Biology subjects

Martinelli, P.

Publications and source records attributed to Martinelli, P..

7 recordsLinked to original sources

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↗

bioRxiv2026

Oncogenic E3-ligase adaptors MAGE-A3/6 promote cancer cell migration via BAP18 degradation

Cancer testis antigens are widely expressed in human malignancies. Melanoma-Associated Antigens (MAGE) A3 and A6 have been proposed to modulate protein turnover and metabolism in cancer cells. However, the substrate specificity of MAGE-A3/6 and the impact on cancer cell behavior remain poorly understood. Although previous research has identified binding partners, a molecularly validated target for MAGE-A3/6-mediated proteasomal degradation has not been described. In this study, we redefine the substrate specificity of MAGE-A3/6 and present a mechanistic framework for substrate binding, polyubiquitination, and subsequent degradation. We identify BPTF-Associated Protein of 18kDa (BAP18) as a bona fide novel substrate of MAGE-A3/6 and demonstrate its direct regulation via a molecularly defined substrate-degron-E3-adaptor interaction. The degradation of BAP18 by MAGE-A3/6 underlies phenotypic alterations in cancer cells, such as enhanced migratory capacity. This previously unrecognized molecular link is observed in both cancer cell lines and human cancer tissues, supporting a role as a fundamental oncogenic process. The discovery of a molecularly defined interaction between MAGE-A3/6 and their substrate enables systematic investigation into oncogenic protein degradation in human cancers and may inform future therapeutic strategies that leverage the molecular function of aberrantly reexpressed germline proteins in cancer.

cancer biology↗

bioRxiv2021

GATA4 and GATA6 loss-of-expression is associated with extinction of the classical programme and poor outcome in pancreatic ductal adenocarcinoma

ObjectiveGATA6 is a master regulator of pancreatic differentiation and a key regulator of the classical phenotype in pancreatic ductal adenocarcinoma (PDAC). Low GATA6 expression is associated with poor patient outcome. GATA4 is the second most expressed GATA factor in the pancreas. The aim was to assess whether, and how, GATA4 contributes to PDAC phenotype and to analyze the association of expression with clinical outcome. DesignWe analyzed PDAC transcriptomic data, stratifying cases according to GATA4 and GATA6 expression, and identified differentially expressed genes and pathways. A multicenter TMA study to assess GATA4 and GATA6 expression in PDAC samples (n=745) from patients undergoing tumour resection was performed using immunohistochemistry with antibodies of validated specificity. GATA4 and GATA6 levels were dichotomized into high/low categorical variables; association with outcome was assessed using univariable and multivariable Cox regression models. ResultsSubtype classification using transcriptomic data revealed that GATA4 mRNA is enriched in classical, compared to basal-like tumours. We classified samples in 4 groups as high/low for GATA4 and GATA6. Reduced expression of GATA4 did not have a major transcriptional impact. However, concomitant low expression of GATA4 enhanced the transcriptomic effects of GATA6 low expression. Reduced expression of both proteins in tumours was associated with the worst patient survival. GATA4 and GATA6 expression significantly decreased in metastases and negatively correlated with basal markers. ConclusionsOur analyses uncover a cooperative interaction between GATA4 and GATA6 to maintain the classical PDAC phenotype and provide compelling clinical rationale for assessing their expression as biomarkers of poor prognosis. SUMMARY BOXO_ST_ABSWhat is already known about this subject?C_ST_ABS- Patients with classical-type PDAC have a better outcome - Retrospective analyses suggest that classical-type PDAC is more sensitive to 5-FU-based chemotherapy - GATA6 is a surrogate biomarker of classical tumours and its expression is associated with better survival - GATA4 and GATA6 have overlapping and unique functions during pancreatic and gastrointestinal development What are the new findings?- Tumours displaying only low GATA4 expression have a transcriptomic profile similar to those with preserved expression of both transcription factors - Combined low expression of GATA4 and GATA6 has the highest transcriptomic impact - In a large multicenter tissue microarray study, patients with tumours showing low expression of both GATA4 and GATA6 have the worst overall survival - Low expression of GATA4 and GATA6 is an independent predictor of survival in patients with resectable PDAC - GATA4 levels are down-regulated in liver metastases and are negatively correlated with basal markers such as KRT5/6, KRT14, and TP63 How might it impact on clinical practice in the foreseeable future?- The combined assessment of GATA4 and GATA6 expression may improve prognostic stratification of patients with PDAC - Prospective studies should confirm whether GATA4 and GATA6 expression is also predictive of response to chemotherapy in PDAC patients

cancer biology↗

bioRxiv2020

A GATA6-centered gene regulatory network involving HNFs and ΔNp63 controls plasticity and immune escape in pancreatic cancer

ObjectiveMolecular taxonomy of tumors is the foundation of personalized medicine and is becoming of paramount importance for therapeutic purposes. Four transcriptomics-based classification systems of pancreatic ductal adenocarcinoma (PDAC) exist, which consistently identified a subtype of highly aggressive PDACs with basal-like features, including {Delta}Np63 expression and loss of the epithelial master regulator GATA6. We investigated the precise molecular events driving PDAC progression and the emergence of the basal program. DesignWe combined the analysis of patient-derived transcriptomics datasets and tissue samples with mechanistic experiments using a novel dual-recombinase mouse model for Gata6 deletion at late stages of KRasG12D-driven pancreatic tumorigenesis (Gata6LateKO). ResultsThis comprehensive human-to-mouse approach allowed us to show that GATA6 loss is necessary, but not sufficient, for the expression of a basal program in patients and in mice. The concomitant loss of HNF1A and HNF4A, likely through epigenetic silencing, is required for the full phenotype switch. Moreover, Gata6 deletion in mice dramatically increased the metastatic rate, with a propensity for lung metastases. Through RNA-Seq analysis of primary cells isolated from mouse tumors, we show that Gata6 inhibits tumor cell plasticity and immune evasion, suggesting that it works as a barrier for acquiring the fully developed basal and metastatic phenotype. ConclusionsOur work provides both a mechanistic molecular link between the basal phenotype and metastasis and a valuable preclinical tool to investigate the most aggressive subtype of PDAC. These data, therefore, are important for understanding the pathobiological features underlying the heterogeneity of pancreatic cancer in both mice and human. What is already known about this subject?O_LIMultiple transcriptomics-based studies have identified a basal-like subtype of pancreatic ductal adenocarcinoma (PDAC) with especially poor prognosis. C_LIO_LILoss of GATA6 in PDAC cells is associated with altered differentiation, including ectopic expression of basal markers such as KRT14. C_LIO_LIAberrant expression of the {Delta}Np63 transcription factor can drive the expression of the basal transcriptional program. C_LI What are the new findings?O_LILoss of GATA6 expression is necessary but not sufficient for the expression of {Delta}Np63 and the basal phenotype. C_LIO_LIConcomitant silencing of HNF4A and HNF1A, possibly through epigenetic mechanisms, is required for the full-blown phenotype. C_LIO_LIGata6 deletion in established murine tumors favors the basal and metastatic phenotype, with a lung tropism, in a next-generation model of KRasG12D-driven PDAC. C_LIO_LILoss of GATA6 expression is associated with features of immune escape in mouse and human PDAC cells. C_LI How might it impact on clinical practice in the foreseeable future?O_LIThe combined analysis of GATA6, HNFs, and TP63 expression in patient-derived samples will provide a more precise classification of PDAC. C_LIO_LIRestoration of the classical PDAC phenotype may not only reduce metastatic potential but also increase immune recognition of tumor cells. C_LI

cancer biology↗

bioRxiv2019

The GATA3 X308_Splice breast cancer mutation is a hormone context-dependent oncogenic driver

As the catalogue of oncogenic driver mutations is expanding, it is becoming clear that alterations in a given gene should not be lumped into one single class, since they might have different functions. The transcription factor GATA3 is a paradigm of this. Here, we address the functions of the most common GATA3 mutation (X308_Splice) which generates a neoprotein that we designate as neoGATA3, associated with good patient prognosis. Based on extensive analyses of molecular and clinical data from approximately 3000 breast cancer patients, supported by mechanistic studies in vitro, we show that neoGATA3 interferes with the transcriptional programs controlled by estrogen and progesterone receptors, without fully abrogating them. This has opposite outputs in the pre- or post-menopausal hormonal context, having pro- or anti-proliferative effects, respectively. NeoGATA3 is an example of a context- and stage-dependent driver mutation. Our data call for functional analyses of putative cancer drivers to guide clinical application.

cancer biology↗

bioRxiv2019

Postnatal development of skeletal muscle in IUGR pigs: morphofunctional phenotype and molecular mechanisms

Intrauterine growth restriction (IUGR) is a serious condition which impairs the achievement of the fetus full growth potential and occurs in a natural and severe manner in pigs. Knowledge on skeletal muscle morphofunctional phenotype and its molecular regulation in IUGR pigs is important to understand postnatal muscle development and may help the establishment of therapies to improve skeletal muscle growth in those individuals. To investigate the impairment of skeletal muscle postnatal development due to IUGR, we evaluated the histomorphometrical pattern of the semitendinosus muscle, the Myosin Heavy Chain (embryonic, I, IIa, IIb and IIx MyHC) fiber composition and the relative expression of genes related to myogenesis, adipogenesis and growth during three specific periods: postnatal myogenesis (newborn to 100 days of age), postnatal development (newborn to 150 days of age), and hypertrophy (100 days to 150 days of age), comparing IUGR and normal birth weight (NW) pigs. Growth restriction in utero affected muscle fiber diameter, total fiber number and muscle cross sectional area which were smaller in IUGR pigs at birth (P < 0.05). Even though the percentage of MyHC-I myofibers was higher in IUGR females at birth (P < 0.05), in older gilts, a lower percentage of MyHC-IIx isoform (P < 0.05) and the presence of emb-MyHC were also observed in that experimental group. Regarding the pattern of gene expression in the postnatal myogenesis period, growth restriction in utero led to a down regulation of myogenic factors, which delayed the expression of signals that induces skeletal muscle myogenesis (PAX7, MYOD, MYOG, MYF5 and DES). Taken together, the muscle morphofunctional aspects described and their ontogenetic regulation define the possible molecular origins of the notorious damage to the postnatal musculature development in IUGR pigs.

cell biology↗

bioRxiv2017

Transcriptional regulation by NR5A2 couples cell differentiation and inflammation in the pancreas

Tissue-specific differentiation and inflammatory programmes are thought to independently contribute to disease. The orphan nuclear receptor NR5A2 is a key regulator of pancreas differentiation and SNPs in or near the human gene are associated with risk of pancreatic cancer. In mice, Nr5a2 heterozygosity sensitizes the pancreas to damage, impairs regeneration, and cooperates with mutant KRas in tumor progression. Through global transcriptomic analysis, we uncover a basal pre-inflammatory state in the pancreas of Nr5a2 heterozygous mice that is reminiscent of pancreatitis-induced inflammation and is conserved in histologically normal human pancreata with reduced NR5A2 mRNA expression. In Nr5a2+/- mice, Nr5a2 undergoes a dramatic transcriptional switch relocating from tissue-specific to inflammatory loci thereby promoting AP-1-dependent gene transcription. Importantly, deletion of c-Jun in the pancreas of these mice rescues the pre-inflammatory phenotype and the defective regenerative response to damage. These findings provide compelling evidence that the same transcriptional networks supporting homeostasis in normal tissue can be subverted to foster inflammation upon genetic or environmental constraints.

cancer biology↗