Onco-Circuit Addiction and Onco-Nutrient mTORC1 Signaling Vulnerability in a Model of Aggressive T Cell Malignancy

Wang, X.; Cornish, A. E.; Do, M. H.; Brunner, J. S.; Hsu, T.-W.; Xu, Z.; Malik, I.; Edwards, C.; Capistrano, K. J.; Zhang, X.; Ginsberg, M. H.; Finley, L. W. S.; Lim, M. S.; Horwitz, S. M.; Li, M. O.

doi:10.1101/2024.04.03.587917

bioRxiv · 10.1101/2024.04.03.587917

Onco-Circuit Addiction and Onco-Nutrient mTORC1 Signaling Vulnerability in a Model of Aggressive T Cell Malignancy

Wang, X.·Cornish, A. E.·Do, M. H.·Brunner, J. S.·Hsu, T.-W.·Xu, Z.·Malik, I.·Edwards, C.·Capistrano, K. J.·Zhang, X.·Ginsberg, M. H.·Finley, L. W. S.·Lim, M. S.·Horwitz, S. M.·Li, M. O.

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Abstract

How genetic lesions drive cell transformation and whether they can be circumvented without compromising function of non-transformed cells are enduring questions in oncology. Here we show that in mature T cells--in which physiologic clonal proliferation is a cardinal feature-- constitutive MYC transcription and Tsc1 loss in mice modeled aggressive human malignancy by reinforcing each others oncogenic programs. This cooperation was supported by MYC-induced large neutral amino acid transporter chaperone SLC3A2 and dietary leucine, which in synergy with Tsc1 deletion overstimulated mTORC1 to promote mitochondrial fitness and MYC protein overexpression in a positive feedback circuit. A low leucine diet was therapeutic even in late-stage disease but did not hinder T cell immunity to infectious challenge, nor impede T cell transformation driven by constitutive nutrient mTORC1 signaling via Depdc5 loss. Thus, mTORC1 signaling hypersensitivity to leucine as an onco-nutrient enables an onco-circuit, decoupling pathologic from physiologic utilization of nutrient acquisition pathways.

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Wang, X., Cornish, A. E., Do, M. H., Brunner, J. S., Hsu, T.-W., Xu, Z., Malik, I., Edwards, C., Capistrano, K. J., Zhang, X., Ginsberg, M. H., Finley, L. W. S., Lim, M. S., Horwitz, S. M., Li, M. O.. 2024-04-04. Onco-Circuit Addiction and Onco-Nutrient mTORC1 Signaling Vulnerability in a Model of Aggressive T Cell Malignancy. https://doi.org/10.1101/2024.04.03.587917

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