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Promoting RObust Systems biology on Patients and Experimental models with obesity-driven liveR cancer

Project description

A closer look at obesity’s link to liver cancer

Obesity poses a multifaceted health challenge, with its detrimental effects extending beyond cardiovascular risks. In obese individuals, the pathological expansion of fat cells triggers inflammation and cell death, exacerbating conditions such as non-alcoholic steatohepatitis (NASH). This cascade of events significantly increases the risk of developing hepatocellular carcinoma (HCC), a deadly form of liver cancer. With the support of the Marie Skłodowska-Curie Actions programme, the PROSPER project aims to unravel this mystery. It uses a systems biology approach, analysing adipose and liver factors in NASH-driven HCC. By studying animal models and patient cohorts, researchers seek to pinpoint key regulators of obesity-driven HCC and immunosuppression. Understanding these mechanisms could lead to novel therapies and preventive strategies against this deadly disease.

Objective

In obesity, pathological expansion of adipocytes leads to increased adipose tissue macrophage (ATM) amounts and adipocyte death. Adipocyte death in turn is linked to ectopic lipid spillover and metabolically triggered inflammation which is a risk factor for diseases such as cancer, particularly hepatocellular carcinoma (HCC) that is linked to nonalcoholic steatohepatitis (NASH). Hepatic fat accumulation leads to chronic hepatocyte metabolic and oxidative stress resulting in cell damage and death. Although oxidative damage, microbiome dysbiosis, mitochondrial dysfunction, sterile inflammation are important in promoting NASH and fibrosis and cirrhosis are crucial for HCC development, the exact trigger(s) remain unknown. In HCC tumor cells take up nutrients, including lipids, to support their proliferation and solid tumors in HCC are characterized by enhanced hypoxia and acidosis resulting from a locally modified metabolism. Beyond malignant cells, the tumor-microenvironment (TME) contains immune cells including tumor-associated macrophages (TAMs) and dendritic cells. TAMs are pro tumorigenic, sabotaging anti-tumor immunity through various mechanisms. Notably, TAMs’ tumour-suppressive phenotype is directly linked to their lipid loading and disrupting lipid formation in TAMs attenuates tumor growth. Further, in the TME, dendritic cells are triglyceride laden, which contributes to immunosuppression by impairing their ability to present antigen. Despite advancements, a systems approach to understand the exact metabolites and lipid species in obesity driven HCC remains a challenge. Moreover, which metabolites are adipocyte-derived or locally produced within the liver remains unclear. Here using systems biology, coupled to NASH and NASH driven HCC animal models as well as patient cohorts spanning the NAFLD, NASH and HCC spectrum, we aim to identify which factors produced by adipose and the liver regulate obesity driven HCC and contribute to immunosuppression.

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HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships

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Call for proposal

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(opens in new window) HORIZON-MSCA-2023-PF-01

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Coordinator

MEDIZINISCHE UNIVERSITAET WIEN
Net EU contribution

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€ 183 600,96
Address
SPITALGASSE 23
1090 Wien
Austria

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Region
Ostösterreich Wien Wien
Activity type
Higher or Secondary Education Establishments
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Total cost

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