Cancer cells departing from primary tumors spread throughout the body using blood and lymphatic circulations. The selective arrest in capillary beds and seeding of distant organs both depend on a variety of molecules and mechanisms. Cancer cells adhere to the wall of blood vessels via recognition of specific adhesion molecules and exit the circulation in response of chemotactic factors generated by normal cells residing in the surrounding tissue stroma. Following extravasation, disseminated tumor cells must rapidly adapt to the new microenvironment, as failing to do so will lead to either death or dormancy. This cellular adaptation depends on the effective utilization of trophic factors that are either already present in the new microenvironment or produced by the stroma in response to signals spawned by the disseminated cancer cells.
Delineate the functional interactions among heterologous cancer cells in metastatic lesions and define the supportive role of the tissue stroma in the metastatic niche.
We initially discovered that bone-tropic prostate cancer cells express high levels of the alpha-receptor for Platelet-Derived Growth Factor (PDGFRα) Oncogene, 2005 and that the exogenous expression of this receptor in low-expressing and non-metastatic cells confers metastatic behavior Oncogene, 2009.
We also reported that this receptor could initiate downstream signaling upon trans-activation by the soluble fraction of bone marrow Cancer Research, 2007 and 2010.
Furthermore, we showed that targeting PDGFRα with a humanized monoclonal antibody reduced bone metastases by 70% in animal models Clinical Cancer Research 2010. This antibody – named Olaratumab – is currently FDA-approved in combination with doxorubicin (Lartruvo) for soft-tissue sarcoma.
The studies above led us to examine human cancer cells expressing or over-expressing PDGFRα as well as cells with low levels or lacking this receptor. Using genome-wide comparative microarrays analyses we have identified three genes correlated with the metastatic behavior of prostate cancer cells Cancer Research 2013. One of these genes, interleukin-1beta (IL-1β), is responsible for co-opting the bone stroma to support the survival and growth of cancer cells, including malignant phenotypes that lack this cytokine and are incapable of independently colonizing the skeleton Oncogene, 2017.
We are currently determined to define the mechanistic role of IL-1β in supporting initial tumor colonization and/or metastatic progression in the skeleton.
Define the role of the chemokine receptor CX3CR1 in metastatic cancer.
Our lab is currently addressing the role played by CX3CR1 in the seeding and progression of cancer cells to the skeleton. We were the first to report the expression of CX3CR1 by prostate cancer cells and of its chemokine ligand Fractalkine by the human bone stroma Cancer Research, 2004. In addition, we showed that this chemokine-receptor pair is implicated in the adhesion of prostate cancer cells to the endothelial cells of the bone marrow sinusoids and is also functionally regulated by the androgen receptor Cancer Research, 2008.
These initial observations were extended to breast adenocarcinoma, and revealed the crucial role of CX3CR1 in the arrival and initial lodging of circulating breast cancer cells to bone by using both transgenic mice knockout for Fractalkine and functional mutants of CX3CR1 Breast Cancer Research, 2011.
We are currently pursuing a drug-discovery program focused on small-molecule antagonists of CX3CR1 and – using clinically relevant animal models of human disease – have shown that pharmacologic targeting of CX3CR1 impairs seeding and progression of breast cancer metastasis and extends overall survival Molecular Cancer Research, 2016.