Aaron R. Goldman, Ph.D.

A primary focus of the Goldman laboratory is collaborating with other researchers to define the role that lipid metabolism plays in melanoma progression and therapy resistance. In one such academic collaboration with researchers at the University of Pennsylvania, specific lipid metabolism pathways were implicated as being affected by lysosomal autophagy inhibition by using a combination of proteomic and lipidomic approaches. Efforts are ongoing to define the mechanisms by which autophagy modulation regulates lipid metabolism using small molecule activators and inhibitors. Combinatorial inhibition of lipid metabolism pathways and lysosomal autophagy is being pursued as a putative therapeutic strategy to mitigate therapy resistance in melanoma.

There is a growing field of research on the interplay between gut microbiota and human health. Recent work has found that the gut microbiome plays roles in tumor biology, infectious diseases, and immune response. Collaborative projects at Wistar led by the laboratories of Drs. Rahul Shinde and Mohamed Abdel-Mohsen have uncovered links between gut microbiota and gut-derived products with pancreatic cancer and COVID-19, respectively. Examples of key gut-derived products uncovered by untargeted metabolomic profiling are trimethylamine N-oxide, which is produced primarily from dietary choline, and various metabolites of tryptophan. The Goldman laboratory is actively developing and implementing methods to expand coverage of gut-derived products to 1) short-chain fatty acids (SCFA; two to six carbons) that regulate cell homeostasis and have been implicated in multiple cancers and other diseases such as HIV and 2) bile acids that are involved in lipid digestion and absorption and are subject to on-going research for their roles in cancer development and progression as well as potential therapeutic applications.

A major clinical challenge in early pregnancy is to distinguish normal intrauterine pregnancy (IUP) from abnormal conditions when ultrasound is not diagnostic. Women with early-stage pregnancy who experience abdominal pain and vaginal bleeding might have: 1) an ongoing viable IUP, 2) a non-viable intrauterine pregnancy or spontaneous abortion (SAB), or 3) ectopic pregnancy (EP). EP occurs in 1-2% of pregnant women and causes 6% of pregnancy-related deaths, while SAB affects 10-20% of pregnancies. Because clinical treatment for these possible outcomes differs greatly, it is critical that an accurate diagnosis is made as early as possible. With researchers from the University of Pennsylvania, we are performing mass spectrometry-based studies to identify putative early pregnancy protein, metabolite and/or lipid biomarkers. The end goal is to develop a novel, multiplexed, MS-based plasma biomarker test for early and accurate diagnosis of pregnancy outcome. Targeted proteomics is being used to validate previously identified candidate biomarkers with a focus on distinguishing protein isoforms to increase accuracy, and discovery metabolomics and lipidomics are being pursued to identify additional targets that may complement protein markers in biomarker panels for early pregnancy outcomes.

Ion Mobility (IM). Goldman and his team are actively evaluating different IM implementations for metabolite and lipid studies. A major challenge in the analysis of small molecules is confident annotation of isomers (molecules with the same chemical formula) and isobars (molecules with the same nominal mass at a given resolution). These compounds are indistinguishable by accurate mass, and MS/MS fragmentation is often information-poor and does not generate diagnostic fragments that are unique to a given species. They may also not be resolved by chromatographic separation. A promising emerging technology to distinguish these types of compounds is IM, which separates ions in the gas phase based on their collisional cross-section (CCS), a property derived from the mobility of the ions in an electric field. In addition to separating currently unresolved species, IM provides a fourth dimension of data to annotate detected compounds more confidently in terms of retention time, accurate mass, MS/MS spectra, and CCS. This technology is also applicable to proteomics, where it can be used to separate isomeric peptides ¬– such as those that are phosphorylated on different residues – and reduce sample complexity to increase depth of analysis.

MS Imaging. Goldman and his team are evaluating alternative instruments and approaches for tissue imaging of metabolites, lipids, and other biomolecules. Tumors are heterogenous and determination of the spatial distribution of biomolecules may provide insights into disease states and allow for stratification of patients by tumor molecular signatures for tailored treatment options. Imaging mass spectrometry (MS) uses a matrix-assisted laser desorption/ionization (MALDI) source to visualize lipids, metabolites, and peptides directly or visualize proteins and glycans with additional processing (enzymatic digestion) at 5-10 µm resolution. Analyte patterns can be compared between conditions to identify important biomolecules and define molecular signatures. These data can be used to select regions for more in-depth study using laser microdissection followed by traditional LC-MS approaches and correlated with orthogonal assays such as immunohistochemistry. Recent instruments support IM and MS/MS fragmentation to allow for higher confidence annotation of analytes.