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Content archived on 2024-05-27

Lipid-mediated activation of b-catenin in melanoma biology

Final Report Summary - LAMB (Lipid-mediated activation of b-catenin in melanoma biology)

Multiple sub-populations of cancer cells coexist within tumors. Cancer stem cells (CSC) are proposed to initiate new tumors and to be therapy-resistant cells. Activation and self-renewal of CSCs is thought to recapitulate normal stem cell activation through signals related to those used by physiological stem cells. The Wnt/b-catenin signaling plays a major role in stem cell activation and differentiation, and is frequently constitutively activated in cancer. In melanoma, Wnt/b-catenin signaling activates melanocyte stem cells, enhances metastasis and inhibits invasiveness by up-regulating the expression of a gene termed MITF that plays a critical role in melanoma progression. Adipocytes play a key role in activation of hair follicle stem cells, can transfer lipids to cancer cells and are frequently encountered during cancer cell invasion. We have examined the impact of lipid uptake on b-catenin signaling and the biological consequences on melanoma.

We have identified a subset of lipids able to control b-catenin signalling and transcriptional activation at physiologically relevant concentrations in melanoma cells through mechanisms independent of the classical signalling pathway known to activate b-catenin. We have shown that lipids regulate the ability of b-catenin to control the activity of key genes in melanoma cell lines. Furthermore, lipids regulate the expression of markers of the so-called epithelial mesenchymal transition that occurs when cells become invasive, but not genes implicated in cell proliferation. We are now examining genome-wide the full repertoire of b-catenin target genes that are regulated by lipid vs Wnt signalling.

Lipids promote morphological changes in melanoma cells and an increase their migration/invasiveness capacity, processes that we show are b-catenin dependent. In addition, our data show changes in the gene-expression profile of lipid metabolism markers between invasive and proliferative cell lines, which can be regulated by lipids.

To confirm the potential impact of adipocytes on melanoma invasiveness and metastatic potential we are performing co-culture with adipocytes and evaluating the biological consequences.

Collectively our results suggest that adipocytes may serve as an exogenous source of lipids that drive melanoma cells to behave differently, switching to a more invasive state. The results provide a key insight into how lipid signalling can impact cancer biology and potentially activate physiological stem cells.

Specifically, the project has highlighted how lipid-mediated melanoma re-programming may play a key role in melanoma progression. Although our results have focused on melanoma, we anticipate that the lessons learned will be widely applicable to non-melanoma cancers. Moreover our results may go some way to understanding the relationship between elevated circulating lipids may drive the observed increased cancer incidence in the obese. The dissection of the molecular mechanisms underlying lipid mediated increases in melanoma invasiveness should also offer new opportunities for targeted therapies directed towards prevention of metastatic spread, the major cause of cancer-related death, and driving drug-resistant cells towards a drug-sensitive phenotype.