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Abstract

Cancer cells often reside in nutrient-deprived tumor environments where conventional nutrient sources such as free amino acids are scarce. To overcome this, Ras-driven cancers exploit alternative nutrient acquisition strategies, including the uptake and catabolism of extracellular proteins through macropinocytosis. Albumin, the most abundant plasma protein, is a major source of amino acids that can be used by tumor cells. However, under physiological conditions, the neonatal Fc receptor (FcRn) protects albumin from lysosomal degradation by rescuing it through endocytic recycling. In my doctoral project, I investigated how oncogenic Ras signaling regulates FcRn expression, and consequently, the fate of internalized albumin. My findings reveal that Ras downregulates FcRn expression through the Raf/Mek/Erk MAPK pathway, independently of PI3K signaling. This repression occurs at the transcriptional level and was observed across a variety of Ras variants and in response to growth factor stimulation. Furthermore, I identified the involvement of Myc and Ets transcription factors in the repression of FcRn downstream of Ras/MAPK signaling. Restoring FcRn expression in Ras-transformed cells limited intracellular albumin accumulation and decreased albumin lysosomal catabolism. Ectopic FcRn expression thereby impaired the proliferation of cells dependent on albumin for amino acid supply, but had no effect when free amino acids were available. Altogether, this project characterized a novel function of oncogenic Ras in the repression of albumin recycling through the downregulation of FcRn and revealed the importance of this mechanism for Ras-transformed cells to adapt to nutrient limitations. These findings broaden our understanding of Ras-mediated metabolic dysregulation and may inform future strategies to target nutrient acquisition in cancer.