The Bensinger laboratory is focused on defining how lipid metabolism influences the ability of immune cells to function properly. Using state-of-the-art mass spectrometry and molecular biology approaches, we have discovered that immune cells rapidly and profoundly reshape their lipid metabolic programs when they recognize foreign invaders. These changes to the lipid architecture of cells are essential for ensuring that invading microorganisms and viruses can be isolated and rapidly cleared from the body. In other instances, we are finding that changes to the lipid composition of immune cells is necessary to turn off the immune response and avoid unwanted inflammation. These findings have led us to ask if manipulating the lipid metabolic machinery of immune cells can help (i) boost immunity when required, such as in cancer immunotherapy, or (ii) shutdown the immune system in autoimmune diseases, such as in lupus or rheumatoid arthritis.
Defining the influence of lipid metabolism in immune cell fate and function.
We have been focused on defining how metabolism influences immune cell function. Over the last 10 years, our studies have described the signal transduction and transcriptional pathways that link immune cell activation to lipid metabolic machinery. This work has also shown that perturbations in an immune cells ability to undergo metabolic reprogramming interferes with their differentiation and function.
Hsieh WY, Zhou QD, York AG, Williams KJ, Scumpia PO, Kronenberger EB, Hoi XP, Su B, Chi X, Bui VL, Khialeeva E, Kaplan A, Son YM, Divakaruni AS, Sun J, Smale ST, Flavell RA, Bensinger SJ. Toll-Like Receptors Induce Signal-Specific Reprogramming of the Macrophage Lipidome. Cell Metab. 2020 Jul 7;32(1):128-143.e5. doi: 10.1016/j.cmet.2020.05.003. Epub 2020 Jun 8. PubMed PMID: 32516576; PubMed Central PMCID: PMC7891175.
Divakaruni A, Hsieh W, Minarrieta L, Duong T, Kim K, Desousa B, Andreyev A, Bowman C, Caradonna K, Dranka B, Ferrick D, Liesa M, Stiles L, Rogers G, Braas D, Ciaraldi T, Wolfgang M, Sparwasser T, Berod L, Bensinger S*, Murphy A* (2018) Etomoxir inhibits macrophage polarization by disrupting CoA homeostasis. Cell Metab. In press. * Co-senior authors
York A, Argus J, Williams K, Brar G, Vergnes L, Gray E, Zhen A, Wu N, Yamada D, Cunningham C, Wilks M, Casero D, Gray D, Yu A, Brooks D, Sun R, Kitchen S, Wu T, Reue K, Stetson D and Bensinger S (2015) Limiting cholesterol biosynthetic flux engages type I IFN signaling in a STING-dependent manner. Cell. 163:1716-29.
Kidani Y, Elsaesser H, Hock M, Vergnes L, Williams K, Argus J, Marbois B, Komisopoulou E, Wilson E, Osborne T, Graeber T, Reue K, Brooks D, Bensinger S (2013) The sterol regulatory element binding proteins are essential for the metabolic programming of effector T cells and adaptive immunity. Nat Immunol. 14:489-99.
Hong C, Kidani Y, A-Gonzalez N, Phung T, Ito A, Rong X, Ericson K, Mikkola H, Beaven S, Miller L, Shao W, Cohen P, Castrillo A, Tontonoz P, Bensinger S (2012) Coordinate regulation of neutrophil homeostasis by liver X receptors in mice. J Clin Invest. 122:337-47.
Metabolism as a regulator of cancer growth and the cancer metabolic phenotype.
We have defined how transcriptional and biochemical regulation of cholesterol and fatty acid biosynthetic pathways influence cancer cell biology and tumor pathogenesis. This work has highlighted the SREBP pathways as potential therapeutic targets for cancer.
Williams K, Argus J, Zhu Y, Wilks M, Marbois B, York A, Kidani Y, Pourzia A, Akhavan D, Lisiero D, Komisopoulou E, Henkin AH, Soto H, Chamberlain BT, Vergnes L, Jung ME, Torres JZ, Liau LM, Christofk H, Prins R, Mischel P, Reue K, Graeber T, Bensinger S (2013) An essential requirement for the SCAP/SREBP signaling axis to protect cancer cells from lipotoxicity. Cancer Res. 73:2850-2862.
Akhavan D, Pourzia A, Nourian A, Williams K, Nathanson D, Babic I, Villa G, Tanaka K, Nael A, Yang H, Dang J, Vinters H, Yong W, Flagg M, Tamanoi F, Sasayama T, James C, Kornblum H, Cloughesy T, Cavenee W, Bensinger S*, Mischel S* (2013) De-repression of PDGFRβ transcription promotes acquired resistance to EGFR tyrosine kinase inhibitors in glioblastoma patients. Cancer Discov. 3:534-47. * Co-corresponding authors
Guo D, Prins R, Dang J, Kuga D, Iwanami A, Soto H, Lin K, Huang T, Akhavan D, Hock M, Zhu S, Kofman A, Bensinger S, Yong W, Vinters H, Horvath S, Watson A, Kuhn J, Robins H, Mehta M, Wen P, DeAngelis L, Prados M, Mellinghoff I, Cloughesy T, Mischel P (2009) EGFR signaling through an AKT- SREBP1-dependent, rapamycin-resistant pathway sensitizes glioblastoma to antilipogenic therapy. Sci Signal. 15:ra82.]
Gholkar A, Cheung K, Williams K, Lo Y, Hamideh SA, Nnebe C, Khuu C, Bensinger S, Torres J (2016) Fatostatin Inhibits Cancer Cell Proliferation by Affecting Mitotic Microtubule Spindle Assembly and Cell Division. J Biol Chem. 33:17001-8.
Examining the fate and function of T cells.
Understanding the molecular events underlying how T cells develop and persist is an important objective for the immunology and rheumatologic communities. Early studies in my career were focused on defining signaling and metabolic pathways regulaing the development and differentiation of T cells.
Bensinger S, Bandeira A, Jordan M, Caton A, Laufer T (2001) Major histocompatibility complex class II-positive cortical epithelium mediates the selection of CD4(+)25(+) immunoregulatory T cells. J Exp Med. 194:427-38.
Wu Z*, Bensinger S*, Zhang J, Chen C, Yuan X, Huang X, Markmann J, Kassaee A, Rosengard B, Hancock W, Sayegh M, Turka L (2004) Homeostatic proliferation is a barrier to transplantation tolerance. Nat Med. 10: 87-92. * equal contribution
Bensinger S*, Walsh P*, Zhang J, Carroll M, Parsons R, Rathmell J, Thompson C, Burchill M, Farrar M, Turka L (2004) Distinct IL-2 receptor signaling pattern in CD4+CD25+ regulatory T cells. J Immunol. 72:5287-96. * equal contribution
Bensinger S, Bradley M, Joseph S, Zelcer N, Janssen E, Hausner M, Shih R, Parks J, Edwards P, Jamieson B, Tontonoz P (2008) LXR signaling couples sterol metabolism to proliferation in the acquired immune response. Cell 134:97–111.
Development of new analytical methodologies to measure lipid metabolism.
A primary objective of our laboratory is to accurately measure how growth and activation signals are dynamically remapping the lipid composition of immune cells. To that end, we have focused a portion of the laboratory’s efforts towards developing novel methodologies for analysis of lipid composition.
Su B, Bettcher LF, Hsieh WY, Hornburg D, Pearson MJ, Blomberg N, Giera M, Snyder MP, Raftery D, Bensinger SJ, Williams KJ. A DMS Shotgun Lipidomics Workflow Application to Facilitate High-Throughput, Comprehensive Lipidomics. J Am Soc Mass Spectrom. 2021 Nov 3;32(11):2655-2663. doi: 10.1021/jasms.1c00203. Epub 2021 Oct 12. PMID: 34637296.
Argus J, Yu A, Wang E, Williams K, Bensinger S (2017) An Optimized Method for Measuring Fatty Acids and Cholesterol in Stable Isotope Labeled Cells. J Lipid Res. 58:460-468.