Biology subjects

del Pozo, N.

Publications and source records attributed to del Pozo, N..

6 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↗

bioRxiv2024

ΔNP63 defines an exocrine-committed multipotent progenitor subset in the murine pancreas

Cellular plasticity underpins heterogeneity in embryogenic progenitor cells and cancer cells. The transcription factor deltaNp63 ({Delta}Np63) has been implicated in regulating cellular plasticity in several epithelial tissues. Despite a recently established role in steering plasticity of pancreatic cancer, {Delta}Np63 remains unstudied in pancreatic development. Using murine single-cell sequencing data and RNA and protein in situ stainings, we assessed the spatio-temporal expression of Trp63 and {Delta}NP63 in the embryonic pancreas. {Delta}NP63 demonstrates a transient and spatially restricted expression in the multipotent pancreatic progenitor (MPP) compartment delineating pro-exocrine progenitor cells. Lineage tracing of TP63+ cells marks a subset of MPPs and descendant exocrine acinar and centro-acinar/terminal duct cells. Lack of {Delta}NP63 in knock-out mice leads to hypotrophic exocrine acini with reduced levels of differentiation markers. In summary, {Delta}Np63 confers heterogeneity within the MPP compartment, supporting exocrine cell development. These new insights in developmental plasticity have potential implications for pancreatic regeneration and cancer.

developmental biology↗

bioRxiv2024

A common CTRB misfolding variant associated with pancreatic cancer risk causes ER stress and inflammation in mice

ObjectiveGenome wide association studies have identified an exon 6 CTRB2 deletion variant that associates with increased risk of pancreatic cancer. To acquire evidence on its causal role, we developed a new mouse strain carrying an equivalent variant in Ctrb1, the mouse orthologue of CTRB2. DesignWe used CRISPR/Cas9 to introduce a 707bp deletion in Ctrb1 encompassing exon 6 (Ctrb1{Delta}exon6). This mutation closely mimics the human deletion variant. Mice carrying the mutant allele were extensively profiled at 3 months to assess their phenotype. ResultsCtrb1{Delta}exon6 mutant mice express a truncated CTRB1 that accumulates in the ER. The pancreas of homozygous mutant mice displays reduced chymotrypsin activity and total protein synthesis. The histological aspect of the pancreas is inconspicuous but ultrastructural analysis shows evidence of dramatic ER stress and cytoplasmic and nuclear inclusions. Transcriptomic analyses of the pancreas of mutant mice reveals acinar program down-regulation and increased activity of ER stress-related and inflammatory pathways. Heterozygous mice have an intermediate phenotype. Agr2 is one of the most up-regulated genes in mutant pancreata. Ctrb1{Delta}exon6 mice exhibit impaired recovery from acute caerulein-induced pancreatitis. Administration of TUDCA or sulindac partially alleviates the phenotype. A transcriptomic signature derived from the mutant pancreata is significantly enriched in normal human pancreas of CTRB2 exon 6 deletion variant carriers from the GTEx cohort. ConclusionsThis mouse strain provides formal evidence that the Ctrb1{Delta}exon6 variant causes ER stress and inflammation in vivo, providing an excellent model to understand its contribution to pancreatic ductal adenocarcinoma development and to identify preventive strategies. SUMMARY BOX What is already known about this subject?- CTRB2 is one of the most abundant proteins produced by human pancreatic acinar cells. - A common exon 6 deletion variant in CTRB2 has been associated with an increased risk of pancreatic ductal adenocarcinoma. - Misfolding of digestive enzymes is associated with pancreatic pathology. What are the new findings?- We developed a novel genetic model that recapitulates the human CTRB2 deletion variant in the mouse orthologue, Ctrb1. - Truncated CTRB1 misfolds and accumulates in the ER; yet, mutant mice display a histologically normal pancreas at 3 months age. - CTRB1 and associated chaperones colocalize in the ER, the cytoplasm, and the nucleus of acinar cells. - Transcriptomics analysis reveals reduced activity of the acinar program and increased activity of pathways involved in ER stress, unfolded protein response, and inflammation. - Mutant mice are sensitized to pancreatic damage and do not recover properly from a mild caerulein-induced pancreatitis. - TUDCA administration partially relieves the ER stress in mutant mice. How might it impact on clinical practice in the foreseeable future?- The new mouse model provides a tool to identify the mechanisms leading to increased pancreatic cancer risk in CTRB2 exon 6 carriers. - The findings suggest that drugs that cause ER stress relief and/or reduce inflammation might provide preventive opportunities.

cancer biology↗

bioRxiv2021

NFIC regulates ribosomal biology and ER stress in pancreatic acinar cells and suppresses PDAC initiation

Tissue-specific differentiation is driven by specialized transcriptional networks. Pancreatic acinar cells crucially rely on the PTF1 complex, and on additional transcription factors, to deploy their transcriptional program. Here, we identify NFIC as a novel regulator of acinar differentiation using a variety of methodological strategies. NFIC binding sites are found at very short distances from NR5A2-bound genomic regions and both proteins co-occur in the same complex. Nfic knockout mice show reduced expression of acinar genes and, in ChIP-seq experiments, NFIC binds the promoters of acinar genes. In addition, NFIC binds to the promoter of, and regulates, genes involved in RNA and protein metabolism; in Nfic knockout mice, p-RS6K1 and p-IEF4E are down-regulated indicating reduced activity of the mTOR pathway. In 266-6 acinar cells, NFIC dampens the ER stress program through its binding to ER stress gene promoters and is required for complete resolution of Tunicamycin-mediated ER stress. Normal human pancreata from subjects with low NFIC mRNA levels display reduced epxression of genes down-regulated in Nfic knockout mice. Consistently, NFIC displays reduced expression upon induced acute pancreatitis and is required for proper recovery after damage. Finally, expression of NFIC is lower in samples of mouse and human pancreatic ductal adenocarcinoma and Nfic knockout mice develop an increased number of mutant Kras-driven pre-neoplastic lesions.

cell 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↗

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↗