Metastatic dissemination and progression is by far the most common cause of patients’ demise from prostate and breast tumors.
The focus of my research is the identification of novel biomarkers and therapeutic targets for the management and therapy of metastatic disease. We are particularly interested in the dissemination and growth of cancer cells in secondary organs such as skeleton, lungs and brain.
My laboratory pursues a translational approach by employing cellular and molecular biology techniques combined with pre-clinical models of cancer growth and dissemination. Particular emphasis is placed on mechanism of activation and downstream signaling of both tyrosine kinase and G protein-coupled receptors.
A first line of investigation concerns the functional interactions between the chemokine fractalkine and its receptor CX3CR1. We were the first to report the expression of CX3CR1 by both prostate and breast cancer cells and its chemokine ligand by the bone stroma. In addition, our group showed that this chemokine-receptor pair is implicated in both adhesion of cancer cells to the endothelial wall of the bone marrow sinusoids and their extravasation in the surrounding tissue.
Through collaborative efforts we are currently screening novel small-molecule inhibitors of CX3CR1 with the ultimate intent of identifying compounds that effectively counteract the seeding of prostate and breast cancer cells at the skeletal level.
A second major project is focused on the identification of molecular factors supporting the survival and growth of disseminated cancer cells and their progression into metastatic lesions.
Our group reported that bone-metastatic prostate cancer cells express high levels of alpha receptor for platelet-derived growth factor (PDGFR) and that targeting PDGFR with a humanized monoclonal antibody reduces bone metastases by 70% in animal models. Based on the strong evidence provided by our pre-clinical data, Eli Lilly is currently conducting phase II clinical trials with the antibody IMC-3G3 (Olaratumab) for advanced prostate adenocarcinoma.
Furthermore, we have also identified PDGFR-regulated genes that directly induce metastatic behavior in prostate cancer cells and represent potential therapeutic targets to counteract metastatic disease.
"Convergence of oncogenic and hormone receptor pathways promotes pro-metastatic phenotypes"
Augello MA, Burd CJ, Birbe R, McNair C, Ertel A, Magee MS, Frigo DE, Wilder-Romans K, Shilkrut M, Han S, Jernigan DL, Dean JL, Fatatis A, McDonnell DP, Visakorpi T, Feng FY, and Knudsen KE
Journal of Clinical Investigation 123, 493-508 (2012).
"The chemokine receptor CX3CR1 is directly involved in the arrest of breast cancer cells to the skeleton"
Jamieson WL, Zhang Y, Fong AM, Meucci O, and Fatatis A
Breast Cancer Research 13, R91 (2011).
"Targeting the alpha receptor for Platelet-Derived Growth Factor as a primary or combination therapy in a preclinical model of prostate cancer skeletal metastasis"
Russell MR, Liu Q and Fatatis A
Clinical Cancer Research 16, 5002-5010 (2010).
"The alpha receptor for Platelet Derived Growth Factor confers bone-metastatic potential to prostate cancer cells by ligand- and dimerization-independent mechanisms"
Russell MR, Liu Q, Lei H, Kazlauskas A and Fatatis A
Cancer Research 70, 4195-4203 (2010).
"Osteoblasts modulate Ca2+ signaling in bone-metastatic prostate and breast cancer cells"
D'Ambrosio J, Fatatis A
Clin. Exp. Metastasis 26, 955-964 (2009)
"Antibody-mediated blockade of Platelet Derived Growth Factor Receptor inhibits early prostate skeletal metastases"
Russell MR, Jamieson WL, Dolloff NG, and Fatatis A
Oncogene 28: 412-421 (2009).
"The CX3CR1 receptor is expressed by the prostate gland as its chemokine ligand fractalkine is detected in bone marrow and cleaved by an androgen-dependent mechanism: potential role in skeletal metastasis from prostate adenocarcinoma"
Jamieson WL Shimizu S, D’Ambrosio JA, Meucci O and Fatatis A
Cancer Research 68, 1715-1722 (2008)
"Human bone marrow activates the Akt pathway in metastatic prostate cells through transactivation of the alpha Platelet-derived Growth factor receptor"
Dolloff NG, Russell MR, Loizos N and Fatatis A
Cancer Research 67, 555-562. (2007).
“Bone-metastatic potential of human prostate cancer cells correlates with Akt/PKB activation by alpha Platelet Derived Growth Factor Receptor”
Dolloff NG Shulby SS, Nelson AV, Stearns ME, Johannes GJ, Thomas JD, Meucci O and Fatatis A
Oncogene, 24: 6848-54 (2005).
“CX3CR1-fractalkine expression regulates cellular mechanisms involved in adhesion, migration and survival of human prostate cancer cells"
Shulby SA, Dolloff NG, Stearns ME, Meucci O, and Fatatis A
Cancer Research, 64:4693-4698 (2004).