The Manning lab is defining the mechanisms and consequences of PI3K-mTOR network dysfunction in a variety of pathological states. One such setting is the neurological and tumor syndrome tuberous sclerosis complex (TSC), as well as the related proliferative lung disorder lymphangioleiomyomatosis (LAM). TSC and LAM are caused by inactivating mutations in TSC1 or TSC2, which are tumor suppressors that form a protein complex (the TSC complex) that is a central negative regulator of mTORC1. In addition to serving as the key link between growth factor signaling and mTORC1 activation, the TSC complex is also a shared downstream target of the most common oncogenic signaling pathways, including PI3K and RAS, resulting in aberrant regulation of the TSC complex and activation of mTORC1 in the majority of sporadic cancers. Through mechanisms that are currently unknown, exquisite control of signaling through the PI3K-mTOR network is also perturbed by nutrient excess and obesity, as well as over the course of organismal aging. In a context-dependent manner, these signaling defects can contribute to metabolic reprogramming in cancer cells and the development of insulin resistance and metabolic dysfunction underlying type-2 diabetes. These are areas of active investigation in the lab.
Relevant Publications
Schrötter S, Yuskaitis CJ, MacArthur MR, Mitchell SJ, Hosios AM, Osipovich M, Torrence ME, Mitchell JR, Hoxhaj G, Sahin M, Manning BD. The non-essential TSC complex component TBC1D7 restricts tissue mTORC1 signaling and brain and neuron growth. Cell Rep. 2022 May 17;39(7):110824. doi: 10.1016/j.celrep.2022.110824. PMID: 35584673; PMCID: PMC9175135.
Valvezan AJ, McNamara MC, Miller SK, Torrence ME, Asara JM, Henske EP, Manning BD. IMPDH inhibitors for antitumor therapy in tuberous sclerosis complex. JCI Insight. 2020 Apr 9;5(7):e135071. doi: 10.1172/jci.insight.135071. PMID: 32271165; PMCID: PMC7205253.
Hoxhaj G, Manning BD. The PI3K-AKT network at the interface of oncogenic signalling and cancer metabolism. Nat Rev Cancer. 2020 Feb;20(2):74-88. doi: 10.1038/s41568-019-0216-7. Epub 2019 Nov 4. PMID: 31686003; PMCID: PMC7314312.
Valvezan AJ, Turner M, Belaid A, Lam HC, Miller SK, McNamara MC, Baglini C, Housden BE, Perrimon N, Kwiatkowski DJ, Asara JM, Henske EP, Manning BD. mTORC1 Couples Nucleotide Synthesis to Nucleotide Demand Resulting in a Targetable Metabolic Vulnerability. Cancer Cell. 2017; pii: S1535-6108(17)30417-8. PMID: 29056426
Manning BD. Game of TOR – The Target of Rapamycin Rules Four Kingdoms. N Engl J Med. 2017; 377(13):1297-9. PMID: 28874074
Ilagan E, Manning BD. Emerging role of mTOR in the response to cancer therapeutics. Trends Cancer 2016; 2:241-251. PMID:27668290
Housden BE, Valvezan AJ, Kelley C, Sopko R, Hu Y, Roesel C, Lin S, Buckner M, Tao R, Yilmazel B, Mohr SE, Manning BD, Perrimon N. Identification of potential drug targets for tuberous sclerosis complex by synthetic screens combining CRISPR-based knockouts with RNAi. Sci Signal. 2015; 8(393):rs9. PMID: 26350902
Kwiatkowski DJ and Manning BD. The molecular basis of giant cells in tuberous sclerosis complex. N. Engl J Med 2014; 371(8):778-80. PMID: 25140966
Menon S, Yecies JL, Zhang HH, Howell JJ, Nicholatos J, Harputlugil E, Bronson RT, Kwiatkowski DJ, Manning BD. Chronic activation of mTOR complex 1 is sufficient to cause hepatocellular carcinoma in mice. Sci Signal. 2012; 5(217):ra24. PMID: 22457330
Huang J, Wu S, Wu CL, and Manning BD. Signaling events downstream of mammalian target of rapamycin complex 2 are attenuated in cells and tumors deficient for the tuberous sclerosis complex tumor suppressors. Cancer Res. 2009; 69(15):6107-14. PMID: 19602587
Manning BD, Logsdon MN, Lipovsky AI, Abbott D, Kwiatkowski DJ, Cantley LC. Feedback inhibition of Akt signaling limits the growth of tumors lacking TSC2. Genes Dev. 2005; 19(15):1773-8. PMID: 16027169