Cellular Mechanisms for the Malignant Exploitation of the Altered Metabolic Landscape in Obese Hormone Receptor Negative Breast Cancer

Blant den allmenne befolkningen er det velkjent at fedme forårsaker både type-2-diabetes og hjerte-og karsykdommer. En annen, og mer dødelig komorbiditet, er kreft. Til tross for at dette er en relativt ny sammenheng, anslås nå opptil 20% av kreftrelaterte dødsfall å være forårsaket av fedme. I lys av det økende antallet overvektige mennesker i de fleste vestlige land, inkludert Norge, representerer dette en stor samfunnsmessig utfordring, både når det kommer til økonomi og pasient velvære. Gjennom denne studien ønsker vi å få en bedre forståelse av hvordan fedme forårsaker kreft. Det overordnede målet er todelt. For det første ønsker vi å utforske hvordan tumorceller adapterer til et fedmemiljø der inkluderer nye celleinteraktioner og ændret niveu af hormoner og næringstoffer. Disse studiene vil med stor sannsynlighet gi ny innsikt i biologien til kreftceller. For det andre, vil vi benytte denne kunnskapen til å utvikle nye og mer effektive terapeutiske strategier, for å bekjempe kreft i overvektige pasienter. På nåværende tidspunkt mottar overvektige pasienter samme behandlingen som ikke-overvektige pasienter, til tross for at det ikke finnes grunnlag for denne behandlingsstrategien. Vi etterstreber derfor å forbedre behandlingsalternativene for overvektige kreftpasienter til en mer effektiv persontilpasset behandling.

The objective of the project was to discover the malignant cellular phenotypes that characterize cancer cells selected for by an obese environment. In the project we have demonstrated that obesity and the subsequent elevation of circulating free fatty acids are main drivers of obesity-induced cancers. We show that this is mediated through epigenetic remodeling of the epigenome towards a stem like state. Phenotypically obesity enhances the tumor initiation capacity through epigenetic activation of transcription factor CEBPB. This project thus provides novel in-depth mechanistic insights to the field linking obesity to cancers. Insights that will also benefit the fields as tumor metabolism, metabolic control of epigenetic landscapes and regulation of cancer stem cells. We are currently exploring possibilities to capitalize on our findings and to initiate a drug development program especially designed to benefit obese cancer patients within the personalized medicine framework.

Cancer progression leading to metastatic spread accounts for >90% of cancer-related death from solid tumors. A major risk factor for the development of aggresive cancer is obesity that is estimated to contribute to 15-20% of all cancer related mortalities. As the global obesity epidemic intensifies, understanding the connection between obesity and cancer is a critical clinical and socio-economic issue. Knowledge of how cancer cells adapt to altered metabolic landscapes is necessary to develop more effective therapeutics for both obese and non-obese cancer patients. In this research proposal we endeavor to address this fundamental health problem by employing an integrated, systematic research strategy that will build on global gene expression profiles from tumors of cancer patients with varying degrees of obesity combined in vivo methodologies to better understand the behaviour of tumor cells in obese and non-obese mice. The main challenge of deciphering the obesity-cancer connection lies in the multitude of physiological and pathophysiological changes caused by overweight and translate them into specific cellular cancer-promoting mechanisms. To avoid any preconceptions an unbiased comprehensive experimental approach comprising systems bioinformatics, mouse modeling, biochemistry and molecular biology methodologies from both obesity and metastasis research, will therefore be used to identify novel genes and cellular pathways used by cancer cells to achieve metastasis in obese patients. This will provide novel insights into the interaction between the metabolic status of the cancer patient and the metastatic spread. These insights will further be used to potentially derive novel therapeutic opportunities for the specific treatment of the rapidly growing population of obese cancer patients.