News and Views
The melanoma metastasis X-factor Rizwan Haq and Keith Flaherty e-mail: [email protected]
Decades of work into the molecular causes of melanoma have lead, for the first time, to credible therapies that effectively target melanoma growth and improve clinical outcomes in patients. However, the prognosis of melanoma patients remains dismal, mostly due to the propensity of melanoma to spread to distant tissues. Metastasis of melanoma is almost always fatal, emphasizing that further improving therapeutic outcomes of patients with melanoma will necessitate identification and direct inhibition of the molecular drivers of the metastatic process. Recent advances in targeting melanoma growth stemmed from comprehensive genomic characterization as well as molecular elucidation of crucial immune checkpoints. Comparatively, the paucity of rigorously validated drivers of metastasis has limited development of direct metastatic modulators. Pancheva et al. have now started to fill this void by identifying a functionally important regulator of metastatic spread. Because the identified target is potentially druggable, the results may enable rapid translation and clinical evaluation, albeit in a preventative setting. The authors’ current work follows their earlier study that identified ApoE, a component of cholesterol-carrying lipoprotein particles, as a melanoma metastasis suppressor (Pencheva et al., 2012). Because APOE is directly regulated by several nuclear receptors, they reasoned that available agonists of one or more of these receptors might block metastasis. Chemical and genetic experiments revealed that the most crucial receptor was LXRb (liver X receptor b), a nuclear hormone receptor that is ubiquitously expressed among melanoma cell lines and clinical samples. Interestingly, broad-spectrum agonism of LXRs potently suppressed the size of endothelial vessels present in tumors, modestly suppressed primary melanoma growth, as well as invasion among genetically diverse melanomas subtypes. The authors found that LXRb expressed in stromal tissues, rather than the tumor itself, was required for the effects of
Coverage on: Pencheva N. et al. BroadSpectrum Therapeutic Suppression of Metastatic Melanoma through Nuclear Hormone Receptor Activation. Cell (2014) Feb 27;156(5):986–1001. doi: 10.1111/pcmr.12285
698
LXR agonists in vivo. Finally, the effects of LXR agonists were shown to be mediated by ApoE, as ApoE depletion abolished their activity. While LXRs are known to play important physiologic roles in the regulating cholesterol metabolism, some existing evidence suggests that they may also be pathologic targets in cancer. For example, LXR agonists may directly modulate cell proliferation through stabilizing the cell cycle inhibitor p27Kip1 in prostate cancer and can induce apoptosis in some melanoma cell lines (Liang et al., 2011). Other reports indicate that they may regulate the expression of interferon-c (IFN-c) in macrophages and limits tumor growth in an IFN-c -dependent manner. Yet other studies have reported that agonists of LXR paradoxically promote tumor growth (Zhang et al., 2014). Pencheva et al. are the first to link these receptors to the metastatic process. Together, the diverse roles of LXRs may be explained by the number and differential expression of the LXR receptors, as well as the relative non-specificity of the agonists employed. A strength of the present study is the use of elegant mouse knockout models. Specifically, authors found that the non-selective LXR agonists required LXRb but not LXRa for their beneficial effects. How feasible is direct inhibition of LXRb? Agonism of LXRs to prevent metabolic diseases has been associated with increased triglyceride levels in rodents and hepatic lipogenesis. A new class of LXR agonists were discouraging because the subjects experienced adverse neurological side effects (Steffensen et al., 2013). In all cases, however, these studies used broad-spectrum LXR agonists. The development of LXRb-specific agonists may circumvent some of these issues. Still, LXRb has been shown to play a critical role in endothelial integrity (Ishikawa et al., 2013) and endogenous ligands also regulate innate immunity. Although no overt side effects of LXR agonism was reported in this preclinical study, it will be important to validate these findings in genetically engineered mouse models of melanoma that are now widely available. More rigorous preclinical evaluation using primary, patientderived melanomas (rather than the use of passaged cell lines) will also be needed to justify early phase clinical testing. If these agents were to evolve to the point of readiness for clinical investigation, a large prevention trial might be needed to discern their ability to alter the
natural history of melanoma in high-risk patients who do “a new class of not yet have metLXR agonists astatic disease, as a purely antican potentially metastatic therbe repurposed apy might have to directly little to no impact suppress on the course of metastasis in established metamelanoma.” static disease in patients. Collectively, this work leads to the proposal that a new class of LXR agonists can potentially be repurposed to directly suppress metastasis in melanoma. As Pencheva et al. have noted, this approach has the attraction of synergy with existing therapies that effectively target melanoma proliferation. While our therapeutic armamentarium for melanoma has vastly expanded over the last several years, targeting metastasis with LXRb agonists or other agents may be a worthy approach to continue our progress in defeating melanoma.
References Ishikawa, T., Yuhanna, I.S., Umetani, J., Lee, W.R., Korach, K.S., Shaul, P.W., and Umetani, M. (2013). LXRbeta/estrogen receptor-alpha signaling in lipid rafts preserves endothelial integrity. J. Clin. Invest. 123, 3488–3497. Liang, H., Zhong, Y., Zhou, S., and Li, Q.Q. (2011). Palmitic acid-induced apoptosis in pancreatic beta-cells is increased by liver X receptor agonist and attenuated by eicosapentaenoate. In Vivo 25, 711–718. Pencheva, N., Tran, H., Buss, C., Huh, D., Drobnjak, M., Busam, K., and Tavazoie, S.F. (2012). Convergent multi-miRNA targeting of ApoE drives LRP1/LRP8dependent melanoma metastasis and angiogenesis. Cell 151, 1068–1082. Steffensen, K.R., Jakobsson, T., and Gustafsson, J.A. (2013). Targeting liver X receptors in inflammation. Expert Opin. Ther. Targets 17, 977–990. Zhang, W., Jiang, H., Zhang, J., Zhang, Y., Liu, A., Zhao, Y., Zhu, X., Lin, Z., and Yuan, X. (2014). Liver X receptor activation induces apoptosis of melanoma cell through caspase pathway. Cancer Cell Int. 14, 16.
ª 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
The melanoma metastasis X-factor Rizwan Haq and Keith Flaherty e-mail: [email protected]
Decades of work into the molecular causes of melanoma have lead, for the first time, to credible therapies that effectively target melanoma growth and improve clinical outcomes in patients. However, the prognosis of melanoma patients remains dismal, mostly due to the propensity of melanoma to spread to distant tissues. Metastasis of melanoma is almost always fatal, emphasizing that further improving therapeutic outcomes of patients with melanoma will necessitate identification and direct inhibition of the molecular drivers of the metastatic process. Recent advances in targeting melanoma growth stemmed from comprehensive genomic characterization as well as molecular elucidation of crucial immune checkpoints. Comparatively, the paucity of rigorously validated drivers of metastasis has limited development of direct metastatic modulators. Pancheva et al. have now started to fill this void by identifying a functionally important regulator of metastatic spread. Because the identified target is potentially druggable, the results may enable rapid translation and clinical evaluation, albeit in a preventative setting. The authors’ current work follows their earlier study that identified ApoE, a component of cholesterol-carrying lipoprotein particles, as a melanoma metastasis suppressor (Pencheva et al., 2012). Because APOE is directly regulated by several nuclear receptors, they reasoned that available agonists of one or more of these receptors might block metastasis. Chemical and genetic experiments revealed that the most crucial receptor was LXRb (liver X receptor b), a nuclear hormone receptor that is ubiquitously expressed among melanoma cell lines and clinical samples. Interestingly, broad-spectrum agonism of LXRs potently suppressed the size of endothelial vessels present in tumors, modestly suppressed primary melanoma growth, as well as invasion among genetically diverse melanomas subtypes. The authors found that LXRb expressed in stromal tissues, rather than the tumor itself, was required for the effects of
Coverage on: Pencheva N. et al. BroadSpectrum Therapeutic Suppression of Metastatic Melanoma through Nuclear Hormone Receptor Activation. Cell (2014) Feb 27;156(5):986–1001. doi: 10.1111/pcmr.12285
698
LXR agonists in vivo. Finally, the effects of LXR agonists were shown to be mediated by ApoE, as ApoE depletion abolished their activity. While LXRs are known to play important physiologic roles in the regulating cholesterol metabolism, some existing evidence suggests that they may also be pathologic targets in cancer. For example, LXR agonists may directly modulate cell proliferation through stabilizing the cell cycle inhibitor p27Kip1 in prostate cancer and can induce apoptosis in some melanoma cell lines (Liang et al., 2011). Other reports indicate that they may regulate the expression of interferon-c (IFN-c) in macrophages and limits tumor growth in an IFN-c -dependent manner. Yet other studies have reported that agonists of LXR paradoxically promote tumor growth (Zhang et al., 2014). Pencheva et al. are the first to link these receptors to the metastatic process. Together, the diverse roles of LXRs may be explained by the number and differential expression of the LXR receptors, as well as the relative non-specificity of the agonists employed. A strength of the present study is the use of elegant mouse knockout models. Specifically, authors found that the non-selective LXR agonists required LXRb but not LXRa for their beneficial effects. How feasible is direct inhibition of LXRb? Agonism of LXRs to prevent metabolic diseases has been associated with increased triglyceride levels in rodents and hepatic lipogenesis. A new class of LXR agonists were discouraging because the subjects experienced adverse neurological side effects (Steffensen et al., 2013). In all cases, however, these studies used broad-spectrum LXR agonists. The development of LXRb-specific agonists may circumvent some of these issues. Still, LXRb has been shown to play a critical role in endothelial integrity (Ishikawa et al., 2013) and endogenous ligands also regulate innate immunity. Although no overt side effects of LXR agonism was reported in this preclinical study, it will be important to validate these findings in genetically engineered mouse models of melanoma that are now widely available. More rigorous preclinical evaluation using primary, patientderived melanomas (rather than the use of passaged cell lines) will also be needed to justify early phase clinical testing. If these agents were to evolve to the point of readiness for clinical investigation, a large prevention trial might be needed to discern their ability to alter the
natural history of melanoma in high-risk patients who do “a new class of not yet have metLXR agonists astatic disease, as a purely antican potentially metastatic therbe repurposed apy might have to directly little to no impact suppress on the course of metastasis in established metamelanoma.” static disease in patients. Collectively, this work leads to the proposal that a new class of LXR agonists can potentially be repurposed to directly suppress metastasis in melanoma. As Pencheva et al. have noted, this approach has the attraction of synergy with existing therapies that effectively target melanoma proliferation. While our therapeutic armamentarium for melanoma has vastly expanded over the last several years, targeting metastasis with LXRb agonists or other agents may be a worthy approach to continue our progress in defeating melanoma.
References Ishikawa, T., Yuhanna, I.S., Umetani, J., Lee, W.R., Korach, K.S., Shaul, P.W., and Umetani, M. (2013). LXRbeta/estrogen receptor-alpha signaling in lipid rafts preserves endothelial integrity. J. Clin. Invest. 123, 3488–3497. Liang, H., Zhong, Y., Zhou, S., and Li, Q.Q. (2011). Palmitic acid-induced apoptosis in pancreatic beta-cells is increased by liver X receptor agonist and attenuated by eicosapentaenoate. In Vivo 25, 711–718. Pencheva, N., Tran, H., Buss, C., Huh, D., Drobnjak, M., Busam, K., and Tavazoie, S.F. (2012). Convergent multi-miRNA targeting of ApoE drives LRP1/LRP8dependent melanoma metastasis and angiogenesis. Cell 151, 1068–1082. Steffensen, K.R., Jakobsson, T., and Gustafsson, J.A. (2013). Targeting liver X receptors in inflammation. Expert Opin. Ther. Targets 17, 977–990. Zhang, W., Jiang, H., Zhang, J., Zhang, Y., Liu, A., Zhao, Y., Zhu, X., Lin, Z., and Yuan, X. (2014). Liver X receptor activation induces apoptosis of melanoma cell through caspase pathway. Cancer Cell Int. 14, 16.
ª 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
