Cebrià-Costa JP, Pascual-Reguant L, Gonzalez-Perez A, Serra-Bardenys G, Querol J, Cosín M, Verde G, Cigliano RA, Sanseverino W, Segura-Bayona S, Iturbide A, Andreu D, Nuciforo P, Bernado-Morales C, Rodilla V, Arribas J, Yelamos J, de Herreros AG, Stracker TH, Peiró S
LOXL2-mediated H3K4 oxidation reduces chromatin accessibility in triple-negative breast cancer cells
Oncogene. Jan 2020 , 39(1):79-121 . Oxidation of H3 at lysine 4 (H3K4ox) by lysyl oxidase-like 2 (LOXL2) generates an H3 modification with an unknown physiological function. We find that LOXL2 and H3K4ox are higher in triple-negative breast cancer (TNBC) cell lines and patient-derived xenografts (PDXs) than those from other breast cancer subtypes. ChIP-seq revealed that H3K4ox is located primarily in heterochromatin, where it is involved in chromatin compaction. Knocking down LOXL2 reduces H3K4ox levels and causes chromatin decompaction, resulting in a sustained activation of the DNA damage response (DDR) and increased susceptibility to anticancer agents. This critical role that LOXL2 and oxidized H3 play in chromatin compaction and DDR suggests that functionally targeting LOXL2 could be a way to sensitize TNBC cells to conventional therapy.
More informationTriana-Martínez F, Picallos-Rabina P, Da Silva-Álvarez S, Pietrocola F, Llanos S, Rodilla V, Soprano E, Pedrosa P, Ferreirós A, Barradas M, Hernández-González F, Lalinde M, Prats N, Bernadó C, González P, Gómez M, Ikonomopoulou MP, Fernández-Marcos PJ, García-Caballero T, Del Pino P, Arribas J, Vidal A, González-Barcia M, Serrano M, Loza MI, Domínguez E, Collado M
Identification and characterization of Cardiac Glycosides as senolytic compounds
Nat Commun. 2019 Oct 21 2019, 10(1):4731 . Compounds with specific cytotoxic activity in senescent cells, or senolytics, support the causal involvement of senescence in aging and offer therapeutic interventions. Here we report the identification of Cardiac Glycosides (CGs) as a family of compounds with senolytic activity. CGs, by targeting the Na+/K+ATPase pump, cause a disbalanced electrochemical gradient within the cell causing depolarization and acidification. Senescent cells present a slightly depolarized plasma membrane and higher concentrations of H+, making them more susceptible to the action of CGs. These vulnerabilities can be exploited for therapeutic purposes as evidenced by the in vivo eradication of tumors xenografted in mice after treatment with the combination of a senogenic and a senolytic drug. The senolytic effect of CGs is also effective in the elimination of senescence-induced lung fibrosis. This experimental approach allows the identification of compounds with senolytic activity that could potentially be used to develop effective treatments against age-related diseases.
More informationRodilla V, Fre S
Cellular Plasticity of Mammary Epithelial Cells Underlies Heterogeneity of Breast Cancer
Biomedicines. 2018 Nov 1 , 6(4) . Delta ligands regulate Notch signaling in normal intestinal stem cells, while Jagged1 activates Notch in intestinal adenomas carrying active β-catenin. We used the ApcMin/+ mouse model, tumor spheroid cultures, and patient-derived orthoxenografts to address this divergent ligand-dependent Notch function and its implication in disease. We found that intestinal-specific Jag1 deletion or antibody targeting Jag1 prevents tumor initiation in mice. Addiction to Jag1 is concomitant with the absence of Manic Fringe (MFNG) in adenoma cells, and its ectopic expression reverts Jag1 dependence. In 239 human colorectal cancer patient samples, MFNG imposes a negative correlation between Jag1 and Notch, being high Jag1 in the absence of MFNG predictive of poor prognosis. Jag1 antibody treatment reduces patient-derived tumor orthoxenograft growth without affecting normal intestinal mucosa. Our data provide an explanation to Jag1 dependence in cancer, and reveal that Jag1-Notch1 interference provides therapeutic benefit in a subset of colorectal cancer and FAP syndrome patients.
More informationLópez-Arribillaga E *, Rodilla V *, Colomer C, Vert A, Shelton A, Cheng JH, Yan B, Gonzalez-Perez A, Junttila MR, Iglesias M, Torres F, Albanell J, Villanueva A, Bigas A, Siebel CW, Espinosa L
Manic Fringe deficiency imposes Jagged1 addiction to intestinal tumor cells
Nat Commun 2018, 9(1) . Wassef M, Rodilla V, Teissandier A, Zeitouni B, Gruel N, Sadacca B, Irondelle M, Charruel M, Ducos B, Michaud A, Caron M, Marangoni E, Chavrier P, Le Tourneau C, Kamal M, Pasmant E, Vidaud M, Servant N, Reyal F, Meseure D, Vincent-Salomon A, Fre S, Margueron R.
Impaired PRC2 activity promotes transcriptional instability and favors breast tumorigenesis.
Genes Dev. 2015 Dec 15 , 29(24):2547-6 . Alterations of chromatin modifiers are frequent in cancer, but their functional consequences often remain unclear. Focusing on the Polycomb protein EZH2 that deposits the H3K27me3 (trimethylation of Lys27 of histone H3) mark, we showed that its high expression in solid tumors is a consequence, not a cause, of tumorigenesis. In mouse and human models, EZH2 is dispensable for prostate cancer development and restrains breast tumorigenesis. High EZH2 expression in tumors results from a tight coupling to proliferation to ensure H3K27me3 homeostasis. However, this process malfunctions in breast cancer. Low EZH2 expression relative to proliferation and mutations in Polycomb genes actually indicate poor prognosis and occur in metastases. We show that while altered EZH2 activity consistently modulates a subset of its target genes, it promotes a wider transcriptional instability. Importantly, transcriptional changes that are consequences of EZH2 loss are predominantly irreversible. Our study provides an unexpected understanding of EZH2's contribution to solid tumors with important therapeutic implications.
More informationRodilla V, Dasti A, Huyghe M, Lafkas D, Laurent C, Reyal F, Fre S.
Luminal progenitors restrict their lineage potential during mammary gland development.
PLoS Biol. 2015 Feb 17 , 13(2):e1002069 . The hierarchical relationships between stem cells and progenitors that guide mammary gland morphogenesis are still poorly defined. While multipotent basal stem cells have been found within the myoepithelial compartment, the in vivo lineage potential of luminal progenitors is unclear. Here we used the expression of the Notch1 receptor, previously implicated in mammary gland development and tumorigenesis, to elucidate the hierarchical organization of mammary stem/progenitor cells by lineage tracing. We found that Notch1 expression identifies multipotent stem cells in the embryonic mammary bud, which progressively restrict their lineage potential during mammary ductal morphogenesis to exclusively generate an ERαneg luminal lineage postnatally. Importantly, our results show that Notch1-labelled cells represent the alveolar progenitors that expand during pregnancy and survive multiple successive involutions. This study reveals that postnatal luminal epithelial cells derive from distinct self-sustained lineages that may represent the cells of origin of different breast cancer subtypes.
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