LIPOMET · Dietary Influences on Metastasis: How, When, and Why

We have recently identified metastasis-initiating cells (MICs) in several types of tumors (Nature, 2017)1.Intriguingly, MICs: (i) are exclusive in their ability to generate metastases when transplanted; (ii) express thefatty acid channel CD36 and have a unique lipid metabolic signature; (iii) are exquisitely sensitive to thelevels of fat in circulation, thus providing a link between the predisposition of metastasis and dietary fat; (iv)are highly sensitive to CD36 inhibition, which almost completely abolishes their metastatic potential.We still do not know how MICs promote metastasis or how MICs are influenced by dietary fat. Inparticular: (A) where are MICs located within the tumor, and does this location influence their behavior?How and where do they attach and expand at metastatic sites? (B) Why are MICs so sensitive to specificdietary lipids, and how do these lipids promote metastasis at the molecular and cellular levels? (C) Is theprolonged consumption of a high-fat diet a risk factor for developing metastatic tumors? If so, what are theunderlying genetic and epigenetic causes for this effect? Can we revert these causes?To answer these questions, we will combine state-of-the-art in vivo functional models of metastasis, withquantitative metabolomics and proteomics, epigenetic and geographical position (3D) single-celltranscriptomic studies, as well as integrative computational analyses, using preclinical models and patientderivedcarcinomas of melanoma, oral cancer and breast cancer.We expect our project to provide fundamental insights into the mechanisms of metastasis, and how they areinfluenced by diet. This is highly relevant as 1) large quantities of fatty acids are typically consumed inWestern diets; and 2) metastasis is the leading cause of cancer-related deaths. We also tackle a timelymedical unmet need by exploring the therapeutic anti-metastatic potential of targeting fatty acid metabolismin cancer patients.