Metastasis is an important clinical challenge, since 90% of cancer patient deaths are due to metastasis, and treatments that prevent or cure metastasis remain elusive. Emerging data indicate that microenvironmental cues, such as hypoxia and the extracellular matrix, may play a critical role in metastasis. During tumorigenesis there is an increase in the deposition of matrix proteins, most notably fibrillar collagens, accompanied by extensive matrix remodeling. The changes in matrix composition and overall content reflect both the biophysical and biological properties of the tumor extracellular matrix, strongly influencing important tumor and stromal cell properties such as proliferation and motility. Our data indicate a direct link between hypoxia and the composition and organization of the extracellular matrix, suggesting that multiple microenvironmental signals converge to synergistically influence metastatic outcome. Our goal is to determine how the hypoxic tumor microenvironment influences matrix production and in turn how hypoxic cells adapt to and overcome the microenvironmental changes.
Gilkes DM, Semenza GL: Role of hypoxia-inducible factors in breast cancer metastasis. Future Oncol 9(11), 1623-1636 (2013).
Gilkes D, Bajpai S, Wong CC et al.: Procollagen lysyl hydroxylase 2 is essential for breast cancer metastasis. Mol Cancer Res, 11(5), 456-466 (2013).
Gilkes DM, Bajpai S, Chaturvedi P, Wirtz D, Semenza GL: HIF-1 promotes extracellular matrix remodeling under hypoxic conditions by inducing P4HA1, P4HA2, and PLOD2 expression in fibroblasts. J Biol Chem, 288(15), 10819-10829 (2013).
Gilkes DM, Chaturvedi P, Bajpai S et al.: Collagen prolyl hydroxylases are essential for breast cancer metastasis. Cancer Res, 73(11), 3285-3296 (2013).
Wong CC, Gilkes DM, Zhang H et al.: Hypoxia-inducible factor 1 is a master regulator of breast cancer metastatic niche formation. Proc Natl Acad Sci U S A 108(39), 16369-16374 (2011).