Cancer, rapid ageing and nutrition - Martin Bergö
Our group is interested in how free radicals and antioxidants interact with nutritional and metabolic needs of tumour cells during cancer development. Contrary to popular wisdom, antioxidants stimulate cancer metastasis and we are now exploring this finding to develop anti-metastatic drugs and to be able to give well-informed nutritional advice to cancer patients. We are also developing a new medicine for children with progeria – an accelerated ageing syndrome.
We found a new enzyme involved in progeria and discovered that inhibiting this enzyme might increase life quality and life span for these children.
Research on CAAX-proteins raised exciting new possibilities
We perform curiosity-driven basic and translational research into cancer, arthritis, atherosclerosis, heart disease, and ageing. Our research begins with a biochemical pathway by which hundreds of CAAX-proteins, as they are known, are enzymatically modified by a cholesterol-like molecule – which is believed to activate CAAX-proteins by stimulating their interaction with membranes. When these CAAX-proteins (e.g. RAS and prelamin A) are dysfunctional they can cause cancer, inflammation, and ageing-like diseases. Our goals are to define the biochemical importance of the CAAX-protein modifications and thereby identify new strategies to treat these diseases.
Our studies have led to exciting and surprising discoveries and below are two examples.
Antioxidants stimulate cancer progression
Healthy people and cancer patients alike use antioxidant supplements, including vitamins A, C, and E, as a daily cancer-fighting strategy despite lack of convincing scientific evidence. We discovered that dietary antioxidants actually accelerate lung cancer growth and metastasis. Antioxidants activate a protein called BACH1 which forces tumour cells to take up glucose and use it for aerobic glycolysis – i.e., the Warburg effect – which drives metastasis. Antioxidants produce similar effects in malignant melanoma and pancreatic cancer. The results suggest that cancer patients should avoid antioxidant supplements and that we may now design drugs that inhibit BACH1-induced glycolysis as a strategy to block metastasis.
A new treatment strategy for children with progeria
Progeria is a rare disease caused by a dysfunctional form of the CAAX-protein prelamin A. Dysfunctional prelamin A causes hair loss, slow growth, osteoporosis, muscle weakness, and death from heart attack or stroke in the teenage years. We discovered that inhibiting ICMT, an enzyme that modifies prelamin A, increases body weight and muscle strength, eliminates osteoporosis, and prevents death in mice with progeria; it also stimulates the growth of cells from children with progeria. We are now developing drugs that inhibit ICMT and preliminary data indicate that our strategy could be successful. But first we have to optimize the drug so it can be tested in children with progeria.
Michelle TruongProject Student
Looking for an internship or a MSc Project?
We are looking for excitable and dedicated master, project, and internship students who want to help us unravel the complex relationships between oxidative stress and metabolic adaptations in cancer cells and determine how these collaborate in tumor initiation, progression, and metastasis. We are also looking for students interested in the biology of accelerated aging who can help us in our efforts to develop and evaluate drugs to treat this deadly disease.
Contact Martin Bergö for more information.
Chen X, Yao H, Kashif M, Hu J, Wang T, Liu Y, Tüksammel E, Revêchon G, Eriksson M, Strömblad S, Philips MR, Wiel C, Ibrahim MX, and Bergo MO. (2021) A small-molecule ICMT inhibitor delays senescence of Hutchinson-Gilford progeria syndrome cells. eLife 10: e63284
Karlsson C, Akula M, Staffas A, Cisowski J, Sayin VI, Ibrahim MX, Lindahl P, and Bergo MO. (2021) Knockout of the RAS endoprotease RCE1 accelerates myeloid leukemia by downregulating GADD45b. Leukemia 35: 606–609
Yao H, Chen X, Kashif M, Wang T, Ibrahim MX, Tüksammel E, Revêchon G, Eriksson M, Wiel C, and Bergo MO. (2020) Targeting RAS converting enzyme 1 overcomes senescence and improves progeria-like phenotypes of ZMPSTE24 deficiency. Aging Cell 19: e13200
Christensen JG, Olson P, Briere T, Wiel C, and Bergo MO. (2020) Targeting KRASG12C-mutant cancer with a mutation-specific inhibitor. J. Intern. Med. 288: 183–191
Wiel C, Ibrahim MX, Le Gal K, Jahangir CA, Ziegler DV, Kashif M, Xu X, Mondal T, Kanduri C, Lindahl P, Sayin VI, and Bergo MO. (2019) BACH1 stabilization by antioxidants stimulates lung cancer metastasis. Cell 78: 330–345
Akula MK, Ibrahim MX, Ivarsson EG, Khan OM, Kumar IT, Erlandsson M, Karlsson C, Xu X, Brisslert M, Brakebusch C, Wang D, Bokarewa M, Sayin VI, and Bergo MO. (2019) Protein prenylation restrains innate immunity by inhibiting RAC1 effector interactions. Nature Commun. 10: 3975
Targeting Filamin A Reduces Macrophage Activity and Atherosclerosis.
Bandaru S, Ala C, Salimi R, Akula MK, Ekstrand M, Devarakonda S, Karlsson J, Van den Eynden J, Bergström G, Larsson E, Levin M, Borén J, Bergo MO, Akyürek LM.
Circulation. 2019 Jul 2;140(1):67-79. doi: 10.1161/CIRCULATIONAHA.119.039697. Epub 2019 Apr 24.
Massive parallel sequencing questions the pathogenic role of missense variants in dilated cardiomyopathy.
Dalin MG, Engström PG, Ivarsson EG, Unneberg P, Light S, Schaufelberger M, et al
Int. J. Cardiol. 2017 Feb;228:742-748
Control of the innate immune response by the mevalonate pathway.
Akula MK, Shi M, Jiang Z, Foster CE, Miao D, Li AS, et al
Nat. Immunol. 2016 08;17(8):922-9
Antioxidants can increase melanoma metastasis in mice.
Le Gal K, Ibrahim MX, Wiel C, Sayin VI, Akula MK, Karlsson C, et al
Sci Transl Med 2015 Oct;7(308):308re8
Oncogene-induced senescence underlies the mutual exclusive nature of oncogenic KRAS and BRAF.
Cisowski J, Sayin VI, Liu M, Karlsson C, Bergo MO
Oncogene 2016 Mar;35(10):1328-33
Wild-type KRAS inhibits oncogenic KRAS-induced T-ALL in mice.
Staffas A, Karlsson C, Persson M, Palmqvist L, Bergo MO
Leukemia 2015 May;29(5):1032-40
Antioxidants accelerate lung cancer progression in mice.
Sayin VI, Ibrahim MX, Larsson E, Nilsson JA, Lindahl P, Bergo MO
Sci Transl Med 2014 Jan;6(221):221ra15
Targeting isoprenylcysteine methylation ameliorates disease in a mouse model of progeria.
Ibrahim MX, Sayin VI, Akula MK, Liu M, Fong LG, Young SG, et al
Science 2013 Jun;340(6138):1330-3
Targeting GGTase-I activates RHOA, increases macrophage reverse cholesterol transport, and reduces atherosclerosis in mice.
Khan OM, Akula MK, Skålen K, Karlsson C, Ståhlman M, Young SG, et al
Circulation 2013 Feb;127(7):782-90
Geranylgeranyltransferase type I (GGTase-I) deficiency hyperactivates macrophages and induces erosive arthritis in mice.
Khan OM, Ibrahim MX, Jonsson IM, Karlsson C, Liu M, Sjogren AK, et al
J. Clin. Invest. 2011 Feb;121(2):628-39
Liu M, Sjogren AK, Karlsson C, Ibrahim MX, Andersson KME, Olofsson FJ, Wahlstrom AM, Dalin M, Chen Z, Yu H, Young SG, Yang SH, and Bergo MO. (2010) Targeting the protein prenyltransferases efficiently reduces tumor development in mice with K-RAS-induced lung cancer. Proc. Natl. Acad. Sci. USA. 107: 6471–6476
- Cancerfonden Postdoctoral Fellowship (2017–2019) (to Clotilde Wiel)
- Marie Curie Postdoctoral Fellowship (2015–2017) (to Clotilde Wiel)