Increased demand for hexosamines escalates mTORC2 activation in PTEN-deficient T cells leading to lymphomagenesis 4255

Abstract Description Tumors have diverse mutations and origins but a common requirement for increased proliferation is the need to elevate nutrient uptake and metabolism. mTOR complex 2 (mTORC2) signaling is often found upregulated in cancers but how it could promote tumorigenesis remains poorly understood. In mice with T-cell specific deficiency in PTEN, normal T cell differentiation occurs until the onset of lymphoma at around 10-20 weeks after birth. To address how lymphomagenesis is triggered, we monitored metabolism and mTOR signaling. We found that mTORC2 activation is progressively amplified during lymphomagenesis. This coincides with increasing levels of GFAT1, the rate-limiting enzyme of the de novo hexosamine biosynthetic pathway (HBP) while the amounts of UDP-GlcNAc, the product of the HBP, declined over time. Co-ablation of PTEN with either rictor (mTORC2 component) or GFAT1 prevents lymphomagenesis. Our findings suggest that during PTEN deficiency, limitation of UDP-GlcNAc during T cell differentiation could amplify mTORC2 signaling leading to lymphomagenesis. Funding Sources Supported by Initiative for Maximizing Student Development T32/PAR-24-031 Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)