Risultati per: Identificato un potenziale marcatore genetico per il trattamento del cancro al pancreas

Il 25 Airc celebra 60 anni d’impegno, 141 milioni alla ricerca

Case presentation A woman in her 70s presented to an Australian centre with right upper quadrant pain, fevers and weight loss. She was born in Greece, having lived in Australia for 50 years. Significant background included chronic lymphocytic leukaemia (CLL), treated with venetoclax and rituximab. Her white cell count was 3.20×109/L with normal liver function tests, bilirubin of 6 µmol/L and C reactive protein of 15 mg/L. Cross-sectional imaging with CT found intrahepatic, extrahepatic, common bile duct dilatation (CBD) to 11 mm, pancreatic duct dilatation to 6 mm (a ‘double duct’ sign) and prominent para-aortic, coeliac and porta lymph nodes (figure 1A). Tumour markers including CA19-9 were normal. She was treated with intravenous ceftriaxone and metronidazole for suspected cholangitis. MR cholangiopancreatography was performed finding widespread upper abdominal lymph nodes suggestive of metastatic disease, with a 4 mm ampullary lesion (figure 1B). A CT chest was performed, showing…

Crollano titoli in Borsa delle aziende del settore

Crollano titoli in Borsa delle aziende del settore

Domani ad Ancona congresso scientifico alla Politecnica Marche

Giorlandino, test dell’esoma per mappare la predisposizione a varie patologie

Emilia più attrattiva. Cittadinanzattiva, nodo malattie croniche

Emilia più attrattiva. Cittadinanzattiva, nodo malattie croniche

Background
Oncogenic ‘hotspot’ mutations of KRAS and GNAS are two major driver alterations in intraductal papillary mucinous neoplasms (IPMNs), which are bona fide precursors to pancreatic ductal adenocarcinoma. We previously reported that pancreas-specific Kras G12D and Gnas R201C co-expression in p48Cre; KrasLSL-G12D; Rosa26LSL-rtTA; Tg (TetO-GnasR201C) mice (‘Kras;Gnas’ mice) caused development of cystic lesions recapitulating IPMNs.

Objective
We aim to unveil the consequences of mutant Gnas R201C expression on phenotype, transcriptomic profile and genomic dependencies.

Design
We performed multimodal transcriptional profiling (bulk RNA sequencing, single-cell RNA sequencing and spatial transcriptomics) in the ‘Kras;Gnas’ autochthonous model and tumour-derived cell lines (Kras;Gnas cells), where Gnas R201C expression is inducible. A genome-wide CRISPR/Cas9 screen was conducted to identify potential vulnerabilities in KrasG12D;GnasR201C co-expressing cells.

Results
Induction of Gnas R201C—and resulting G(s)alpha signalling—leads to the emergence of a gene signature of gastric (pyloric type) metaplasia in pancreatic neoplastic epithelial cells. CRISPR screening identified the synthetic essentiality of glycolysis-related genes Gpi1 and Slc2a1 in Kras G12D;Gnas R201C co-expressing cells. Real-time metabolic analyses in Kras;Gnas cells and autochthonous Kras;Gnas model confirmed enhanced glycolysis on Gnas R201C induction. Induction of Gnas R201C made Kras G12D expressing cells more dependent on glycolysis for their survival. Protein kinase A-dependent phosphorylation of the glycolytic intermediate enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) was a driver of increased glycolysis on Gnas R201C induction.

Conclusion
Multiple orthogonal approaches demonstrate that Kras G12D and Gnas R201C co-expression results in a gene signature of gastric pyloric metaplasia and glycolytic dependency during IPMN pathogenesis. The observed metabolic reprogramming may provide a potential target for therapeutics and interception of IPMNs.

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