UC San Diego

Chemokines have been a long-standing interest in the field of immunology due to their role in directing the migration of immune cells. Approximately a decade ago, chemokines and their receptors became a major focus area in cancer biology due to their role in directing the "migration", or metastasis, of cancer cells from tissues of origin to distant sites. A renewed interest in the role of chemokines in cancer has come with the expanding field of the tumor microenvironment, in particular, with a drive towards understanding the contributions of non-cancerous stromal cells, immune cells, and extracellular matrix components to the survival, growth, proliferation and invasive properties of cancer cells. These constituents of the microenvironment are known to release a variety of molecules including cytokines, growth factors, proteases and chemokines that modulate the growth and development of tumors. My dissertation work has focused on understanding the role of chemokines and their receptors in the cell survival, proliferation, and metastasis of cancer cells. Specifically, I have examined the functions and signaling pathways induced by the chemokine CXCL12 and its receptors, CXCR4 and CXCR7, in two types of cancer: Chronic Lymphocytic Leukemia (CLL) and breast cancer. To this end, a variety of traditional cellular biology, molecular biology and pharmacological approaches as well as more global phosphoproteomics methods were employed. Overall, this work demonstrates the importance of CXCL12 to the survival and malignancy of CLL and unveils numerous potential molecular targets for therapeutic intervention, including the proposed use of a multi-kinase inhibitor, sorafenib, for treatment of CLL. Additionally, investigation of the individual and combined contributions of CXCR4 and CXCR7 to breast cancer progression has provided insight into some important signaling differences and cross-modulation of these receptors. Using a mouse model for metastasis, we have demonstrated that although high CXCR4 expression promotes breast cancer metastasis, co-expression with high levels of CXCR7 dramatically reduces metastasis without reducing primary tumor growth. Mechanisms by which CXCR7 may modulate CXCR4 function are also explored. A better understanding of how chemokines function in the context of health and disease may provide promising leads for future drug discovery