPs, because this is a large family of proteins that are rather understudied in melanoma, despite the fact that they can impinge on multiple transcriptional networks with major consequences in cancer development and response to therapy. Our group has recently identified a series of RBPs (CEPB4, CELF1 and IGF2BP1) with links to lineage-specific oncogenes in melanoma, and collaborated to identify new roles of translational modulators (UNR) to this disease. Yet, our knowledge of RBPs that bind dsRNA (dsRBPs) is still incomplete. Characterizing these proteins is relevant, as most mRNAs in eukaryotic cells are highly structured, representing targets for multiple dsRBPs. Still, the expression and specific requirement of dsRBPs to melanoma (as for other tumor types) are unclear. Computational analyses of our group identified STAU1 as one of the most altered dsRBPs in datasets from melanoma patients. We then decided to focus on this protein for its multiple and context-dependent roles in mRNA metabolism with no previous association to this tumor type. This PhD thesis aimed to characterize the expression of STAU1 at different stages of melanoma progression, define the mode of action of this protein, and determine its functional impact. To this end, we used melanoma cell lines, genetically modified mouse melanoma models and clinical specimens. Next, we identified downstream effectors of STAU1, mapping downstream targets with a tri-pronged integration (proteomics, transcriptomics and interactomics). Notably, this strategy revealed an unanticipated impact of STAU1 in controlling double-stranded RNA (dsRNA) homeostasis, serving as an internal brake to an otherwise damaging interferon signaling cascade. Novel immunomodulatory signals found here linked to STAU1 included a variety of factors involved in antigen processing and presentation. Moreover, we found STAU1 as a putative novel biomarker of immunotherapy resistance in melanoma patients. Together, these data identify new roles of STAU1 in melanoma with important translational potential