ena-STUDY-EUROPEAN RESEARCH INSTITUTE FOR THE BIOLOGY OF AGEING, UNIVERSITY OF GRONINGEN, UNIVERSITY MEDICAL CENTER GRONINGEN-15-06-2018-13:21:08:318-4252
Single-cell whole genome sequencing of colorectal cancer cell lines
Deviating from the normal karyotype dramatically changes gene dosage, in turn decreasing the robustness of biological networks. Consequently, aneuploidy is poorly tolerated by normal somatic cells and acts as a barrier to transformation. Paradoxically however, karyotype heterogeneity drives tumour evolution and the emergence of therapeutic drug resistance. To better understand how cancer cells tolerate aneuploidy, we focused on the p38 stress response kinase. We show here that p38-deficient cells upregulate the hypoxia-inducible transcription factor Hif-1?? this in?turn turbocharges glycolysis allowing cells to buffer the metabolic collapse that occurs following chromosome missegregation. Consequently, p38-deficient cells avoid post-mitotic apoptosis, leading to the emergence of aneuploid subclones. Because hypoxia and aneuploidy are both barriers to tumour progression, the ability of Hif-1? to promote cell survival following chromosome missegregation raises a novel concept, namely that aneuploidy tolerance co-evolves with adaptation to hypoxia.
Deviating from the normal karyotype dramatically changes gene dosage, in turn decreasing the robustness of biological networks. Consequently, aneuploidy is poorly tolerated by normal somatic cells and acts as a barrier to transformation. Paradoxically however, karyotype heterogeneity drives tumour evolution and the emergence of therapeutic drug resistance. To better understand how cancer cells tolerate aneuploidy, we focused on the p38 stress response kinase. We show here that p38-deficient cells upregulate the hypoxia-inducible transcription factor Hif-1?? this in?turn turbocharges glycolysis allowing cells to buffer the metabolic collapse that occurs following chromosome missegregation. Consequently, p38-deficient cells avoid post-mitotic apoptosis, leading to the emergence of aneuploid subclones. Because hypoxia and aneuploidy are both barriers to tumour progression, the ability of Hif-1? to promote cell survival following chromosome missegregation raises a novel concept, namely that aneuploidy tolerance co-evolves with adaptation to hypoxia.