Group Per Lindahl

Research summary

Excessive intake of dietary antioxidants accelerates lung cancer progression in human and mice, and human lung tumors accumulate somatic mutations that increase their own production of endogenous antioxidants. These findings indicate that oxidative stress is a barrier that cancer cells must overcome to progress and metastasize, and that cancer cells may therefore be susceptible to pro-oxidant therapies. Our research goal is to develop pro-oxidant cancer therapies that are directed against endogenous antioxidants.

Cancer cells maintain redox homeostasis by several interconnected systems. Glutathione is the most abundant intracellular antioxidant and a major determinant of the cellular redox environment. The thioredoxin system is another thiol-based antioxidant system that plays an important role in cancer. Our current research focus is to develop therapies directed against the glutathione or thioredoxin systems. For these therapies to be effective, we will identify drugs or drug combinations that are synthetic lethal with genetic or genomic alterations that are specific to cancer cells. 

This challenge is best approached with unbiased and genome-wide methods that can identify novel and unexpected targets. We have established a genome-wide CRISPR-CAS9 screening platform in human lung cancer cells that is used in combination with drug perturbations. Data from such screens can reveal targets for combination therapies, mechanisms of drug effects, drug resistance mechanisms, and targets that are synthetic lethal with cancer genotypes.

The clinical response to novel therapies is governed by genetic and environmental factors that are not fully recapitulated in conventional cancer models. We are therefore setting up patient-derived 3D organoid cultures from surgically resected lung tumors. Such models retain the architecture and drug response pattern of the parental tumor and can bridge the gap between conventional cancer models and clinical trials. 

Research tools and resources

We have developed a genome-wide lentiviral CRISPR-CAS9 screening platform in human lung cancer cells. The platform is used in combination with drug perturbations to identify targets for combination therapies, mechanisms of drug effects, drug resistance mechanisms, and synthetic lethal interactions between drugs and cancer genotypes. 

Current group members

Per Lindahl, Professor, Principal Investigator
Viktor Garellick, PhD Student
Dyar Mustafa, PhD Student

Selected publications

1. Antioxidants Promote Intestinal Tumor Progression in Mice.
   Zou ZV, Le Gal K, El Zowalaty AE, Pehlivanoglu LE, Garellick V, Gul N, Ibrahim MX, Bergh PO, Henricsson M, Wiel C, Akyürek LM, Bergo MO, Sayin VI, Lindahl P. Antioxidants (Basel). 2021 Feb 4;10(2):241.
    
2. Knockout of the RAS endoprotease RCE1 accelerates myeloid leukemia by downregulating GADD45b.
   Karlsson C, Akula MK, Staffas A, Cisowski J, Sayin VI, Ibrahim MX, Lindahl P, Bergo MO. Leukemia. 2021 Feb;35(2):606-609.
    
3. Genomic profiling of the transcription factor Zfp148 and its impact on the p53 pathway.
   Zou ZV, Gul N, Lindberg M, Bokhari AA, Eklund EM, Garellick V, Patel AAH, Dzanan JJ, Titmuss BO, Le Gal K, Johansson I, Tivesten Å, Forssell-Aronsson E, Bergö MO, Staffas A, Larsson E, Sayin VI, Lindahl P. Sci Rep. 2020 Aug 25;10(1):14156.
    
4. The MTH1 inhibitor TH588 is a microtubule-modulating agent that eliminates cancer cells by activating the mitotic surveillance pathway.
   Gul N, Karlsson J, Tängemo C, Linsefors S, Tuyizere S, Perkins R, Ala C, Zou Z, Larsson E, Bergö MO, and Lindahl P. Sci Rep. 2019 Oct 11;9(1):14667.
    
5. BACH1 Stabilization by Antioxidants Stimulates Lung Cancer Metastasis.
   Wiel C, Le Gal K, Ibrahim MX, Jahangir CA, Kashif M, Yao H, Ziegler DV, Xu X, Ghosh T, Mondal T, Kanduri C, Lindahl P, Sayin VI, Bergo MO. Cell. 2019 Jul 11;178(2):330-345.e22.
    
6. Targeting Zfp148 activates p53 and reduces tumor initiation in the gut.
   Nilton A, Sayin VI, Zou ZV, Sayin SI, Bondjers C, Gul N, Agren P, Fogelstrand P, Nilsson O, Bergo MO, Lindahl P. Oncotarget. 2016 Aug 30;7(35):56183-56192.
    
7. Antioxidants can increase melanoma metastasis in mice.
   Le Gal K, Ibrahim MX, Wiel C, Sayin VI, Akula MK, Karlsson C, Dalin MG, Akyürek LM, Lindahl P, Nilsson J, Bergo MO. Sci Transl Med. 2015 Oct 7;7(308):308re8.
    
8. Loss of one copy of Zfp148 reduces lesional macrophage proliferation and atherosclerosis in mice by activating p53.
   Sayin VI, Khan OM, Pehlivanoglu LE, Staffas A, Ibrahim MX, Asplund A, Agren P, Nilton A, Bergström G, Bergo MO, Borén J, Lindahl P. Circ Res. 2014 Oct 10;115(9):781-9.
    
9. Antioxidants accelerate lung cancer progression in mice.
   Sayin VI, Ibrahim MX, Larsson E, Nilsson JA, Lindahl P*, Bergo MO*. Sci Transl Med. 2014 Jan 29;6(221):221ra15. *corresponding authors.
    
10. Zfp148 deficiency causes lung maturation defects and lethality in newborn mice that are rescued by deletion of p53 or antioxidant treatment.
    Sayin VI, Nilton A, Ibrahim MX, Ågren P, Larsson E, Petit MM, Hultén LM, Ståhlman M, Johansson BR, Bergo MO, Lindahl P. PLoS One. 2013;8(2):e55720.

More group Per Lindahl publications on PubMed