Sancho-Bru, P. (Pau)

Filtering

2019 - 201912020 - 20231

Settings

Author search.filters.isAuthorOfPublication.2ff85ad0-c7d1-404a-9c20-a5ea58963258

Search Results

Now showing 1 - 2 of 2
  • Thumbnail Image
    Identification and experimental validation of druggable epigenetic targets in hepatoblastoma
    (Elsevier, 2023) Indersie, E. (Emilie); Latasa, M.U. (María Ujué); Berraondo, P. (Pedro); Corrales, F.J. (Fernando José); Berasain, C. (Carmen); Arechederra, M. (María); Domingo-Sàbat, M. (Montserrat); Pineda-Lucena, A. (Antonio); Sancho-Bru, P. (Pau); Zanatto, L. (Laura); Armengol, C. (Carolina); Uriarte, I. (Iker); Ciordia, S. (Sergio); Avila, M.A. (Matías Antonio); Alaggio, R. (Rita); Alonso, C. (Cristina); Sangro, B. (Bruno); García-Fernandez-Barrena, M. (Maite); Herranz, J.M. (José M.); Cairo, S. (Stefano); García-Marin, J.J. (Jose Juan); Francalanci, P. (Paola); Prosper-Cardoso, F. (Felipe); Claveria-Cabello, A. (Alex); Martinez-Chantar, M.L. (María Luz); Zucman-Rossi, J. (Jessica)
    Background & Aims: Hepatoblastoma (HB) is the most frequent childhood liver cancer. Patients with aggressive tumors have limited therapeutic options; therefore, a better understanding of HB pathogenesis is needed to improve treatment. HBs have a very low mutational burden; however, epigenetic alterations are increasingly recognized. We aimed to identify epigenetic regulators consistently dysregulated in HB and to evaluate the therapeutic efficacy of their targeting in clinically relevant models. Methods: We performed a comprehensive transcriptomic analysis of 180 epigenetic genes. Data from fetal, pediatric, adult, peritumoral (n = 72) and tumoral (n = 91) tissues were integrated. Selected epigenetic drugs were tested in HB cells. The most relevant epigenetic target identified was validated in primary HB cells, HB organoids, a patient-derived xenograft model, and a genetic mouse model. Transcriptomic, proteomic and metabolomic mechanistic analyses were performed. Results: Altered expression of genes regulating DNA methylation and histone modifications was consistently observed in association with molecular and clinical features of poor prognosis. The histone methyltransferase G9a was markedly upregulated in tumors with epigenetic and transcriptomic traits of increased malignancy. Pharmacological targeting of G9a significantly inhibited growth of HB cells, organoids and patient-derived xenografts. Development of HB induced by oncogenic forms of b-catenin and YAP1 was ablated in mice with hepatocyte-specific deletion of G9a. We observed that HBs undergo significant transcriptional rewiring in genes involved in amino acid metabolism and ribosomal biogenesis. G9a inhibition counteracted these pro-tumorigenic adaptations. Mechanistically, G9a targeting potently repressed the expression of c-MYC and ATF4, master regulators of HB metabolic reprogramming. Conclusions: HBs display a profound dysregulation of the epigenetic machinery. Pharmacological targeting of key epigenetic effectors exposes metabolic vulnerabilities that can be leveraged to improve the treatment of these patients.
  • Thumbnail Image
    Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis
    (Springer Science and Business Media LLC, 2019) Latasa, M.U. (María Ujué); Blokhin, I.O. (Ilya O.); Monga, S.P. (Satdarshan P.); Dubuquoy, L. (Laurent); Berasain, C. (Carmen); Lozano, J.J. (Juan J.); Morgan, M.Y. (Marsha Y.); Vernetti, L.A. (Lawrence A.); Sancho-Bru, P. (Pau); Altamirano, J. (Jose); Wahlestedt, C. (Claes); Fondevilla, C. (Constantino); Gómez, J.L. (Juan L.); Arab, J.P. (Juan P.); Thursz, M.R. (Mark R.); Cao, S. (Sheng); Avila, M.A. (Matías Antonio); Atkinson, S.R. (Stephen R.); Rusyn, I. (Ivan); Edmunds, L.R. (Lia R.); Cabezas, J. (Joaquín); Furuya, S. (Shinji); Bell, A. (Aaron); Aragón, T. (Tomás); Mann, J. (Jelena); Shah, V.H. (Vijay H.); Jurczak, M.J. (Michael J.); Louvet, A. (Alexandre); Taylor, D.L. (D. Lansing); Lackner, C. (Carolin); Bataller, R. (Ramón); Odena, G. (Gemma); Caballeria, J. (Juan); Stärkel, P. (Peter); Gue, J.P. (Joel P.); Ventura-Cots, M. (Meritxell); Argemí, J. (Josepmaria); Mathurin, P. (Philippe); Massey, V. (Veronica); Van-Booven, D. (Derek)
    Alcoholic hepatitis (AH) is a life-threatening condition characterized by profound hepatocellular dysfunction for which targeted treatments are urgently needed. Identification of molecular drivers is hampered by the lack of suitable animal models. By performing RNA sequencing in livers from patients with different phenotypes of alcohol-related liver disease (ALD), we show that development of AH is characterized by defective activity of liver-enriched transcription factors (LETFs). TGFβ1 is a key upstream transcriptome regulator in AH and induces the use of HNF4α P2 promoter in hepatocytes, which results in defective metabolic and synthetic functions. Gene polymorphisms in LETFs including HNF4α are not associated with the development of AH. In contrast, epigenetic studies show that AH livers have profound changes in DNA methylation state and chromatin remodeling, affecting HNF4α-dependent gene expression. We conclude that targeting TGFβ1 and epigenetic drivers that modulate HNF4α-dependent gene expression could be beneficial to improve hepatocellular function in patients with AH.