Jurre Kamphorst - Cancer Metabolomics

University of Glasgow / Beatson Associate

Cancer Research UK Career Development Fellow

Introduction

KamphorstJ

Lipids make up a large and diverse subset of the metabolome, exerting many important physiological functions. They are also widely implicated in a variety of diseases. This includes cancer, where the unremitting growth of tumour cells requires a continuous lipid supply for the construction of cell membranes. Additionally, signalling lipids, such as PIP3, play central roles in oncogenic signalling. Despite their clear importance, technical limitations have thus far prevented a full-scale, systematic investigation of the role of lipids in tumour biology. To address this, we innovate the use of state-of-the-art analytical technology, particularly mass spectrometry-based lipidomics, to study lipid metabolism and signalling in cancer. We work on the following topics:

Assigning structures and functions to deregulated lipids in cancer. While as a class lipids have been linked to tumour cell survival, growth, and migration, many lipids remain undetected as analytical coverage of the 'lipidome' is still very poor. In addition, recent lipidomics studies found that only half of several thousand detected lipids could be assigned to structures, let alone functions. Based on these observations, we hypothesize that a substantial body of clinically relevant lipid biology remains to be discovered. Our approach is to maximise coverage of the lipidome using a smart combination of extraction procedures, separation modalities, mass spectrometry strategies, and bioinformatics approaches (Tumanov et al., 2017). We use this platform to study local and systemic lipid deregulation by combining 'top-down' (i.e. human and mouse tissues and biofluids) and 'bottom-up' (cancer cells and other cell populations) experiments, to maximise both clinical relevance and mechanistic understanding. We focus on pancreatic cancer.

Elucidating how cancer cells maintain lipid homeostasis during metabolic stress. Lipids are 'bulk' materials needed by cells for continued proliferation. This places considerable stress on the lipid synthetic machinery. On top of this, cancer cells oftentimes face limited nutrient and oxygen supplies. Determining how cancer cells satisfy lipid demand for growth while maintaining homeostasis in an adverse tumour microenvironment is one of our main interests. We have previously shown that low oxygen limits acetyl-CoA availability for fatty acid synthesis and that acetate acts as an alternative source for acetyl-CoA in these circumstances (Kamphorst et al., 2014) (Tumanov et al., 2016) (Bulusu et al., 2017). We also found that low oxygen compromises fatty acid desaturation, causing a toxic build-up of saturated fatty acids and a dependency on exogenous unsaturated lipids for survival (Kamphorst et al., 2013). To further elucidate lipid homeostatic mechanisms, we innovate the combination of lipidomics and stable isotope tracing. This allows us to capture the dynamic activity of lipid metabolic pathways, both in vitro and in vivo. Ongoing projects include characterising a role for lipid droplets in buffering cellular lipid composition, investigating cholesterol metabolism, and assessing how the unfolded protein response (UPR) regulates lipid metabolism.

Lab Report

icon Kamphorst Lab Report

icon Metabolomics article (from CRUK Annual Research Publication 2015)

 See Current Opinion in Biotechnology issue (Volume 43, Pages 1-146, February 2017) on metabolomics edited by Jurre J Kamphorst and Ian A Lewis

Key Publications

Bulusu V, Tumanov S, Michalopoulou E, van den Broek NJ, Mackay G, Nixon C, Dhayade S, Schug ZT, Vande Voorde J, Blyth K, Gottlieb E, Vazquez A, Kamphorst JJ. Acetate recapturing by nuclear acetyl-CoA synthetase 2 prevents loss of histone acetylation during oxygen and serum limitation. Cell Reports 18: 647-58, 2017

Kamphorst JJ, Nofal M, Commisso C, Hackett SR, Lu W, Grabocka E, Vander Heiden MG, Miller G, Drebin JA, Bar-Sagi D, Thompson CB, Rabinowitz JD. Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein. Cancer Research 75: 544-53, 2015

Kamphorst JJ, Chung MK, Fan J, Rabinowitz JD. Quantitative analysis of acetyl-CoA production in hypoxic cancer cells reveals substantial contribution from acetate. Cancer & Metabolism 2:23, 2014

Kamphorst JJ, Cross JR, Fan J, Mathew R, White E, Thompson CB, Rabinowitz JD. Hypoxic and Ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids. PNAS 110: 8882-7, 2013

Commisso C, Davidson SM, Soydaner-Azeloglu RG, Parker SJ, Kamphorst JJ, Hackett S, Nofal M, Drebin JJ, Thompson CB, Rabinowitz JD, Metallo CM, Vander Heiden MG, Bar-Sagi D. Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature 497: 633-7, 2013

Biography

Education and qualifications

2010: PhD, Leiden University, Supervisor Thomas Hankemeier
2005: MSc, Biopharmaceutical Sciences, Leiden University

Appointments

2014-present: Group Leader, CRUK Beatson Institute
2017-present: Reader, University of Glasgow
2014-2017: Senior Lecturer, University of Glasgow
2009-2013: Postdoctoral Fellow with Joshua Rabinowitz, Princeton University

Honours and awards

2014-2020: Cancer Research UK Career Development Fellowship
2011-2013: Hope Funds for Cancer Research Postdoctoral Fellowship

Recent Publications

2017

Bulusu V, Tumanov S, Michalopoulou E, van den Broek NJ, Mackay G, Nixon C, Dhayade S, Schug ZT, Vande Voorde J, Blyth K, Gottlieb E, Vazquez A, Kamphorst JJ. Acetate recapturing by nuclear acetyl-CoA synthetase 2 prevents loss of histone acetylation during oxygen and serum limitation. Cell Reports 18: 647-58, 2017

Tumanov S, Kamphorst JJ. Recent advances in expanding the coverage of the lipidome. Curr Opin Biotechnol 43: 127-33, 2017

Kamphorst JJ, Lewis IA. Editorial overview: Recent innovations in the metabolomics revolution. Curr Opin Biotechnol 43: iv-vii, 2017 http://www.sciencedirect.com/science/article/pii/S0958166917300113

2016

Meiser J, Tumanov S, Maddocks O, Labuschagne CF, Athineos D, Van Den Broek N, Mackay GM, Gottlieb E, Blyth K, Vousden K, Kamphorst JJ, Vazquez A. Serine one-carbon catabolism with formate overflow. Science Advances 2: e1601273, 2016

Tumanov S, Bulusu V, Gottlieb E, Kamphorst JJ. A rapid method for quantifying free and bound acetate based on alkylation and GC-MS analysis. Cancer & Metabolism 4: 17, 2016

Kamphorst JJ, Gottlieb E. Cancer metabolism: Friendly neighbours feed tumour cells. Nature 536: 401-402, 2016

Michalopoulou E, Bulusu V, Kamphorst JJ. Metabolic scavenging by cancer cells: when the going gets tough, the tough keep eating. Br J Cancer 115: 635-40, 2016

Vazquez A, Kamphorst JJ, Markert EK, Schug ZT, Tardito S, Gottlieb E. Cancer metabolism at a glance. J Cell Sci 129: 3367-73, 2016

2015

Cardaci S, Zheng L, MacKay G, van den Broek NJ, MacKenzie ED, Nixon C, Stevenson D, Tumanov S, Bulusu V, Kamphorst JJ, Vazquez A, Fleming S, Schiavi F, Kalna G, Blyth K, Strathdee D, Gottlieb E. Pyruvate carboxylation enables growth of SDH-deficient cells by supporting aspartate biosynthesis. Nat Cell Biol 17: 1317-26, 2015

Kamphorst JJ, Nofal M, Commisso C, Hackett SR, Lu W, Grabocka E, Vander Heiden MG, Miller G, Drebin JA, Bar-Sagi D, Thompson CB, Rabinowitz JD. Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein. Cancer Research 75: 544-53, 2015

Rajeshkumar NV, Dutta P, Yabuuchi S, de Wilde RF, Matrinez GV, Le A, Kamphorst JJ, Rabinowitz JD, Jain SK, Hidalgo M, Dang CV, Gillies RJ, Maitra A. Therapeutic targeting of the Warburg effect in pancreatic cancer relies on an absence of p53 function. Cancer Res 75: 3355-64, 2015

Schug ZT, Peck B, Jones DT, Zhang Q, Grosskurth S, Alam IS, Goodwin LM, Smethurst E, Mason S, Blyth K, McGarry L, James D, Shanks E, Kalna G, Saunders RE, Jiang M, Howell M, Lassailly F, Thin MZ, Spencer-Dene B, Stamp G, van den Broek NJ, Mackay G, Bulusu V, Kamphorst JJ, Tardito S, Strachan D, Harris AL, Aboagye EO, Critchlow SE, Wakelam MJ, Schulze A, Gottlieb E. Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress. Cancer Cell 27: 57-71, 2015

Tumanov S, Bulusu V, Kamphorst JJ. Analysis of fatty acid metabolism using stable isotope tracers and mass spectrometry. Methods in Enzymology 561: 197-201, 2015

Buescher JM, Antoniewicz MR, Boros LG, Burgess SC, Brunengraber H, Clish CB, DeBerardinis RJ, Feron O, Frezza C, Ghesquiere B, Gottlieb E, Hiller K, Jones RG, Kamphorst JJ, Kibbey RG, Kimmelman AC, Locasale JW, Lunt SY, Maddocks ODK, Malloy C, Metallo CM, Meuillet EJ, Munger J, Noh K, Rabinowitz JD, Ralser M, Sauer U, Stephanopoulos G, St-Pierre J, Tennant DA, Wittmann C, Vander Heiden M, Vazquez A, Vousden K, Young JD, Zamboni N, Fendt SM. A roadmap for interpreting 13C metabolite labeling patterns from cells. Current Opinion in Biotechnology 34: 189-201, 2015

2014

Kamphorst JJ, Chung MK, Fan J, Rabinowitz JD. Quantitative analysis of acetyl-CoA production in hypoxic cancer cells reveals substantial contribution from acetate. Cancer & Metabolism 2: 23, 2014

Fan J, Ye J, Kamphorst JJ, Shlomi T, Thompson CB, Rabinowitz JD. Quantitative flux analysis reveals folate-dependent NADPH production. Nature 510: 298-302, 2014

Kamphorst JJ, Murphy DJ. The Beatson International Cancer Conference: Powering the Cancer Machine. Cancer Metab 2: 25, 2014

2013

Fan J, Kamphorst JJ, Mathew R, Chung M, White E, Shlomi T, Rabinowitz JD. Glutamine-driven oxidative phosphorylation is a major ATP source in transformed mammalian cells in both normoxia and hypoxia. Molecular Systems Biology 9: 712, 2013

Fan J, Kamphorst JJ, Rabinowitz JD, Shlomi T. Fatty acid labeling from glutamine in hypoxia can be explained by isotope exchange without net reductive IDH flux. Journal of Biological Chemistry 288: 31363-9, 2013

Guo JY, Karsli-Uzunbas G, Mathew R, Aisner SC, Kamphorst JJ, Strohecker AM, Chen G, Price S, Lu W, Teng X, Snyder E, Santanam U, Dipaola RS, Jacks T, Rabinowitz JD, White E. Autophagy suppresses progression of K-ras-induced lung tumors to oncocytomas and maintains lipid homeostasis. Genes & Development 27: 1447-61, 2013

Kamphorst JJ, Cross JR, Fan J, Mathew R, White E, Thompson CB, Rabinowitz JD. Hypoxic and Ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids. PNAS 110: 8882-7, 2013

Commisso C, Davidson SM, Soydaner-Azeloglu RG, Parker SJ, Kamphorst JJ, Hackett S, Nofal M, Drebin JJ, Thompson CB, Rabinowitz JD, Metallo CM, Vander Heiden MG, Bar-Sagi D. Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature 497: 633-7, 2013

2012

Bray K, Mathew R, Lau A, Kamphorst JJ, Fan J, Chen J, Chen HY, Ghavami A, Stein M, DiPaola RS, Zhang D, Rabinowitz JD, White E. Autophagy suppresses RIP kinase dependent necrosis enabling survival to mTOR inhibition. PLoS ONE 7: e41831, 2012

Lab Members

kamphorst group

Lab Manager

Jacqueline Tait-Mulder

Post-docs

Vinay Bulusu
Francesca Romana Auciello
Sergey Tumanov

PhD Students

Grace McGregor (joint with Owen Sansom)
Evdokia Michalopoulou

Research

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Seminars

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