Welcome to the Gilkes Lab

Previous studies have implicated hypoxia-induced changes in the composition and stiffness of the extracellular matrix in the metastatic process. We verified that hypoxia induces the expression of integrins that bind to collagen (ITGA1, ITGA11, ITGB1) and fibronectin (ITGA5, ITGB1). Hypoxia-inducible factor 1 (HIF-1) and HIF-2 seem to be required for ITGA5 induction under hypoxic conditions, which leads to enhanced migration and invasion in 3D but not in 2D.

Extracellular matrix (ECM) composition, organization, and compliance provide both architectural and chemical cues that modulate tissue structure and function. Previously, we have demonstrated that P4HA1, P4HA2, and PLOD2 genes mediate remodeling of ECM composition, alignment, and mechanical properties in response to hypoxia. HIF-1-dependent ECM remodeling by hypoxic fibroblasts induces changes in breast cancer cell morphology, adhesion, and motility that promote invasion and metastasis. We are looking for cues regarding ECM impact in cancer cells expression and resistance.

ECM remodeling and hypoxia have been associated with cancer aggressiveness. In this context, we are looking at human samples to determine how important are these contributions.

Human breast tumors contain regions of hypoxia in which cells that are located far from a functional blood vessel have significantly reduced oxygen concentrations when compared with normal mammary tissue. Breast cancer cells adapt to hypoxic conditions by increasing levels of hypoxia-inducible factors (HIFs), which induce the expression of multiple genes involved in angiogenesis, glucose utilization, resistance to oxidative stress, cell proliferation, resistance to apoptosis, invasion and metastasis. Breast cancer patients with increased HIF expression levels in primary tumor biopsies are at increased risk of metastasis. This is an important finding since 90% of breast cancer deaths are the result of metastasis, primarily to the bone, lungs, liver, brain and regional lymph nodes. Although the prognostic significance of reduced oxygen levels in primary breast tumors of cancer patients is well recognized, the underlying mechanisms are to be uncovered. To explore this question further, we are working on a live marking system to keep track of the hypoxic impact in breast cancer metastasis.