Hypoxia Induced Metastasis and the Premetastatic Niche

Niches are defined as particular regions within a defined environment where specialized inhabitants reside. The key points in this definition are “environment” and “specialized inhabitants”. We have accumulated a significant amount of data that implicates an important role for hypoxia in recruiting bone marrow-derived tumor cells through the modulation of the extracellular matrix. Previous studies have suggested that tumor cell metastasis is facilitated by formation of “pre-metastatic niches” in destination organs, comprised of bone marrow-derived cells (BMDCs) such as CD11b+ myeloid cells recruited by poorly defined mechanisms.  We found that lysyl oxidase (LOX) that is secreted by hypoxic tumor cells is essential for BMDC recruitment at pre-metastatic sites. LOX secreted by hypoxic breast tumor cells accumulates at pre-metastatic sites, cross-links collagen-IV in the basement membrane, and is essential for CD11b+ myeloid cell recruitment.  Our findings demonstrate a critical role for hypoxia in formation of the pre-metastatic niche and metastatic disease. We recently discovered that the receptor tyrosine kinase, AXL, is in part regulated by the von Hippel Lindau (VHL) tumor suppressor in ccRCC cell lines. Most importantly, AXL expression in ccRCC patients correlates with the lethal phenotype, strongly indicating an important role for AXL in the pathogenesis of ccRCC. In addition, AXL is an upstream regulator of both SRC and cMET signaling which are independent prognostic factors for poor survival in ccRCC patients. Genetic and pharmacologic inhibition of AXL signaling is sufficient to inhibit ccRCC tumor invasion and metastasis. While these findings establish an important biologic role for AXL in renal metastasis, there is a significant deficit of therapeutic agents that specifically target AXL signaling in the clinic. For this purpose, we produced an ultra-high-affinity soluble AXL (sAXL) FC-fusion protein. In our preclinical studies, we demonstrated that sAXL is a potent and selective inhibitor of GAS6 and is safe in mice.  Furthermore, sAXL blocked GAS6 mediated signaling and tumor cell invasion and produced antitumor efficacy in multiple tumor models. We hypothesize that sAXL, an anti-metastatic agent, will be effective in treating sunitinib sensitive and resistant ccRCC and work in combination with immunotherapy to enhance antitumor efficacy in ccRCC. We are also exploring anti-AXL thertapy in other cancers.

Selected Publications

  1. Erler, J.T., Bennewith, K.L., Nicolau, M., Dornhoefer, N., Kong, C., Le, Q-T., Chi, J-T.A., Jeffrey, S.J. and Giaccia, A.J.  Lysyl oxidase is essential for hypoxia-induced metastasis.  Nature 440:1222-1226, 2006 (PMID: 16642001).
  2. Erler, J.T., Bennewith, K.L., Cox, T.R., Lang, G., Bird, D., Koong, A., Le, Q.T. and Giaccia, A.J.  Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the pre-metastatic niche.  Cancer Cell 15:35-44, 2009 (PMCID: PMC3050620).
  3. Kariolis, M.S., Miao, Y.R., Jones II, D.S., Kapur, S., Matthews, I.I., Giaccia, A.J., and Cochran, J.R. An engineered Axl “decoy receptor’ effectively silences the Gas6/Axl signaling axis. Nat Chem Biol 10:977-983, 2014 (PMCID: PMC4372605).
  4. Rankin, E., Fuh, K.C., Castellini, L., Viswanathan, K., Finger, E.C., Diep, A., LaGory, E., Kariolis, M., Chan, A., Lindgren, D., Axelson, H., Miao, Y, Krieg, A., and Giaccia, A.J.  Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET.  Proc Natl Acad Sci USA 111:13373-13378, 2014
  5. Rankin, E.B. and Giaccia, A.J.  Hypoxic control of metastasis. Science 352:175-180, 2016
  6. Rankin, E.B. Nam, J-M. and Giaccia, A.J.  Hypoxia:  Signaling the Metastatic Cascade.  Trends in Cancer doi: 10.1016/j.trecan.2016.05.006.
  7. Johnson, R.W., Finger, E.C., Olcina, M., Vilalta, M., Aguilera, T., Miao, Y., Merkel, A.R., Johnson, J.R., Sterling, J.A., Wu, J.Y. and Giaccia, A.J.   Induction of leukemia inhibitory factor receptor (LIFR) confers a dormancy phenotype in breast cancer cells disseminated to the bone marrow. Nature Cell Biology (in press).