Metabolic Adaptation Fuels Lymph Node Metastasis

Many cancers metastasize regionally through lymphatics before metastasizing systemically through blood vessels. However, metastasis through blood has been studied much more extensively than metastasis through lymph. Recently in Science, Lee et al., 2019Lee C.K. Jeong S.H. Jang C. Bae H. Kim Y.H. Park I. Kim S.K. Koh G.Y. Tumor metastasis to lymph nodes requires YAP-dependent metabolic adaptation.Science. 2019; 363: 644-649Crossref PubMed Scopus (176) Google Scholar offered new insight into lymph node metastasis by showing that melanoma cells must undergo metabolic changes during this process and that it is driven by localized accumulation of bile acids. Many cancers metastasize regionally through lymphatics before metastasizing systemically through blood vessels. However, metastasis through blood has been studied much more extensively than metastasis through lymph. Recently in Science, Lee et al., 2019Lee C.K. Jeong S.H. Jang C. Bae H. Kim Y.H. Park I. Kim S.K. Koh G.Y. Tumor metastasis to lymph nodes requires YAP-dependent metabolic adaptation.Science. 2019; 363: 644-649Crossref PubMed Scopus (176) Google Scholar offered new insight into lymph node metastasis by showing that melanoma cells must undergo metabolic changes during this process and that it is driven by localized accumulation of bile acids. Metastasis is a highly inefficient process in which few disseminated cancer cells survive to form tumors at distant sites (Vanharanta and Massagué, 2013Vanharanta S. Massagué J. Origins of metastatic traits.Cancer Cell. 2013; 24: 410-421Abstract Full Text Full Text PDF PubMed Scopus (385) Google Scholar). In many cancers, it appears that the initial stages of metastasis are more likely to occur through lymphatics, followed later by systemic metastasis through the blood (Ferris et al., 2012Ferris R.L. Lotze M.T. Leong S.P. Hoon D.S. Morton D.L. Lymphatics, lymph nodes and the immune system: barriers and gateways for cancer spread.Clin. Exp. Metastasis. 2012; 29: 729-736Crossref PubMed Scopus (31) Google Scholar). But despite the clinical importance of this phenomenon, it is not known why this occurs and the underlying mechanisms are poorly understood. It is technically more difficult to obtain lymph, as compared to blood, and many fewer cancer cells can be isolated for study from lymph. Consequently, metastasis through lymphatics has been less studied as compared to metastasis through blood. In some cancers, including melanoma and breast cancer, regional lymph node metastasis is associated with an increased risk of distant metastasis and worse outcomes (Ferris et al., 2012Ferris R.L. Lotze M.T. Leong S.P. Hoon D.S. Morton D.L. Lymphatics, lymph nodes and the immune system: barriers and gateways for cancer spread.Clin. Exp. Metastasis. 2012; 29: 729-736Crossref PubMed Scopus (31) Google Scholar). Sentinel lymph nodes proximal to primary tumors are often analyzed for the presence of cancer cells to determine whether the cancer has started to metastasize. The detection of regional lymph node metastases can trigger more aggressive treatment. Studies performed in mice have confirmed that cancer cells from primary tumors can move through lymphatics to enter the blood, then use the blood to spread to distant sites where they form metastatic tumors (Brown et al., 2018Brown M. Assen F.P. Leithner A. Abe J. Schachner H. Asfour G. Bago-Horvath Z. Stein J.V. Uhrin P. Sixt M. Kerjaschki D. Lymph node blood vessels provide exit routes for metastatic tumor cell dissemination in mice.Science. 2018; 359: 1408-1411Crossref PubMed Scopus (221) Google Scholar, Pereira et al., 2018Pereira E.R. Kedrin D. Seano G. Gautier O. Meijer E.F.J. Jones D. Chin S.M. Kitahara S. Bouta E.M. Chang J. et al.Lymph node metastases can invade local blood vessels, exit the node, and colonize distant organs in mice.Science. 2018; 359: 1403-1407Crossref PubMed Scopus (254) Google Scholar). The identification of tumor-associated lymphatic markers and the development of approaches to image lymph node metastasis in mice have advanced the ability to study these processes (Karaman and Detmar, 2014Karaman S. Detmar M. Mechanisms of lymphatic metastasis.J. Clin. Invest. 2014; 124: 922-928Crossref PubMed Scopus (334) Google Scholar). Numerous studies have demonstrated that cancer cells undergo metabolic changes during metastasis (Elia et al., 2018Elia I. Doglioni G. Fendt S.M. Metabolic hallmarks of metastasis formation.Trends Cell Biol. 2018; 28: 673-684Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar). We found that melanoma cells must undergo reversible metabolic changes in order to survive in new environments during metastasis (Piskounova et al., 2015Piskounova E. Agathocleous M. Murphy M.M. Hu Z. Huddlestun S.E. Zhao Z. Leitch A.M. Johnson T.M. DeBerardinis R.J. Morrison S.J. Oxidative stress inhibits distant metastasis by human melanoma cells.Nature. 2015; 527: 186-191Crossref PubMed Scopus (737) Google Scholar). These changes include increased dependence upon metabolic pathways that confer oxidative stress resistance, including the folate pathway. The idea that cancer cells undergo reversible metabolic changes during metastasis is appealing as many efforts to identify metastasis mutations (recurrent mutations that confer metastatic potential) were unsuccessful (Valastyan and Weinberg, 2011Valastyan S. Weinberg R.A. Tumor metastasis: molecular insights and evolving paradigms.Cell. 2011; 147: 275-292Abstract Full Text Full Text PDF PubMed Scopus (2649) Google Scholar). That is, cancer cells appear to use reversible mechanisms to adapt during metastasis (such as metabolic or epigenetic changes) rather than irreversible mechanisms (such as mutations). These observations raise the question of whether lymph node metastasis requires specific metabolic changes. An important recent study published in Science has confirmed that melanoma cells and breast cancer cells undergo metabolic changes to survive during lymph node metastasis (Lee et al., 2019Lee C.K. Jeong S.H. Jang C. Bae H. Kim Y.H. Park I. Kim S.K. Koh G.Y. Tumor metastasis to lymph nodes requires YAP-dependent metabolic adaptation.Science. 2019; 363: 644-649Crossref PubMed Scopus (176) Google Scholar). They found in mouse models that cancer cells undergo a metabolic shift toward fatty acid oxidation in lymph nodes. By comparing cancer cells from primary cutaneous tumors and tumor-draining lymph nodes, they found that yes-associated protein (YAP), a downstream mediator of the Hippo pathway, is selectively activated in lymph node metastases, leading to the induction of fatty acid oxidation (Figure 1). Pharmacological inhibition of fatty acid oxidation or deletion of YAP from the cancer cells inhibited lymph node metastasis, but not blood-borne metastasis, indicating that the metabolic shift toward fatty acid oxidation is preferentially required for lymph node metastasis. It should be noted, however, that while lymph node metastasis may not be required for metastasis through the blood, the initial metastasis of many cancers is more likely to occur through lymph nodes. So if this event could be blocked, it may delay disease progression and thus render more cancers curable by surgery. Metabolomic analysis revealed a significant increase in the levels of bile acids in lymph node metastases as compared to primary tumors and normal lymph nodes. Through a series of in vitro and in vivo experiments, Lee et al. found that bile acids could be synthesized by the cancer cells to promote the dephosphorylation and nuclear translocation of YAP. However, it requires further investigation to determine whether the cancer cells themselves produce the bile acids or whether the bile acids are synthesized by other cells but accumulate in the lymph node tumors. The precise mechanism by which the bile acids promote the dephosphorylation and nuclear translocation of YAP is also uncertain, but it may be mediated by vitamin D nuclear receptor, whose transcriptional activity can be altered by binding bile acids (Han et al., 2010Han S. Li T. Ellis E. Strom S. Chiang J.Y.L. A novel bile acid-activated vitamin D receptor signaling in human hepatocytes.Mol. Endocrinol. 2010; 24: 1151-1164Crossref PubMed Scopus (96) Google Scholar). These observations in mouse models appear to be relevant to humans as the authors confirmed that increased nuclear YAP staining in regional melanoma lymph node metastases correlates with increased distant metastasis in patients. Additional prospective studies will be required to test if nuclear YAP staining in cancer cells can be used to predict disease progression in patients. Moreover, the discovery that cancer cells require YAP function and fatty acid oxidation to form lymph node metastases raises the possibility that therapeutic inhibition of these adaptations could inhibit disease progression. By further broadening our understanding of the metabolic differences between the lymphatic and blood vessel environments, as well as the changes cancer cells undergo during metastasis, additional strategies will likely be identified to inhibit disease progression. It will also be important to assess the extent to which cancer cell-intrinsic versus cell-extrinsic mechanisms regulate the metabolic plasticity of metastasizing cells and the extent to which metastatic potential is determined by metabolic states that are already present in primary tumor cells. S.J.M. is a Howard Hughes Medical Institute (HHMI) Investigator, the Mary McDermott Cook Chair in Pediatric Genetics, the Kathryn and Gene Bishop Distinguished Chair in Pediatric Research, the director of the Hamon Laboratory for Stem Cells and Cancer, and a Cancer Prevention and Research Institute of Texas Scholar. This work was supported by grants from the Cancer Prevention and Research Institute of Texas (RP170114 and RP180778). The authors thank Gou Young Koh for his comments on the text.