Our goal is to understand the molecular mechanisms through which obesity and excessive fat consumption increase the risk of cancer development. Epidemiological studies have shown that of all cancers, obesity has the most dramatic effect on the common form of liver cancer - hepatocellular carcinoma (HCC). In addition to its important metabolic functions, the liver is an immune organ that is severely impacted by obesity, resulting in non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH), inflammatory conditions that greatly increase HCC risk. To genetically and molecularly investigate how obesity increases HCC risk, we established mouse models in which liver fat accumulation (hepatosteatosis) strongly enhances development of chemically-induced HCC; models that a recent review found to be highly relevant to the etiology and pathogenesis of human HCC. Using these models, we had demonstrated that obesity-induced liver inflammation plays a key role in HCC pathogenesis by activating the oncogenic transcription factor STAT3. However, hepatosteatosis also results in chronic activation of Target of Rapamycin (TOR) complex 1 (TORC1), thereby suppressing autophagy. We postulate that TORC1 activation and suppressed autophagy are additional mechanisms that contribute to the molecular pathogenesis of obesity-promoted HCC. To investigate this central hypothesis of the current proposal, four specific aims will be pursued: 1) Determine whether inhibition of TORC1 prevents obesity-promoted hepatocarcinogenesis; 2) Investigate the contribution of chronic TORC1 activation to DEN-induced hepatocarcinogenesis; 3) Identify effector pathways that mediate TORC1 effects on obesity-promoted hepatocarcinogenesis; and 4) Examine whether TORC1 feedback regulation by Sestrin has a role in obesity-promoted hepatocarcinogenesis. Whereas the first two aims will ask whether TORC1 activation is required and sufficient for obesity-promoted hepatocarcinogenesis, the third aim will explore the hypothesis that the most critical pathogenic function of chronic TORC1 activation is suppression of basal autophagy. The last aim will investigate the connection between tumor suppressor p53 and the regulation of TORC1 activity and autophagy, which depends on expression of Sestrins, a small family of p53-regulated proteins that activate AMPK. Studies will be performed mainly in vivo using both constitutive and inducible gene targeting as well as a novel approach for isolation and specific manipulation of pre-neoplastic HCC initiating cells. We will also develop new tools for uncoupling TORC1 from inhibition of autophagy. Collectively, the proposed experiments will shed new light on the pathogenic mechanisms that link hypernutrition and obesity to tumor development and progression via TORC1 and its ability to suppress basal autophagy. The proposed studies will also lead to new preventive and therapeutic strategies that will reduce the toll of obesity-promoted liver cancer as well as other cancers, such as pancreatic cancer, that are also strongly impacted by the obesity epidemic.
The obesity epidemic has precipitated a marked increase in the incidence of hepatocellular carcinoma (HCC) or liver cancer. The mechanisms by which obesity increases HCC risk are not fully known but their understanding is required for the design of effective therapeutic and preventive strategies. We will use recently developed mouse models and innovative technology for isolation of pre-neoplastic cells to fully understand how obesity promotes HCC development.
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|Kim, Ju Youn; Garcia-Carbonell, Ricard; Yamachika, Shinichiro et al. (2018) ER Stress Drives Lipogenesis and Steatohepatitis via Caspase-2 Activation of S1P. Cell 175:133-145.e15|
|Zhong, Zhenyu; Umemura, Atsushi; Sanchez-Lopez, Elsa et al. (2016) NF-?B Restricts Inflammasome Activation via Elimination of Damaged Mitochondria. Cell 164:896-910|
|Kim, Jeong Sig; Ro, Seung-Hyun; Kim, Myungjin et al. (2015) Sestrin2 inhibits mTORC1 through modulation of GATOR complexes. Sci Rep 5:9502|
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|Font-Burgada, Joan; Shalapour, Shabnam; Ramaswamy, Suvasini et al. (2015) Hybrid Periportal Hepatocytes Regenerate the Injured Liver without Giving Rise to Cancer. Cell 162:766-79|
|Nakagawa, Hayato; Umemura, Atsushi; Taniguchi, Koji et al. (2014) ER stress cooperates with hypernutrition to trigger TNF-dependent spontaneous HCC development. Cancer Cell 26:331-343|
|Inokuchi-Shimizu, Sayaka; Park, Eek Joong; Roh, Yoon Seok et al. (2014) TAK1-mediated autophagy and fatty acid oxidation prevent hepatosteatosis and tumorigenesis. J Clin Invest 124:3566-78|
|Parmigiani, Anita; Nourbakhsh, Aida; Ding, Boxiao et al. (2014) Sestrins inhibit mTORC1 kinase activation through the GATOR complex. Cell Rep 9:1281-91|
|Umemura, Atsushi; Park, Eek Joong; Taniguchi, Koji et al. (2014) Liver damage, inflammation, and enhanced tumorigenesis after persistent mTORC1 inhibition. Cell Metab 20:133-44|
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