HNRNPC-mediated RNA processing promotes VHL-associated excessive vasculogenesis in von Hippel-Lindau syndrome revealed from patient-derived blood vessel models

Abstract

Von Hippel-Lindau Syndrome (VHLS) is an inherited disorder characterized by excessive vascularization, which contributes to the development of hemangioblastomas and benign or malignant tumors, as well as renal cell carcinoma (RCC) and cysts in multiple organs. VHLS is caused by mutations in VHL tumor suppressor gene, which encodes a component of an E3 ubiquitin ligase complex. Although therapeutic agents targeting hypoxia-inducible factor 2 alpha (HIF2A), which is stabilized by VHL loss and promotes tumor angiogenesis, have been approved for clinical use, their therapeutic response remains limited in RCC patients associated with VHLS. Therefore, there is an unmet need for the development of alternative therapeutic approaches independent of HIF2A. Here, we establish a human iPSCs-based model of VHLS-associated excessive vasculogenesis using induced pluripotent stem cells (iPSCs) derived from VHLS patients and VHL-edited isogenic iPSC lines. Vascular cells (VCs) differentiated from these VHLS-specific iPSCs exhibited excessive blood vessel formation compared to healthy donor-derived VCs, leading to vascular lesion formation characterized by abundant blood vessels and abnormal cellular growth in vivo. Mechanistically, RNA-binding proteins (RBPs) were preferentially stabilized in the patient-VCs. Among these RBPs, the stabilization of heterogeneous nuclear ribonucleoprotein C1/C2 (HNRNPC), which is a substrate for pVHL-mediated protein degradation independent of HIF2A expression, was critical for the dysregulated vascularization caused by VHL inactivation in this model. These findings provide an iPSCs-derived vascular platform to elucidate VHLS mechanisms and identify HNRNPC as a potential therapeutic target for VHL-driven vascular lesion formations through an HIF2A-independent mechanism.