Abstract B030: Profilin-1 regulates mitochondrial function and tumorigenicity in chromophobe renal cell carcinoma

Abstract Chromophobe renal cell carcinoma (ChRCC), the second most common non–clear cell renal cell carcinoma, is a molecularly distinct kidney cancer with limited treatment options for advanced disease. Despite the success of immune checkpoint inhibitors and VEGF/VEGFR-directed tyrosine kinase inhibitors in clear cell RCC, responses in ChRCC are modest and largely extrapolated from mixed-histology trials, highlighting a critical need for subtype-specific therapeutic strategies. ChRCC is characterized by unique mitochondrial abnormalities, including mtDNA mutations, impaired oxidative metabolism, and ferroptosis sensitivity, suggesting that mitochondrial vulnerabilities could be exploited therapeutically. Profilin-1 (Pfn1), a ubiquitously expressed actin-binding protein, has recently been implicated in mitochondrial regulation, and cytoskeleton-driven control of mitochondrial function has been reported in other tumor types. We hypothesized that Pfn1-dependent cytoskeletal remodeling supports mitochondrial function and tumorigenic behavior in ChRCC. Using TCGA ChRCC datasets, we found that PFN1 mRNA expression was significantly higher in advanced-stage tumors and that elevated PFN1 expression correlated with reduced overall survival. To interrogate functional consequences, we manipulated Pfn1 levels in multiple ChRCC cell models using siRNA-mediated knockdown and doxycycline-inducible overexpression. We assessed oncogenic phenotypes (proliferation, migration, invasion, and colony formation) alongside mitochondrial morphology, reactive oxygen species (ROS) accumulation, and bioenergetic function (Seahorse metabolic flux analysis). Across ChRCC models, Pfn1 depletion markedly reduced oncogenic capacity, with impaired proliferation, migration, invasion, and clonogenic growth, whereas Pfn1 overexpression consistently enhanced these phenotypes. At the mitochondrial level, Pfn1 loss increased ROS accumulation and was associated with fragmented mitochondrial networks and decreased basal and maximal oxygen consumption rate, consistent with compromised oxidative phosphorylation and reduced spare respiratory capacity. Conversely, Pfn1 upregulation reduced ROS burden, promoted maintenance of tubular mitochondrial morphology, and partially restored mitochondrial respiratory capacity. Together, these data identify Pfn1 as a critical regulator of mitochondrial homeostasis and malignant behavior in ChRCC. Our findings support a model in which ChRCC co-opts Pfn1-dependent cytoskeletal remodeling to maintain mitochondrial fitness, limit oxidative stress, and sustain aggressive tumor phenotypes. Targeting the Pfn1–mitochondria axis may represent a novel strategy to exploit intrinsic metabolic vulnerabilities and improve outcomes for patients with this understudied and treatment-refractory kidney cancer subtype. Citation Format: Kaylee M. Montanari, Anup Acharya, Cais Vo, Elizabeth Henske, David Gau. Profilin-1 regulates mitochondrial function and tumorigenicity in chromophobe renal cell carcinoma abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Kidney Cancer Research: From Molecular Insights to Therapeutic Breakthroughs; 2026 Mar 13-16; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86 (5Suppl₂): Abstract nr B030.