P14.02.A OPTOCHEMOGENETIC MODELING OF NEURO-CANCER CROSSTALK IN VON HIPPEL-LINDAU DISEASE

Abstract BACKGROUND Von Hippel-Lindau (VHL) disease leads to tumors in the nervous system, including cerebellar and spinal cord hemangioblastomas (CBHB, SCHB), and pheochromocytomas (PCC), involving significant neuro-cancer interactions. Understanding these bidirectional interactions is limited by the absence of accurate genetically engineered mouse (GEM) models. Traditional approaches for modeling localized gene recombination face issues such as off-target effects and systemic toxicity. MATERIAL AND METHODS We employed a novel optochemogenetic (OCG) switch technology, using photoactivatable caged 4-hydroxycyclofen (4-OHC) with localized UV illumination, to precisely induce genetic alterations in specific nervous system compartments (cerebellum, spinal cord) and peripheral nervous tissue (adrenal medulla). Using reporter mice (UBC-CreERT2 mTmGf/+), we optimized this UV-driven method to achieve targeted gene recombination. Subsequently, we created GEM models (UBC-CreERT2 Vhlf/f and UBC-CreERT2 Vhlf/f Ptenf/f) to investigate tumor initiation and progression driven by localized neuro-cancer interactions. RESULTS Preliminary findings validated effective localized gene recombination via the OCG switch, demonstrating specificity without systemic side effects. Conventional systemic induction methods caused rapid lethality, highlighting the necessity for spatially controlled gene recombination to study neural-tumor crosstalk accurately. Ongoing experiments focus on refining UV illumination conditions to effectively model the neural influences on cancer initiation and progression. CONCLUSION Our optochemogenetic approach uniquely enables precise investigation of neural influences on tumor formation and tumor-induced neural alterations specific to VHL disease. These GEM models are expected to uncover novel neural-cancer crosstalk mechanisms, advancing our understanding of cancer neuroscience and paving the way for targeted therapeutic strategies.