The Angel Lab
All eukaryotic cells are surrounded by an extracellular matrix (ECM) composed of secreted collagens, elastin, and a mixture of glycoproteins. Translational and post-translational regulation of ECM proteins are the basis for functional differences in tissues during development and disease. My laboratory group, in collaboration with other MUSC Proteomic Center investigators, Drs. Richard Drake and Anand Mehta, works on approaches to understand ECM proteins in large clinical cohorts as prognostic and diagnostic markers in disease.
RESEARCH METHODS (Figure 1):
1. Deciphering the “collagen switch” in racial disparities of breast cancer.
Although European-American (EA) women have a higher incidence of breast cancer, African-American (AA) women have higher mortality rates with increased occurrence of lethal cancers at a younger age. AA women have significantly greater odds of high breast density, a breast cancer risk factor, compared to EA women. Increasing breast density is due to increased production of extracellular matrix proteins, especially collagens. In breast cancer, stroma composition may become denser due to aberrant myoepithelial-luminal regulation of stroma collagens and later abnormal regulation of fibrillary collagen by infiltrating macrophages. Detailed microscopy work has suggested the presence of a “collagen switch” whereby collagen proteins surrounding the tumor are re-organized to facilitate metastatic spread of cancer activated fibroblasts. However, although microscopy work links the “collagen switch” to decreased survival, the mechanisms that allow this process are unknown. The “collagen switch” has not yet been evaluated for contributions to racial disparities in breast cancer. A main challenge has been a lack of analytical methods that access sequence information, such as site mutation and post-translational modifications, from extracellular matrix proteins
2. Development of high throughput N-glycan assays by imaging mass spectrometry.
Around the world, dozens of laboratories are engaged in biomarker research by MS profiling of N-glycoforms from tissue (e.g., method by the Drake lab at MUSC 2013, Powers et al, Analytical Chemistry; Everest-Dass et al., 2016; Gustafsson et al., 2015; Heijs et al., 2016; Holst et al., 2016; Scott et al, 2018; Briggs et al, 2016; deHaan et al, 2015; West et al, 2018). Once an N-glycoform has been detected as regulated in tumor, the study typically moves to the next phase of characterizing the glycoforms at that mass. However, once a biomarker N-glycan has been discovered, it takes several days and millions of cells to derivatize and analyze cell specific N-glycan expression. This project collaborates with Drs. Drake and Mehta to develop analytical techniques for simplified approaches to N-glycan profiling of cells and biological fluids.
3. Extracellular matrix remodeling in liver, lung and cardiovascular disease.
Fibrosis is a hallmark of disease progression in many organs, but particularly the heart, liver and lung. Fibrosis is defined as deregulated secretion of extracellular matrix proteins that limits the tissue function. Altered extracellular matrix results in changes to cell-specific disease processes such as cell differentiation, migration, and proliferation. Altered cell processes in turn feed back into abnormal extracellular matrix remodeling that progress disease. Understanding cell specific secretion of aberrant extracellular matrix is critical to understanding the cell->extracellular matrix circuitry in disease.
This project further advances imaging mass spectrometry of extracellular matrix proteomics by defining cell type niches that produce aberrant collagen. This project focuses specifically on determining new ways to quantitatively measure post-translational regulation and site mutations of collagen type I (COL1A1 and COL1A2) and collagen type III (COL3A1) in liver fibrosis, lung adenocarcinoma, and cardiovascular remodeling.