The Goldman Laboratory
The Goldman laboratory extensively utilizes state-of-the-art high resolution mass spectrometry to study metabolic and lipid changes in cancer and infectious diseases in collaboration with researchers at Wistar and many other institutions. Most projects are systems-level studies that assimilate data from multiple sources to better understand the mechanisms underlying diseases, to identify potential therapeutic targets, and to uncover putative diagnostic and prognostic biomarkers.
Metabolomics and lipidomics are the study of the set of polar metabolites and lipids (non-polar metabolites), respectively, in a biological system. Unbiased profiling of these small molecules provides insight into metabolic pathways and processes perturbed in disease states that could lead to testable hypotheses for disease progression or therapy response. Alternatively, these methods can confirm findings suggested by orthogonal assays such as transcriptomics or proteomics. Use of these techniques has exponentially increased in recent years as mass spectrometry technologies have enabled greater depth of analysis and more confident identification of specific metabolites and lipids.
Motivated candidates are encouraged to inquire about the positions below by contacting Dr. Goldman at firstname.lastname@example.org
A Postdoctoral Fellow and a Research Assistant position are available to work on multiple ongoing projects in the Goldman laboratory. The research focus of these positions could include (depending upon interest and expertise): small molecule omics studies of melanoma tumor progression and resistance to therapies; pregnancy biomarker validation; and/or implementation of new and improved mass spectrometry-based analyses of polar metabolites and lipids (see project descriptions above). Postdoctoral Fellow candidates should have recently received or be close to obtaining their Ph.D. degree (or equivalent) and have a strong background in small molecule mass spectrometry. Research Assistant candidates should have a B.S. degree in biochemistry or equivalent. Experience with MS is preferred but not required.
The Goldman laboratory is focused on improving both mass spectrometry-based metabolomics and lipidomics methods and applying these state-of-the-art methods to a wide-range of collaborative studies investigating cancers including ovarian, pancreatic, prostate, melanoma, and leukemia, as well as infectious diseases including HIV and COVID-19. A combination of untargeted and targeted approaches both at steady-state and using isotopic labeling (flux analysis) have led to important findings associated with disease progression and treatment, including changes in energy metabolism, perturbation of specific macromolecule biosynthesis pathways, and extensive lipid remodeling. Results of mass spectrometry studies have often been used to validate findings from RNAseq and other orthogonal approaches, and integration with other data sets has yielded combinatorial biomarkers.
Major areas of interest:
LIPID REMODELING IN TUMOR PROGRESSION AND THERAPY RESISTANCE IN MELANOMA
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.
THE ROLE OF THE GUT MICROBIOME IN DISEASE
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.
DISCOVERY AND VALIDATION OF EARLY PREGNANCY BIOMARKERS
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.
EMERGING MS TECHNOLOGIES FOR SMALL MOLECULE STUDIES
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.
Agarwal, E., Goldman, A.R., Tang, H.Y., Kossenkov, A.V., Ghosh, J.C., Languino, L.R., Vaira, V., Speicher, D.W., Altieri, D.C. “A Cancer Ubiquitome Landscape Identifies Metabolic Reprogramming as Target of Parkin Tumor Suppression.” Sci Adv. 2021 Aug 25;7(35):eabg7287. doi: 10.1126/sciadv.abg7287. Print 2021 Aug.
Di Marcantonio, D., Martinez, E., Kanefsky, J.S., Huhn, J.M., Gabbasov, R., Gupta, A., Krais, J.J., Peri, S., Tan, Y., Skorski, T., et al. “ATF3 Coordinates Serine and Nucleotide Metabolism to Drive Cell Cycle Progression in Acute Myeloid Leukemia.” Mol Cell. 2021 Jul 1;81(13):2752-2764.e6.doi: 10.1016/j.molcel.2021.05.008. Epub 2021 Jun 2.
Giron, L.B., Dweep, H., Yin, X., Wang, H., Damra, M., Goldman AR, Gorman N, Palmer CS, Tang HY, Shaikh MW, et al. “Plasma Markers of Disrupted Gut Permeability in Severe COVID-19 Patients.” Front Immunol. 2021 Jun 9;12:686240. doi: 10.3389/fimmu.2021.686240. eCollection 2021.
Alicea, G.M., Rebecca, V.W., Goldman, A.R., Fane, M.E., Douglass, S.M., Behera, R., Webster, M.R., Kugel, C.H. 3rd, Ecker, B.L., Caino, M.C., et al. “Changes in Aged Fibroblast Lipid Metabolism Induce Age-Dependent Melanoma Cell Resistance to Targeted Therapy via the Fatty Acid Transporter FATP2.” Cancer Discov. 2020 Sep;10(9):1282-1295. doi: 10.1158/2159-8290.CD-20-0329. Epub 2020 Jun 4.
Rebecca, V.W., Nicastri, M.C., Fennelly, C., Chude, C.I., Barber-Rotenberg, J.S., Ronghe, A., McAfee, Q., McLaughlin, N.P., Zhang, G., Goldman, A.R., et al. “PPT1 Promotes Tumor Growth and Is the Molecular Target of Chloroquine Derivatives in Cancer.” Cancer Discov. 2019 Feb;9(2):220-229. doi: 10.1158/2159-8290.CD-18-0706. Epub 2018 Nov 15.
Alessandro Gardini, Ph.D.
Associate Professor, Gene Expression & Regulation Program, Ellen and Ronald Caplan Cancer Center