Abstract B010: Metabolic Starvation Reprograms YAP1 Signaling to Enhance Tumorigenesis in Hepatoblastoma

Abstract Hepatoblastoma (HB) is the most common malignant liver tumor in children. While patients with localized disease often respond well to therapy, those with metastasis, therapeutic resistance, and widespread liver infiltration face dramatically lower survival rates of only 20–50%. One key driver of HB progression is Yes-associated protein 1 (YAP1), a mechanosensory protein and transcriptional co-activator. High levels of nuclear YAP1 are linked to aggressive tumor behavior, poor outcomes, and serve as an independent marker of poor prognosis. Although prior studies suggest that the tumor microenvironment can modulate YAP1 localization, the underlying mechanisms and functional consequences remain poorly defined. In this project, we examined how metabolic starvation influences YAP1 signaling and downstream transcriptional programs. Under glucose and glutamine (GQ) starvation, HB cells exhibited a striking increase in the nuclear localization of YAP1. Concomitantly, the expression of key YAP1 targets was dramatically altered: CCN1 was significantly upregulated, while CCN2 protein was completely lost and failed to recover even upon nutrient restoration. These genes are well-established contributors to tumor progression, with roles in promoting invasion and migration across multiple cancer types. Notably, HNF4α, a hepatocyte differentiation factor downstream of CCN2, was also markedly reduced under metabolic stress. Given that CCN2 loss has been associated with enhanced metastatic potential and that HNF4α promotes hepatic differentiation, these findings suggest that metabolic starvation shifts HB cells toward a more aggressive, less differentiated state. Our findings reveal a YAP1-dependent transcriptional response to metabolic stress that reprograms extracellular matrix signaling and differentiation status in HB. This work highlights a novel mechanism by which metabolic cues can drive tumor progression and metastasis in hepatoblastoma and opens potential therapeutic avenues targeting the YAP–ECM axis under nutrient stress. Citation Format: Md Moin Talukder, SAFIYA KHURSHID. Metabolic Starvation Reprograms YAP1 Signaling to Enhance Tumorigenesis in Hepatoblastoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Breakthrough Therapies; 2025 Sep 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_2):Abstract nr B010.