Abstract 4722: Genetic background shapes mitochondrial metabolic adaptations underlying thyroid cancer progression

Abstract Introduction: Anaplastic Thyroid Cancer (ATC) is characterized by rapid progression and unclear dissemination mechanisms. Tumor evolution is not solely defined by the selective pressure acting on pre-existing subclones, but is intricately intertwined with the rapid, environmentally mediated acquisition of adaptive phenotypes. Metabolic plasticity is a critical process that lies at the intersection of these complementary evolutionary paradigms, actively fueling malignant progression and conferring metastatic competence. Elucidating how metabolic rewiring contributes to the emergence and expansion of highly invasive ATC clones is critical to counteract TC progression Experimental procedures: We established a TC tumorigenesis model by leveraging human embryonic stem cells and CRISPR/Cas9 genome engineering to generate distinct TC progenitor cells, harbouring specific mutations. We developed highly invasive in vitro TC cells to identify the metabolic signatures linked to cellular aggressiveness. The data were corroborated in orthotopic TC mouse models, which recapitulated the disease progression. The metabolic profile was characterized by measuring oxygen consumption rate (OCR), extracellular acidification rate (ECAR). RNA-seq data were analyzed to obtain transcriptomic and metabolism-related signatures associated with specific genetic background. Cells were treated with MitoQ, Treatment effects were assessed on primary tumor growth and metastatic dissemination. New, unpublished data: We observed that BRAF V600E single/double-mutated cells cluster based on their metabolic profile and undergo a similar metabolic shift during the selection of super-invasive subpopulations. BRAFV600E-mutated ATC-derived aggressive clones experience a reprogramming toward oxidative phosphorylation (OXPHOS). ATC superoxide clones exhibit heightened mitochondrial respiration, increased mitochondrial membrane potential, and accumulation of mitochondrial reactive oxygen species, in line with their enhanced invasive capacity. Leveraging this metabolic dependency uncovered a therapeutic opportunity: treatment with the mitochondria-targeted antioxidant MitoQ significantly reduced cellular invasiveness in vitro and suppressed lung metastasis formation in vivo in mouse models. This defined metabolic vulnerability provides a distinct signature that may aid in stratifying relevant thyroid cancer patient subsets. Conclusions: Our study demonstrates that mitochondrial metabolic rewiring is not a universal feature of ATC but is instead tightly dictated by the tumor’s genetic background. These findings underscore the critical interplay between genetic context and metabolic adaptation, providing a refined framework for developing targeted therapeutic strategies aimed at pharmacologically restraining the metastatic progression of BRAFV600E-mutated ATC Citation Format: Vincenzo Davide Pantina, Chiara Modica, Francesco Verona, Giulia Bozzari, Roberta Drago, Caterina D'accardo, Gaetana Porcelli, Sebastiano Di Bella, Rosario Brancato, Pierre Sonveaux, Matilde Todaro, Giorgio Stassi. Genetic background shapes mitochondrial metabolic adaptations underlying thyroid cancer progression abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4722.