2. Academic Validation
  3. Truncated PPM1D impairs stem cell response to genotoxic stress and promotes growth of APC-deficient tumors in the mouse colon

Truncated PPM1D impairs stem cell response to genotoxic stress and promotes growth of APC-deficient tumors in the mouse colon

  • Cell Death Dis. 2019 Oct 28;10(11):818. doi: 10.1038/s41419-019-2057-4.
Monika Burocziova 1,  Kamila Burdova 1,  Andra S Martinikova 1,  Petr Kasparek 2,  Petra Kleiblova 3,  Stine A Danielsen 4,  Marianna Borecka 3,  Gabriela Jenikova 1,  Lucie Janečková 5,  Jozef Pavel 1,  Petra Zemankova 3,  Michaela Schneiderova 6,  Lucie Schwarzova 7,  Ivana Ticha 8 9,  Xiao-Feng Sun 8,  Katerina Jiraskova 10,  Vaclav Liska 11,  Ludmila Vodickova 10 11 12,  Pavel Vodicka 10 11 12,  Radislav Sedlacek 2,  Zdenek Kleibl 3,  Ragnhild A Lothe 4,  Vladimír Korinek 5,  Libor Macurek 13
Affiliations

Affiliations

  • 1 Cancer Cell Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic.
  • 2 Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic.
  • 3 Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic.
  • 4 Department Molecular Oncology, Institute for Cancer Research, & K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway.
  • 5 Cell and Developmental Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic.
  • 6 Department of Abdominal, Thoracic Surgery and Traumatology, First Faculty of Medicine, Charles University and General Faculty Hospital in Prague, Prague, Czech Republic.
  • 7 Department of Endocrinology and Metabolism, First Faculty of Medicine, Charles University and General Faculty Hospital in Prague, Prague, Czech Republic.
  • 8 Department of Oncology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
  • 9 Institute of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
  • 10 Molecular Biology of Cancer, Institute of Experimental Medicine, ASCR, Prague, Czech Republic.
  • 11 Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Prague, Czech Republic.
  • 12 Institute of Biology and Medical Genetics, First Medical Faculty, Charles University, Prague, Czech Republic.
  • 13 Cancer Cell Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic. [email protected].
PMID: 31659152 DOI: 10.1038/s41419-019-2057-4
Abstract

Protein Phosphatase magnesium-dependent 1 delta (PPM1D) terminates cell response to genotoxic stress by negatively regulating the tumor suppressor p53 and other targets at chromatin. Mutations in the exon 6 of the PPM1D result in production of a highly stable, C-terminally truncated PPM1D. These gain-of-function PPM1D mutations are present in various human cancers but their role in tumorigenesis remains unresolved. Here we show that truncated PPM1D impairs activation of the cell cycle checkpoints in human non-transformed RPE cells and allows proliferation in the presence of DNA damage. Next, we developed a mouse model by introducing a truncating mutation in the PPM1D locus and tested contribution of the oncogenic PPM1DT allele to colon tumorigenesis. We found that p53 pathway was suppressed in colon stem cells harboring PPM1DT resulting in proliferation advantage under genotoxic stress condition. In addition, truncated PPM1D promoted tumor growth in the colon in APCmin mice and diminished survival. Moreover, tumor organoids derived from colon of the APCminPpm1dT/+ mice were less sensitive to 5-fluorouracil when compared to APCminPpm1d+/+and the sensitivity to 5-fluorouracil was restored by inhibition of PPM1D. Finally, we screened colorectal Cancer patients and identified recurrent somatic PPM1D mutations in a fraction of colon adenocarcinomas that are p53 proficient and show defects in mismatch DNA repair. In summary, we provide the first in vivo evidence that truncated PPM1D can promote tumor growth and modulate sensitivity to chemotherapy.

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