Metastasis: Slipping Control

I think that it is our intention to deny cancer any control over us. —Elizabeth Edwards (interviewed on 60 Minutes)“And now here it was again, now grown, now in its new home.” In her book Resilience, Elizabeth Edwards recalls what raced through her mind when she learned that her cancer had come back and had metastasized. After surgery, radiation, and chemotherapy, she thought that the cancer “had been chased away.”How does cancer find a new home and become metastatic? The short answer is simple: it is complicated. As cancer forms and develops, some cancer cells manage to be disseminated from the primary tumor, travel through the circulatory system, and infiltrate and colonize distant organs, eventually forming clinically detectable metastasis. Given the complexity of the metastatic process and technical and experimental bottlenecks, systematically investigating metastasis has been challenging, and to this date, metastatic cancer also remains largely incurable and fatal. Nevertheless, with the availability of more pathophysiologically relevant disease models and technological advances in areas such as imaging and single-cell sequencing, recent studies are beginning to paint a clearer picture.Why does cancer come back as metastatic in some patients after the primary tumor has been successfully removed? The answer might have to do with the timing of metastatic dissemination. Earlier data from several tumor types already suggest that, contrary to more conventional thinking, dissemination can occur rather early during cancer development, but the mechanism of early dissemination is unknown. A pair of studies now offers important clues as to how this happens in breast cancer (Hosseini et al., 2016xHosseini, H., Obradovic, M.M., Hoffmann, M., Harper, K.L., Sosa, M.S., Werner-Klein, M., Nanduri, L.K., Werno, C., Ehrl, C., Maneck, M. et al. Nature. 2016; Crossref | Scopus (38)See all References, Harper et al., 2016xHarper, K.L., Sosa, M.S., Entenberg, D., Hosseini, H., Cheung, J.F., Nobre, R., Avivar-Valderas, A., Nagi, C., Girnius, N., Davis, R.J. et al. Nature. 2016; Crossref | Scopus (31)See all References). Using a Her2-driven breast cancer mouse model, Housseini et al. and Harper et al. provide evidence not only that cancer cells disseminate very early, before detectable primary tumor formation, but also that early disseminated cancer cells (eDCCs) have more migration, invasion, and metastasis-initiating capacities (but not more tumor-initiating capacity) than DCCs from primary tumors at a later stage. Both studies also indicate a critical early involvement of HER2 in the dissemination of eDCCs, before its proliferation-promoting role after the primary tumor has formed. Collectively, these new findings have significant implications and suggest that metastasis might be preventable if a targetable Achilles’ heel in eDCCs can be identified.Targeting cancer. Image from iStockphoto/Aunt_SprayView Large Image | View Hi-Res Image | Download PowerPoint SlideAmong the many steps toward clinical manifestation of metastasis, organ colonization is perhaps the most rate-limiting one given that most arriving cancer cells don’t survive the new organ’s microenvironment and of the few that do, some might enter a state of dormancy. By definition, metastasis-initiating cells (MICs) are tumor cells with the capability to seed secondary tumors in distant organs. Two new studies dissect the mechanism of metastatic colonization from different angles. In one study, Pascual et al. set out to ask if there exists a small population of MICs within tumor-initiating cells (TICs) that can drive metastasis in oral squamous cell carcinomas (OSCCs) (Pascual et al., 2017xPascual, G., Avgustinova, A., Mejetta, S., Martin, M., Castellanos, A., Attolini, C.S., Berenguer, A., Prats, N., Toll, A., Hueto, J.A. et al. Nature. 2017; 541: 41–45Crossref | PubMed | Scopus (46)See all ReferencesPascual et al., 2017). Using CD44 as a TIC marker, they identify a subpopulation of CD44bright cells that are marked by high-level expression of genes associated with lipid metabolism and metastasis. Among the product of those genes is CD36, a cell-surface fatty acid receptor responsible for lipid uptake to provide ATP energy via fatty acid β-oxidation. Pascual et al. show that CD36 is required for OSCC metastasis to lymph nodes but has only a slight effect on primary tumor growth. Feeding mice with a high-fat diet or exposing OSCC cells to palmitic acid, a dietary fatty acid recognized by CD36, also promotes CD36-dependent lymph node metastasis. Importantly, orthotopic inoculation of limiting dilution experiments demonstrates that CD36+CD44bright cells are metastasis initiating.In a separate study, van der Weyden et al. use a tour de force approach to look for contributing factors from the host microenvironment (van der Weyden et al., 2017xvan der Weyden, L., Arends, M.J., Campbell, A.D., Bald, T., Wardle-Jones, H., Griggs, N., Velasco-Herrera, M.D., Tuting, T., Sansom, O.J., Karp, N.A...., and Sanger Mouse Genetics Project. Nature. 2017; 541: 233–236Crossref | PubMed | Scopus (17)See all Referencesvan der Weyden et al., 2017). The authors screened 810 mutant mouse lines by using an experimental metastasis assay and identified 23 genes as potential host regulators of metastatic colonization, many of which have not been previously implicated in metastasis. Interestingly, mice deficient in the sphingosine-1-phosphate (S1P) transporter spinster homolog 2 (Spns2) show the greatest metastatic suppression. S1P is a bioactive lysophospholipid mediator that has been linked to lymphocyte trafficking. van der Weyden et al. now report that global or lymphatic endothelial cell-specific deletion of Spns2 reduces melanoma or colorectal cancer metastasis to the lung by retaining more anti-tumor effector T cells and natural killer cells in the lung.As proof of principle, Pascual et al. and van der Weyden et al. also provide in vivo evidence that CD36 and the SIP1-SPNS2 axis could be explored as potential drug targets for anti-metastasis therapy. In the case of CD36, administration of a CD36-neutralizing antibody in an immunocompetent orthotopic mouse model of OSCC induces strong metastatic inhibition, and in some cases, complete regression of lymph node and lung metastases, without toxicity. Although it is still too early to conclude whether targeting CD36 or SPNS2 might be a clinically viable strategy, these two studies shed new light on the thus far underexplored roles of lipids in metastasis. Future studies of lipids, a diversified group of molecules with a multitude of biological and physiological functions, might reveal ways in which metastasis will be losing its control.