Biology subjects

Esposito, I.

Publications and source records attributed to Esposito, I..

5 recordsLinked to original sources

bioRxiv2026

GALE-dependent glycoproteome remodelling is a determinant of oncogenic RAS transformation

Oncogenic transformation is accompanied by extensive remodelling of the cellular glycosylation landscape, yet the mechanisms linking oncogenic signalling to glycoproteome reprogramming remain poorly defined. We used site-resolved intact glycoproteomics to systematically map oncogenic RAS-dependent changes across the N- and O-linked glycoproteome. Integrating multiomics profiling with functional approaches, we identify UDP-glucose 4-epimerase (GALE) as a transcriptional target of oncogenic RAS that is induced through MAPK signalling and MYC-dependent transcription. GALE depletion selectively disrupted RAS-dependent glycoproteome remodelling, preferentially impairing sialylation of N-linked glycans and O-linked GalNAc-type glycosylation. Functionally, these glycosylation defects were accompanied by suppressed anchorage-independent growth and reduced in vivo tumorigenicity of KRAS-mutant cells, establishing GALE-dependent nucleotide-sugar interconversion as a requirement for malignant growth. Clinically, GALE expression was elevated in pancreatic ductal adenocarcinoma, wherein KRAS mutations are highly prevalent, and across a broad spectrum of human cancers. Collectively, our findings define a regulatory axis that connects oncogenic signalling to nucleotide-sugar precursor availability and diversification of the cellular glycan repertoire, revealing GALE as a metabolic dependency in RAS-driven cancer.

Cancer Biology↗

bioRxiv2026

GATA4 loss promotes mutant Kras-driven pancreatic ductal adenocarcinoma in the absence of canonical precursor lesions

ABSTRACTGATA6 and GATA4 play key roles in pancreatic development and are essential to maintain the classical transcriptional program in pancreatic ductal adenocarcinoma (PDAC). Using genetic mouse models we show that, in contrast to GATA6, GATA4 is dispensable for the maintenance of acinar homeostasis in the adult pancreas. Deletion of Gata4 in mice expressing mutant Kras in the embryonic pancreas (KG4C) leads to PDAC development in the absence of tissue remodeling, pancreatic intraepithelial neoplasia (PanIN), or other canonical precursor lesions present in Gata4-proficient (KC) mice. Similar observations were made when Gata4 was selectively inactivated in adult, Kras-mutant, acinar cells. We identify Pale Acinar Lesions (PALes) as a previously unrecognized pancreatic lesion, distinct from acino-ductal metaplasia (ADM) and PanINs, present in KC and KG4C mice but not in wild type mice. PALes display weak expression of acinar and ductal markers and lack mucins; they have lower proliferation rates than PanINs. RNA-seq and ChIP-seq reveal that GATA4 and GATA6 partially share genomic binding sites and transcriptomic effects, but they exert opposing influences on mutant Kras-induced, haematopoietic cell-dependent, transcriptional inflammatory programs. Adenoviral-mediated pancreatic expression of IL17 restored the formation of ductal lesions in KG4C mice but failed to rescue PanIN development. Our data indicate that GATA4 functions through the coordinated action of multiple inflammatory factors that are required for ADM/PanIN formation but are dispensable for PDAC development. Collectively, these findings challenge current paradigms of PDAC initiation and progression.

cancer biology↗

bioRxiv2021

EIF4EBP1 is transcriptionally upregulated by MYCN and associates with poor prognosis in neuroblastoma

BackgroundNeuroblastoma (NB) accounts for 15% of cancer-related deaths in childhood despite considerable therapeutic improvements. While several risk factors, including MYCN amplification and alterations in RAS and p53 pathway genes, have been defined in NB, the clinical outcome is very variable and difficult to predict. Since genes of the mTOR pathway are up-regulated in MYCN-amplified NB, we aimed to define the predictive value of the mTOR substrate-encoding gene eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1) expression in NB patients. MethodsSeveral independent NB patient cohorts with corresponding mRNA expression data were analyzed for EIF4EBP1 expression. An institutional NB cohort consisting of 69 prospectively collected tumors was employed to immunohistochemically analyze expression of EIF4EBP1-encoded protein (4EBP1). In addition, we performed an in vitro luciferase reporter gene assay with an episomal EIF4EBP1 promoter and genetically modulated MYCN expression in NB cells. FindingsEIF4EBP1 mRNA expression was positively correlated with MYCN expression and elevated in stage 4 and high-risk NB patients. High EIF4EBP1 mRNA expression was associated with reduced overall and event-free survival in the entire group of NB patients in three cohorts, as well as in stage 4 and high-risk patients. High levels of 4EBP1 were significantly associated with prognostically unfavorable NB histology. Functional analyses in vitro revealed that EIF4EBP1 expression is transcriptionally controlled by MYCN binding to the EIF4EBP1 promoter. InterpretationHigh EIF4EBP1 expression is associated with poor prognosis in NB patients and may serve to stratify patients with high-risk NB. FundingG.L. was supported by funding from the Elterninitiative Dusseldorf e.V., the Research Commission of the Medical Faculty of Heinrich Heine University, the Deutsche Forschungsgemeinschaft (Grant LE 3751/2-1), and the German Cancer Aid (Grant 70112624). The laboratory of T.G.P.G. is supported by the Barbara und Wilfried Mohr Foundation. BR is supported by the Israel Science Foundation (grant No. 1436/19). RESEARCH IN CONTEXT Evidence before this studyNB represents a particularly heterogeneous cancer entity, with 5-year event-free survival rate ranging from 50% to 98% depending on the patients risk group. While genes of the nutrient-sensing mTOR pathway were found to be up-regulated in MYCN-amplified NB tumors, their clinical relevance and prognostic value in NB patients remain unclear. In particular, the mTOR substrate-encoding gene EIF4EBP1 was studied in NB by three different groups and high EIF4EBP1 mRNA expression was observed in MYCN-amplified or contradictorily in more favorable stages 1 and 2 patients. Also, EIF4EBP1 was included in a prognostic gene signature for poor overall survival in NB. However, the prognostic value of EIF4EBP1 alone was not determined in NB and the expression of EIF4EBP1 encoded protein, 4EBP1, was not analyzed in NB tumor tissues and not correlated with clinicopathological features such as histological subtypes. Additionally, the transcriptional regulation of the EIF4EBP1 promoter by MYCN was not characterized. Added value of this studyThis study uncovers the prognostic potential of EIF4EBP1 at the mRNA and protein levels in NB patients. We report that high EIF4EBP1 expression is correlated with poor survival in three independent cohorts and that high 4EBP1 levels is associated with a prognostically unfavorable histological subtype. High EIF4EBP1 expression is also a factor of poor prognosis in stage 4 and high-risk patient groups. Finally, we found that MYCN activates the human EIF4EBP1 promoter through binding at three binding motifs. Implications of all the available evidenceEIF4EBP1 mRNA and 4EBP1 protein expression have prognostic value in NB, especially to stratify patients with advanced and more aggressive NB, such as patients with stage 4 disease and high-risk patients including those with unfavorable histological subtype NB. Enhanced EIF4EBP1 mRNA and 4EBP1 protein expression in NB are driven by direct transcriptional activation of EIF4EBP1 by MYCN.

cancer biology↗

bioRxiv2021

NOXA expression drives synthetic lethality to RUNX1 inhibition in pancreatic cancer

Evasion from drug-induced apoptosis is a crucial mechanism of cancer treatment resistance. The pro-apoptotic protein NOXA marks an aggressive pancreatic ductal adenocarcinoma (PDAC) subtype. To identify drugs that unleash the death-inducing potential of NOXA, we performed an unbiased drug screening experiment. In NOXA-deficient isogenic cellular models we identified an inhibitor of the transcription factor heterodimer CBF{beta}/RUNX1. By genetic gain and loss of function experiments we validated that the mode of action depends on RUNX1 and NOXA. Of note, RUNX1 expression is significantly higher in PDACs compared to normal pancreas. We show that pharmacological RUNX1 inhibition significantly blocks tumor growth in vivo and in primary patient-derived PDAC organoids. Through genome wide analysis, we detected that RUNX1-loss reshapes the epigenetic landscape, which gains H3K27ac enrichment at the NOXA promoter. Our study demonstrates a previously unknown mechanism of NOXA-dependent cell death, which can be triggered pharmaceutically. Therefore, our data show a novel way to target a therapy resistant PDAC, an unmet clinical need. SignificanceRecent evidence demonstrated the existence of molecular subtypes in pancreatic ductal adenocarcinoma (PDAC), which resist all current therapies. The paucity of therapeutic options, including a complete lack of targeted therapies, underscore the urgent and unmet medical need for the identification of targets and novel treatment strategies for PDAC. Our study unravels a function of the transcription factor RUNX1 in apoptosis regulation in PDAC. We show that pharmacological RUNX1 inhibition in PDAC is feasible and leads to NOXA-dependent apoptosis. The development of targeted therapies that influence the transcriptional landscape of PDAC might have great benefits for patients who are resistant to conventional therapies. RUNX1 Inhibition as a new therapeutic intervention offers an attractive strategy for future therapies.

cancer biology↗

bioRxiv2019

HNF1A recruits UTX to activate a differentiation program that suppresses pancreatic cancer

Defects in transcriptional regulators of pancreatic exocrine differentiation have been implicated in pancreatic tumorigenesis, but the molecular mechanisms are poorly understood. The locus encoding the transcription factor HNF1A harbors susceptibility variants for pancreatic ductal adenocarcinoma (PDAC), while KDM6A, encoding the histone demethylase UTX, carries somatic mutations in PDAC. Here, we show that pancreas-specific Hnf1a null mutations phenocopy Utx deficient mutations, and both synergize with KrasG12D to cause PDAC with sarcomatoid features. We combine genetic, epigenomic and biochemical studies to show that HNF1A recruits UTX to genomic binding sites in pancreatic acinar cells. This remodels the acinar enhancer landscape, activates a differentiation program, and indirectly suppresses oncogenic and epithelial-mesenchymal transition genes. Finally, we identify a subset of non-classical PDAC samples that exhibit the HNF1A/UTX-deficient molecular phenotype. These findings provide direct genetic evidence that HNF1A-deficiency promotes PDAC. They also connect the tumor suppressive role of UTX deficiency with a cell-specific molecular mechanism that underlies PDAC subtype definition.

genomics↗