{"id":3703,"date":"2021-01-12T14:52:28","date_gmt":"2021-01-12T13:52:28","guid":{"rendered":"https:\/\/staging.wp-ibdm.nicolasg.fr\/lequipe-maina-publie-dans-le-journal-of-hepatology\/"},"modified":"2022-07-09T11:30:28","modified_gmt":"2022-07-09T09:30:28","slug":"lequipe-maina-publie-dans-le-journal-of-hepatology","status":"publish","type":"post","link":"https:\/\/staging.wp-ibdm.nicolasg.fr\/fr\/lequipe-maina-publie-dans-le-journal-of-hepatology\/","title":{"rendered":"L’\u00e9quipe Maina publie dans le Journal of Hepatology"},"content":{"rendered":"

Le microenvironnement de la tumeur a des effets profonds sur l’initiation, la progression et la r\u00e9sistance aux m\u00e9dicaments du cancer. ADAMTSL5 est une prot\u00e9ine s\u00e9cr\u00e9t\u00e9e par les cellules HCC, qui n’\u00e9tait pas auparavant li\u00e9e au cancer. Nous avons d\u00e9couvert que ADAMTSL5 est un oncog\u00e8ne \u00e9pig\u00e9n\u00e9tiquement activ\u00e9 surexprim\u00e9 chez une grande partie des patients humains atteints de HCC et dans des mod\u00e8les murins de HCC. Nous avons d\u00e9montr\u00e9 qu’ADAMTSL5 est impliqu\u00e9 non seulement dans la tumorigen\u00e8se, mais aussi dans la r\u00e9sistance aux m\u00e9dicaments, car le ciblage d’ADAMTSL5 conf\u00e8re une sensibilit\u00e9 aux m\u00e9dicaments utilis\u00e9s en clinique.<\/p>\n

Article en anglais\u00a0<\/em><\/p>\n

\"The
The scheme illustrates how in healthy liver (both mouse and human), ADAMTSL5 is expressed at very low levels due to the absence of methylation in the gene body CpG island. Instead, in HCC, ADAMTSL5 is overexpressed due to gene body CpG island hypermethylation. Top: ADAMTSL5 confers tumorigenicity and drug-resistance to HCC cells while its targeting resulted in sensitization to clinically relevant drugs. Additionally, demethylating agents (Decitabine) reduces ADAMTSL5 expression in HCC cells. Bottom: In HCC patients, ADAMTSL5 overexpression correlates with worse prognosis, reduced genetic alterations, and with alcohol consumption as a main risk factor in HCC patients.<\/figcaption><\/figure>\n

ADAMTSL5 is an epigenetically activated gene underlying tumorigenesis and drug resistance in hepatocellular carcinoma<\/b><\/h3>\n

Summary.\u00a0<\/b>The tumour microenvironment shapes tumour growth through cellular communications that include both direct interactions and secreted factors. The aim of this study was to characterize the impact of the secreted glycoprotein ADAMTSL5, whose role in cancer has not been previously investigated, on hepatocellular carcinoma (HCC).<\/b><\/p>\n

Methylome analysis revealed hypermethylated gene body CpG islands at the\u00a0ADAMTSL5<\/i>\u00a0locus in both mouse and human HCC, correlating with higher ADAMTSL5 expression. ADAMTSL5 targeting interfered with tumorigenic properties of HCC cells in vitro and in vivo, whereas ADAMTSL5 overexpression conferred tumorigenicity to pre-tumoral hepatocytes sensitized to transformation by a modest level of MET receptor expression. Mechanistically, ADAMTSL5 abrogation led to reduction of several oncogenic inputs relevant to HCC, including reduced expression and\/or phosphorylation levels of receptor tyrosine kinases MET, EGFR, PDGFR\u03b2, IGF1R\u03b2, or FGFR4. This phenotype was associated with significantly increased sensitivity of HCC cells to clinically relevant drugs, namely Sorafenib, Lenvatinib, Regorafenib. Moreover, ADAMTSL5 depletion drastically increased expression of AXL, accompanied by a sensitization to Bemcentinib. Our results point to a role for ADAMTSL5 in maintaining the function of key oncogenic signalling pathways, suggesting that it may act as a master regulator of tumorigenicity and drug resistance in HCC.<\/b><\/p>\n

To know more :<\/h3>\n