Biology subjects

IOVANNA, J. L.

Publications and source records attributed to IOVANNA, J. L..

5 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↗

bioRxiv2023

Redefining phenotypic intratumor heterogeneity of pancreatic ductal adenocarcinoma: a bottom-up approach

BackgroundPancreatic ductal adenocarcinoma (PDAC) tumor inter-patient heterogeneity has been well described with two major prognostic subtypes (classical and basal-like). An important intra-patient heterogeneity has been reported but has not yet been extensively studied due to the lack of standardized, reproducible and easily accessible high throughput methods. Material and MethodsWe built an immunohistochemical (IHC) tool capable of differentiating RNA-defined classical and basal-like tumors by selecting relevant antibodies using a multi-step process. The successive stages of i) an in-silico selection from a review literature and a bulk transcriptome analysis of 309 PDACs, ii) a tumor-specific selection from 30 patient-derived xenografts followed by iii) the validation on tissue microarrays in 50 PDAC were conducted. We used our final IHC panel on two independent cohorts of resected PDAC (n=95, whole-slide, n=148, tissue microarrays) for external validation. After digitization and registration of pathology slides, we performed a tile-based-analysis in tumor and pre-neoplastic epithelial areas and a k-means clustering to identify relevant marker combinations. ResultsSequential marker selection led to the following panel: GATA6, CLDN18, TFF1, MUC16, S100A2, KRT17, PanBasal. Four different phenotypes were identified: 1 classical, 1 intermediate (KRT17+) and 2 basal-like (MUC16+ vs S100A2+) with specific biological properties. The presence of a minor basal contingent drastically reduced overall survival, even in classical predominant PDACs (HR=2.36, p=0.01). Analysis of preneoplastic lesions suggested that pancreatic carcinogenesis may follow a progressive evolution from classical toward a basal through an early intermediate phenotype. ConclusionOur IHC panel redefined and easily assessed the high degree of intra- and inter-tumoral heterogeneity of PDAC.

cancer biology↗

bioRxiv2022

Adaptation of redox metabolism in drug-tolerant persister cells is a vulnerability to prevent relapse in pancreatic cancer

Pancreatic Ductal Adenocarcinoma (PDAC) remains a major unresolved disease because of its remarkable therapeutic resistance. Even patients who respond to initial therapy experience relapse in most cases. The mechanisms underlying therapy-acquired resistance supporting relapse are poorly understood. In this study, we aimed to determine the metabolic features of PDAC during relapse, specifically adaptations of mitochondrial and redox metabolism. We used preclinical PDAC mouse models (patient-derived xenografts and murine syngeneic allografts) that present complete regression under initial chemotherapeutic treatment but relapse after a certain time. Relapsed tumors were analyzed ex vivo by flow cytometry to measure mitochondrial and redox characteristics. Molecular mechanisms were investigated by quantification of ATP and antioxidants levels, RT-qPCR and bulk RNA-sequencing. Our findings show that mitochondrial metabolism is reprogrammed during relapse, with increased mitochondrial mass, ATP levels, mitochondrial superoxide anions, and total ROS levels, in relapsed compared to control tumors in both models; mitochondrial membrane potential is increased in the xenografts model only. This mitochondrial metabolic reprogramming occurs during treatment-induced regression and at relapse onset. At the molecular level, antioxidant defenses are increased in relapsed tumors and during treatment. These data suggest that treatment-induced oxidative stress may cause the appearance of treatment-adapted cells, known as drug-tolerant persister (DTP) cells. Finally, the combined treatment of arsenic trioxide (ROS inducer) and buthionine sulfoximine (glutathione synthesis inhibitor) is able to completely prevent relapse in PDAC xenografts. In conclusion, targeting redox metabolism via ROS production and antioxidant inhibition is a very promising approach to prevent relapse in PDAC patients. SignificanceMitochondrial and redox metabolisms are reprogrammed during treatment-acquired resistance in pancreatic cancer promoting the survival of drug-tolerant persister cancer cells, opening up new avenues for better therapeutic management of patients.

cancer biology↗

bioRxiv2021

p97/VCP induces GLI1 to control XBP1-dependent endoplasmic reticulum stress transcriptional response

Upon accumulation of improperly folded proteins in the ER, an adaptive pathway named the UPR is triggered to restore ER homeostasis. The induction of stress genes controlling ER dynamics is a condition sine qua non for an effective UPR. Although this requirement has been extensively characterized, the transcriptional mechanism underlying this process remains in part elucidated. Here, we show that p97/VCP, an AAA+ ATPase known to modulate ER stress-induced gene expression, dynamically interacts with RUVBL2 and the mSin3A-HDAC1/2 complex. Further analysis of the mechanism defined a novel interplay between the aforementioned molecules and the transcription factor USF2 to control expression of GLI1, a primary effector of Hedgehog (Hh) signaling. Under basal conditions, GLI1 is repressed by RUVBL2-mSin3A-HDAC1/2 while upon ER stress GLI1 is induced through a mechanism requiring p97/VCP-mediated extraction of the repressor complex. Further analysis showed that GLI1 cooperate with ATF6f to activate the expression of XBP1, a transcription factor regulating the expression of genes controlling cellular stress response, under ER conditions. Overall, our work demonstrates that p97/VCP orchestrates the activation of GLI1 upon ER stress in a Hh ligand-independent fashion and defines the interplay between the newly identified p97/VCP-mSin3A-HDAC1/2 complex and the transcription factor USF2 as an essential player in this process.

cancer biology↗

bioRxiv2021

Metabolomic profiling of pancreatic adenocarcinoma reveals fundamental clinical features

In this study, we perform the metabolomics profiling of 77 PDAC patient-derived tumor xenografts (PDTX) to investigate the relationship of metabolic profiles with overall survival (OS) in PDAC patients, tumor phenotypes and resistance to five anticancer drugs (gemcitabine, oxaliplatin, docetaxel, SN-38 and 5-Fluorouracil). We identified a metabolic signature that was able to predict the clinical outcome of PDAC patients (p < 0.001, HR=2.68 [95% CI: 1.5-4.9]). The correlation analysis showed that this metabolomic signature was significantly correlated with the PDAC molecular gradient (PAMG) (R = 0.44 and p < 0.001) indicating significant association to the transcriptomic phenotypes of tumors. Resistance score established, based on growth rate inhibition metrics using 35 PDTX-derived primary cells, allowed to identify several metabolites related to drug resistance which was globally accompanied by accumulation of several diacy-phospholipids and decrease in lysophospholipids. Interestingly, targeting glycerophospholipid synthesis improved sensitivity to the three tested cytotoxic drugs indicating that interfering with metabolism could be a promising therapeutic strategy to overcome the challenging resistance of PDAC. Short abstractTargeting metabolism of cancer cells gives a precious opportunity to overcome challenges related to the high mortality and chemoresistance in PDAC. Metabolic profiling of PDAC patient-derived tumor xenografts used in this study allowed highlighting the strong link between metabolism and both clinical outcome of the patients and chemoresistance. Metabolic signature was able to discriminate between good and bad prognosis groups of patients based on their level of key metabolites. Identification of key metabolic markers associated to chemoresistance allowed to improve sensitivity to anticancer drugs. These results provide new insights to help to predict patient survival and elaborate new combinatory therapies against chemoresistance in PDAC patients attesting of the important clinical value of this work.

cancer biology↗