Sartor, M. | bioRxiv Science

bioRxiv2018

IDH1R132H acts as a tumor suppressor in glioma via epigenetic upregulation of the DNA damage response

One sentence summaryMutant IDH1 acts as a tumor suppressor when co-expressed together with TP53 and ATRX inactivating mutations in glioma, inducing genomic stability, DNA repair and resistance to genotoxic therapies.\n\nAbstractGlioma patients whose tumors carry a mutation in the Isocitrate Dehydrogenase 1 (IDH1R132H) gene are younger at the time of diagnosis and survive longer. The molecular glioma subtype which we modelled, harbors IDH1R132H, tumor protein 53 (TP53) and alpha-thalassemia/mental retardation syndrome X-linked (ATRX) loss. The impact of IDH1R132H on genomic stability, DNA damage response (DDR) and DNA repair in this molecular glioma subtype is unknown. We discovered that IDH1R132H expression in the genetic context of ATRX and TP53 inactivation: (i) increases median survival (MS), (ii) enhances DDR activity via epigenetic upregulation of Ataxia-telangiectasia mutated (ATM) signaling, and (iii) elicits tumor radioresistance. Pharmacological inhibition of ATM or checkpoint kinase 1 and 2 (CHK1/2), two essential kinases in the DDR pathways, restored tumors radiosensitivity. Translation of these findings for mlDH1 glioma patients could significantly improve the therapeutic efficacy of radiotherapy, and thus have a major impact on patient survival.

cancer biology↗

bioRxiv2017

Heterogeneity of normal human breast stem and progenitor cells as revealed by transcriptional profiling

During development and pregnancy, the human mammary gland undergoes extensive remodeling in processes driven by populations of stem and progenitor cells. We recently reported that breast cancers are also hierarchically organized and driven by distinct populations of cancer stem cells characterized as CD44+CD24low/- or by expression of Aldehyde dehydrogenase (ALDH). These sets of markers identify largely non-overlapping mesenchymal and epithelial populations, each of which is capable of tumor initiation when transplanted into immunosuppressed mice. Less is known about these two populations, individually or their overlap, in the normal human mammary gland. The goal of this study was to understand the biology of the ALDH+ and CD44+CD24- populations in the normal human breast, using flow cytometry based sorting paired with functional ex vivo analyses, RNA-sequencing, and single cell RNA expression profiling. ALDH+ cells and ALDH-CD44+CD24- cells, generally, have epithelial-like and mesenchymal-like characteristics, respectively. Despite this, there are substantial similarities in the biological pathways activated in both populations when compared to differentiated cells. Additionally, we found a substantial proportion of cells that simultaneously express ALDH+ and CD44+CD24- whose abundance varies between individuals. At the single cell level, these cells have the greatest mammosphere forming capacity and express high levels of stemness and EMT-associated genes including ID1, SOX2, TWIST1, and ZEB2. Through unbiased analysis of individual ALDH+ cells, we find cells with either epithelial or mesenchymal expression phenotypes. We also identify a subpopulation of cells with a hybrid epithelial/mesenchymal expression phenotype that overexpress genes associated with aggressive triple negative breast cancers. These results highlight the utility of single cell analyses to characterize tissue heterogeneity, even in marker enriched cell populations, and further identifies the genes and pathways that define this heterogeneity.

developmental biology↗