Chemokines are small signaling proteins secreted by cells of the immune system. They affect the migratory pattern and positioning of immune cells and are required for health. The receptors that respond to chemokine gradients, known as chemokine receptors, are classically expressed by white blood cells, however, these receptors become deregulated in cancer. Healthy cells at distant sites can secrete chemokines that attract the cancer cells overexpressing chemokine receptors in the process known as metastasis. Aberrant chemokine receptor expression supports tumor growth, altering the microenvironment of the tumor and providing cancer cells a survival advantage. Targeting chemokine receptors and disrupting their interaction with associated proteins may result in improved treatment efficacy for cancer and many other inflammation-related diseases.
Project One- describing the role chemokine receptors play in cancer health disparities across racially and socioeconomically diverse groups:
We are specifically interested in the chemokine receptors ACKR3 and CXCR4, two proteins known to be contributors to breast cancer progression. In recent findings we identified ACKR3 and CXCR4 being differentially expressed in sub-sets of tumor cells. In addition, we find that ACKR3 and CXCR4 are expressed in opposing directions in breast cancer tumor tissues from different racial groups. However, the control of these factors, ACKR3 and CXCR4, across different racial groups is not understood. There is an unmet need for studies that assess the tumor variations produced within our bodies, known as tumor microenvironment effects. These studies are necessary to make more informed choices when developing the best treatment options to significantly improve patients’ treatments and quality of life, regardless of what social or racial group they are part of. This project will assess how the tumor variations across different racial groups affect the control of two important chemokine receptors highly relevant to breast cancer and by default, also illustrate these receptor’s contribution to the observed racial disparities in breast cancer outcomes.
Project Two– Analyzing the relationship of antibody structure with function:
Antibodies and FC-fusion proteins are at the forefront of biomedical research as some of the best treatments available for many cancers and inflammatory disease. Antibodies activate innate immune processes including antibody dependent cellular cytotoxicity and antibody dependent cellular phagocytosis. Monoclonal antibodies may also induce complement-dependent cytotoxicity and inhibition of survival signals to trigger apoptosis; and due to their evolution-optimized properties, they are biologically active in vivo longer than small molecules. Antibodies depend heavily on the glycan (sugar chain) modifications of their FC-(Fragment crystallizable) region to exert their properties. In this project we will classify, phenotypically and structurally, the modifications that enhance the anti-tumor activity of the parent antibody against chemokine receptors.
Project Three- identifying tumor and tumor-endothelial-cell markers to assess their interactions with cancer cells:
The cells that support tumor-associated vessels, known as tumor endothelial cells, are not part of the initial cancer clone and are less likely to develop resistance to therapies. Expression profiling shows altered profiles in tumor endothelial cells, revealing that this specialized type of cell, although not cancer originally, is integral to cancer progression. We are identifying chemokine receptor-associated proteins in this cell type to determine whether antibody-dependent antagonism disrupts interactions with cancer cells.
Our research is supported by: