United They Stand, Divided They Fall
Authors: Isaac S. Harris, Joan S. Brugge
Journal: Cell Metabolism (2019)

Cancer cells that leave their natural environment during metastatic spread must adapt to numerous stresses to survive. In this issue, Labuschagne et al., 2019Labuschagne C.F. Cheung E.C. Blagih J. Domart M.C. Vousden K.H. Cell clustering promotes a metabolic switch that supports metastatic colonization.Cell Metab. 2019; 30 (this issue): 720-734Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar highlight one adaptive mechanism to overcome these stresses that involves cell clustering, which induces a hypoxic environment and metabolic rewiring to buffer oxidative stress. Cancer cells that leave their natural environment during metastatic spread must adapt to numerous stresses to survive. In this issue, Labuschagne et al., 2019Labuschagne C.F. Cheung E.C. Blagih J. Domart M.C. Vousden K.H. Cell clustering promotes a metabolic switch that supports metastatic colonization.Cell Metab. 2019; 30 (this issue): 720-734Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar highlight one adaptive mechanism to overcome these stresses that involves cell clustering, which induces a hypoxic environment and metabolic rewiring to buffer oxidative stress. Life as a cancer cell is intrinsically stressful. This stressful state is significantly enhanced when cancer cells detach from their natural niches during metastasis. Previous studies have defined the oxidative and metabolic stresses associated with matrix detachment (Hawk and Schafer, 2018Hawk M.A. Schafer Z.T. Mechanisms of redox metabolism and cancer cell survival during extracellular matrix detachment.J. Biol. Chem. 2018; 293: 7531-7537Crossref PubMed Scopus (48) Google Scholar); however, there is a limited understanding of mechanisms that mediate the adaptions to these stresses during metastasis (Le Gal et al., 2015Le Gal K. Ibrahim M.X. Wiel C. Sayin V.I. Akula M.K. Karlsson C. Dalin M.G. Akyürek L.M. Lindahl P. Nilsson J. Bergo M.O. Antioxidants can increase melanoma metastasis in mice.Sci. Transl. Med. 2015; 7: 308re8Crossref PubMed Scopus (422) Google Scholar, 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 (739) Google Scholar). A new study by Labuschagne et al. has uncovered an unexpected non-genetic mechanism of survival. This mechanism involves formation of large cell clusters, leading to hypoxic stress, which promotes survival via a metabolic rewiring to overcome oxidative stress (Labuschagne et al., 2019Labuschagne C.F. Cheung E.C. Blagih J. Domart M.C. Vousden K.H. Cell clustering promotes a metabolic switch that supports metastatic colonization.Cell Metab. 2019; 30 (this issue): 720-734Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar) (Figure 1). To gain a better understanding of how tumor cells survive following detachment, Labuschagne and coworkers measured metabolic changes that cancer cells undergo when cultured in suspension. Consistent with a study by the DeBerardinis lab (Jiang et al., 2016Jiang L. Shestov A.A. Swain P. Yang C. Parker S.J. Wang Q.A. Terada L.S. Adams N.D. McCabe M.T. Pietrak B. et al.Reductive carboxylation supports redox homeostasis during anchorage-independent growth.Nature. 2016; 532: 255-258Crossref PubMed Scopus (367) Google Scholar), detached cancer cells were found to promote reductive carboxylation, a process in which the TCA cycle is driven in reverse. While the previous study focused on the regeneration of NADPH molecules by reductive carboxylation as a mechanism of adaptation to loss of matrix attachment, this study showed that NAD+ was also regenerated at a higher rate due to cytosolic NAD+ recycling through LDHA and MDH1. The increased abundance of NAD+ was linked to a shift to, and dependency on, glycolytic metabolism. These findings demonstrate an unappreciated connectivity between reductive carboxylation and glycolysis to promote cancer cell survival during metastasis. Interestingly, the authors observed another alteration associated with detachment—severe damage to mitochondria. They proposed that the dependency of detached tumor cells on glycolysis was due not only to the metabolic rewiring involving NAD+ supply, but also to mitochondrial damage, which confers a reliance on glycolysis for energy generation. To investigate the mechanism involved in the switch to glycolysis, the authors examined the role of clustering in regulating metabolism since detachment enhances cancer cell clustering and clustering promotes metastatic spread (Gkountela et al., 2019Gkountela S. Castro-Giner F. Szczerba B.M. Vetter M. Landin J. Scherrer R. Krol I. Scheidmann M.C. Beisel C. Stirnimann C.U. et al.Circulating tumor cell clustering shapes DNA methylation to enable metastasis seeding.Cell. 2019; 176: 98-112.e14Abstract Full Text Full Text PDF PubMed Scopus (419) Google Scholar). Interestingly, clustering of cancer cells was found to result in a hypoxic environment, stabilization of the transcription factor Hif1α, and mitophagy-mediated clearance of damaged mitochondria (Zhang et al., 2008Zhang H. Bosch-Marce M. Shimoda L.A. Tan Y.S. Baek J.H. Wesley J.B. Gonzalez F.J. Semenza G.L. Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia.J. Biol. Chem. 2008; 283: 10892-10903Crossref PubMed Scopus (1283) Google Scholar). Finally, the authors investigated the mechanisms whereby these alterations in detached cells promote survival. Clearance of damaged mitochondria and the switch to reductive carboxylation and glycolysis were found to prevent the accumulation of oxidative stress and promote metastatic growth both in vitro and in vivo. This is consistent with previous studies showing that buffering of oxidative stress is critical for survival of normal and tumor cells in suspension (Hawk and Schafer, 2018Hawk M.A. Schafer Z.T. Mechanisms of redox metabolism and cancer cell survival during extracellular matrix detachment.J. Biol. Chem. 2018; 293: 7531-7537Crossref PubMed Scopus (48) Google Scholar) as well as metastatic spread of tumors (Le Gal et al., 2015Le Gal K. Ibrahim M.X. Wiel C. Sayin V.I. Akula M.K. Karlsson C. Dalin M.G. Akyürek L.M. Lindahl P. Nilsson J. Bergo M.O. Antioxidants can increase melanoma metastasis in mice.Sci. Transl. Med. 2015; 7: 308re8Crossref PubMed Scopus (422) Google Scholar, 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 (739) Google Scholar). While mitophagy is shown here to reduce reactive oxygen species (ROS), mitophagy mediated by RIPK1 in detached cells has also been shown to increase ROS and promote non-apoptotic death due to reduction of NADPH production (Hawk et al., 2018Hawk M.A. Gorsuch C.L. Fagan P. Lee C. Kim S.E. Hamann J.C. Mason J.A. Weigel K.J. Tsegaye M.A. Shen L. et al.RIPK1-mediated induction of mitophagy compromises the viability of extracellular-matrix-detached cells.Nat. Cell Biol. 2018; 20: 272-284Crossref PubMed Scopus (52) Google Scholar). This suggests a delicate balance between positive and negative consequences of elevated mitophagy. It also raises the question of whether there is a tipping point at which damaged mitochondria generate excessive oxidative stress to damage adjacent mitochondria, generating a feedforward loop. In addition, Hif1α can not only promote mitophagy, but also directly promote a shift to glycolysis by increasing the transcription of PDK1 (Kim et al., 2006Kim J.W. Tchernyshyov I. Semenza G.L. Dang C.V. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia.Cell Metab. 2006; 3: 177-185Abstract Full Text Full Text PDF PubMed Scopus (2593) Google Scholar). Thus, Hif1α could work in conjunction with increased reductive carboxylation, as well as the numerous other Hif1α targets, including those that suppress mitochondrial biogenesis (Zhang et al., 2007Zhang H. Gao P. Fukuda R. Kumar G. Krishnamachary B. Zeller K.I. Dang C.V. Semenza G.L. HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity.Cancer Cell. 2007; 11: 407-420Abstract Full Text Full Text PDF PubMed Scopus (676) Google Scholar), to regulate metabolism and survival. Furthermore, Hif2α, which is also induced by hypoxia, could also contribute to survival of cancer cells upon matrix detachment. In addition, other transcription factors, such as NFE2L2 (NRF2), NFkB, and HSF1, can also alleviate oxidative stress and could potentially coordinate with Hif1α, or act independently, to promote survival of detached cells. Lastly, these findings raise the question of whether hypoxia is important for survival in other contexts in which cells lose their natural matrix attachments, such as with glandular tissues when hyperproliferative cells grow into a lumen or at distant organs after metastatic seeding. The finding that hypoxic programs promote survival under conditions of detachment represents a previously unrecognized mechanism for tumor cell anchorage-independent survival and presents an interesting paradigm—that is, that clustering of cancer cells upon matrix detachment promotes induction of a stress condition (hypoxia), which in turn alleviates another stress (oxidative stress). Similar mechanisms of adaptation to metabolic stress caused by targeted cancer therapeutics have been shown to induce drug resistance (Muranen et al., 2012Muranen T. Selfors L.M. Worster D.T. Iwanicki M.P. Song L. Morales F.C. Gao S. Mills G.B. Brugge J.S. Inhibition of PI3K/mTOR leads to adaptive resistance in matrix-attached cancer cells.Cancer Cell. 2012; 21: 227-239Abstract Full Text Full Text PDF PubMed Scopus (302) Google Scholar). One question is whether the findings of Labuschagne and colleagues can be clinically translated to impair metastasis by preventing clustering of cancer cells or blocking the metabolic rewiring required for survival in suspension. This represents a significant challenge since metastasis prevention requires chronic therapies without morbidity and as such might be difficult to achieve. Nonetheless, the insights gained from this study provide information critical for understanding fundamental mechanisms of metastasis. Cell Clustering Promotes a Metabolic Switch that Supports Metastatic ColonizationLabuschagne et al.Cell MetabolismAugust 22, 2019In BriefLabuschagne et al. show that the clustering of cancer cells following detachment from the extracellular matrix (ECM) results in hypoxia, which activates mitophagy to remove damaged mitochondria and reductive metabolism to support glycolysis. These responses limit mitochondrial ROS production, allowing cell survival and metastasis. Full-Text PDF Open Access