Cancer beyond mutations: Developmental programs of nutrient acquisition influence oncogenic competence in YAP-driven liver cancer

Cancer has long been regarded as a genetic disease arising from the accumulation of oncogenic mutations. However, emerging evidence emphasizes the role of ‘oncogenic competence', whereby the tumorigenic potential of oncogenic mutations is determined by specific non-genetic cellular and environmental contexts. Furthermore, many tumors exhibit ‘oncofetal reprogramming', reactivating cell states characteristic of embryonic development. Despite growing recognition of their significance in cancer biology, the molecular mechanisms underlying oncogenic competence and oncofetal reprogramming are still poorly understood. Liver cancer represents a compelling model to study oncogenic competence, as genomic sequencing of histologically normal liver biopsies have revealed a high mutational burden that includes oncogenic mutations. To examine the role of developmental programs in hepatic oncogenic competence, we have employed a novel zebrafish model of liver cancer (p53KO; TO:YAP) that recapitulates clinical features. Our model combines a loss-of-function mutation in p53 with a hepatocyte-specific doxycycline-inducible expression of the oncogene YAP. Using this conditional model of liver cancer, we have found that developmental age determines oncogenic competence. Specifically, early induction of YAP at lecithotrophic (yolk-dependent nutrition) stages of embryogenesis led to profound tumor formation, whereas later induction of YAP at exotrophic (external feeding) stages of development had no tumorigenic effect. Yolk sac resection studies revealed that yolk-derived lipids were required for tumor formation when YAP was induced during the lecithotrophic stage. Similarly, supplementation of a lipid-rich diet during the exotrophic stages was sufficient to imbue oncogenic competence. To identify the nascent transcriptional changes occurring in hepatocytes during lecithotrophic and exotrophic stages of development, we performed unbiased SLAM-IT-seq in both oncogenic competent and refractory states. We found that lipid metabolism is reprogrammed during the lecithotrophic to exotrophic transition, and that oncogenic competence is associated with contexts involving increased cell plasticity. Finally, we performed a lipid metabolism-focused chemical screen and identified that PCSK9-driven cholesterol uptake strongly contributes to the observed differences in oncogenic competence. Together, these studies reveal that developmental programs of nutrient acquisition have a dominant influence on oncogenic competence and tumor initiation. Importantly, these studies highlight that the reprogramming of cholesterol metabolism is a key barrier to oncogenic competence that is overcome during tumor initiation.