Peter Espenshade, Ph.D.
Department of Cell Biology
Johns Hopkins University School of Medicine
855 N. Wolfe Street, 432 Rangos
Baltimore, MD 21205
Research Topic: Regulation of nutrient sensing and metabolic homeostasis
Our laboratory’s research focuses on understanding (1) how cells measure levels of available nutrients and (2) how cells adapt to changes in nutrient supply to control metabolic homeostasis. Our studies have primarily centered on changes in cholesterol and oxygen supply.
Elevated blood cholesterol is a primary risk factor for heart disease, and overaccumulation of cholesterol and fatty acids is toxic to cells. A negative feedback mechanism prevents excessive lipid accumulation in cells by regulating sterol regulatory element-binding proteins (SREBPs), a family of membrane-bound transcription factors that activate genes required for cholesterol and fatty acid synthesis and uptake of cholesterol-rich lipoproteins. Using yeast genetics as a discovery tool, we found that fungal SREBPs respond to environmental oxygen and control cellular adaptation to hypoxia. The fungal SREBP pathway is required for hypoxic growth and importantly for host infection by fungal pathogens, making it a candidate antifungal drug target.
Solid tumors are poorly vascularized, leading to hypoxia and limited nutrient supply. Further, lipid synthesis is highly oxygen-consumptive, so neoplastic cells in a hypoxic environment are challenged with meeting the demand for lipid supply. Our discoveries in fungi motivated us to extend our studies to mammalian cells in order to examine (1) whether the SREBP pathway also responds to hypoxia in mammals and (2) whether SREBPs are required for cancer initiation, progression, and metastasis.
Current project areas:
Mechanisms for regulation of SREBPs – Using genetics and cell biology, we are searching for new regulators of the SREBP pathway and cellular lipid homeostasis.
SREBP pathway as a therapeutic target in cancer – Using xenograft and genetically engineered mouse models, we are testing whether SREBPs are required for cancer initiation, tumor growth, and metastasis. In parallel, we are developing chemical inhibitors of the pathway as potential cancer therapeutics.
RECENT PUBLICATIONS:
Peña de la Sancha P, Wieser BI, Schauer S, Reicher H, Sattler W, Breinbauer R, Schweiger M, Lechleitner M, Frank S, Zechner R, Kratky D, Espenshade PJ, Hoefler G, Vesely PW. Lipolysis-derived fatty acids are needed for homeostatic control of sterol element-binding protein-1c driven hepatic lipogenesis. Commun Biol. 2025 Apr 9;8(1):588. doi: 10.1038/s42003-025-08002-1.
Phulara NR, Ishida CT, Espenshade PJ, Seneviratne HK. Gemcitabine Alters Phosphatidylcholine Metabolism in Mouse Pancreatic Tumors. J Proteome Res. 2025 Mar 7;24(3):1209-1218. doi: 10.1021/acs.jproteome.4c00839.
Ishida CT, Myers SL, Kubota CS, Shao W, McGuire MR, Liu C, Ewachiw TE, Mukhopadhyay D, Ke S, Wang H, Rasheed ZA, Anders RA, Espenshade PJ. SREBP-Dependent Regulation of Lipid Homeostasis Is Required for Progression and Growth of Pancreatic Ductal Adenocarcinoma. Cancer Res Commun. 2024 Sep 1;4(9):2539-2552. doi: 10.1158/2767-9764.CRC-24-0120.
Ishida CT, Kubota CS, Carlyle E, Tsukamoto T, Espenshade PJ. A High-Throughput Screening Platform Identifies FDA-Approved Drugs That Inhibit SREBP Pathway Activation. ACS Chem Biol. 2024 Aug 16;19(8):1695-1704. doi: 10.1021/acschembio.4c00354.
Kubota CS, Myers SL, Seppälä TT, Burkhart RA, Espenshade PJ. In vivo CRISPR screening identifies geranylgeranyl diphosphate as a pancreatic cancer tumor growth dependency. Mol Metab. 2024 Jul;85:101964. doi: 10.1016/j.molmet.2024.101964.
Phulara NR, Ishida CT, Espenshade PJ, Seneviratne HK. Cytosolic 5′-Nucleotidase III and Nucleoside Triphosphate Diphosphohydrolase 1 Dephosphorylate the Pharmacologically Active Metabolites of Gemcitabine and Emtricitabine. Drug Metab Dispos. 2024 Mar 13;52(4):288-295. doi: 10.1124/dmd.123.001508. PubMed PMID: 38331874.
CT, Shao W, Espenshade PJ. Assaying Sterol-Regulated ER-to-Golgi Transport of SREBP Cleavage-Activating Protein Using Immunofluorescence Microscopy. Methods Mol Biol. 2023;2557:755-764. doi: 10.1007/978-1-0716-2639-9_45.
Bolshette N, Ezagouri S, Dandavate V, Karavaeva I, Golik M, Wang H, Espenshade PJ, Osborne TF, Han X, Asher G. Carbon dioxide regulates cholesterol levels through SREBP2. PLoS Biol. 2023 Nov;21(11):e3002367. doi: 10.1371/journal.pbio.3002367.
Osborne TF, Espenshade PJ. Lipid balance must be just right to prevent development of severe liver damage. J Clin Invest. 2022 Jun 1;132(11). doi: 10.1172/JCI160326.
McGuire MR, Mukhopadhyay D, Myers SL, Mosher EP, Brookheart RT, Kammers K, Sehgal A, Selen ES, Wolfgang MJ, Bumpus NN, Espenshade PJ. Progesterone receptor membrane component 1 (PGRMC1) binds and stabilizes cytochromes P450 through a heme-independent mechanism. J Biol Chem. 2021 Nov;297(5):101316. doi: 10.1016/j.jbc.2021.101316.
Shao W, Hwang J, Liu C, Mukhopadhyay D, Zhao S, Shen MC, Selen ES, Wolfgang MJ, Farber SA, Espenshade PJ. Serum lipoprotein-derived fatty acids regulate hypoxia-inducible factor. J Biol Chem. 2020 Dec 25;295(52):18284-18300. doi: 10.1074/jbc.RA120.015238.