A long-standing question in the pancreatic ductal adenocarcinoma (PDAC) field has been whether alternative genetic alterations could substitute for oncogenic KRAS mutations in initiating malignancy. Here, we report that Neurofibromin1 (NF1) inactivation can bypass the requirement of mutant KRAS for PDAC pathogenesis. An in-depth analysis of PDAC databases reveals various genetic alterations in the NF1 locus, including nonsense mutations, which occur predominantly in tumors with wild-type KRAS. Genetic experiments demonstrate that NF1 ablation culminates in acinar-to-ductal metaplasia, an early step in PDAC. Furthermore, NF1 haploinsufficiency results in a dramatic acceleration of Kras-driven PDAC. Finally, we show an association between NF1 and p53 that is orchestrated by PML, and mosaic analysis with double markers demonstrates that concomitant inactivation of NF1 and Trp53 is sufficient to trigger full-blown PDAC. Together, these findings open up an exploratory framework for apprehending the mechanistic paradigms of PDAC with normal KRAS, for which no effective therapy is available.
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http://dx.doi.org/10.1016/j.celrep.2022.111623 | DOI Listing |
Neoplasia
January 2025
Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW 2031, Australia; School of Clinical Medicine, Faculty of Medicine & Health, University of New South Wales, Kensington, New South Wales 2031, Australia; UNSW Centre for Childhood Cancer Research, Faculty of Medicine &Health, University of New South Wales, Kensington, New South Wales 2031, Australia; Australian Centre for NanoMedicine, University of New South Wales, Sydney, NSW 2031, Australia. Electronic address:
Introduction: The impact of endoplasmic reticulum (ER) stress in tumor-associated cells, such as cancer associated fibroblasts (CAFs), immune cells and endothelial cells, on patient outcomes in clinical specimens have not been examined. For the first time, we characterized the expression and spatial locations of ER stress markers, BiP and CHOP, in tumor-associated cells and assessed their prognostic significance in a panel of pancreatic ductal adenocarcinoma (PDAC) patient samples.
Methods: Multiplex immunofluorescence was performed on tumor microarrays and images were analyzed using HALO AI software.
World J Gastrointest Oncol
January 2025
Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, Bucharest 050474, Romania.
Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive lethal malignancy with limited options for treatment and a 5-year survival rate of 11% in the United States. As for other types of tumors, such as colorectal cancer, aberrant lipid synthesis and reprogrammed lipid metabolism have been suggested to be associated with PDAC development and progression.
Aim: To identify the possible involvement of lipid metabolism in PDAC by analyzing in tumoral and non-tumoral tissues the expression level of the most relevant genes involved in the long-chain fatty acid (FA) import into cell.
World J Gastrointest Oncol
January 2025
Pathology Department, Xuanhan County People's Hospital, Dazhou 636150, Sichuan Province, China.
Background: Pancreatic cancer remains one of the most lethal malignancies worldwide, with a poor prognosis often attributed to late diagnosis. Understanding the correlation between pathological type and imaging features is crucial for early detection and appropriate treatment planning.
Aim: To retrospectively analyze the relationship between different pathological types of pancreatic cancer and their corresponding imaging features.
Transl Cancer Res
December 2024
Department of Oncology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China.
Background: Pancreatic ductal adenocarcinoma (PDAC) ranks among the deadliest cancers globally. Despite gemcitabine being a primary chemotherapeutic agent, many patients with PDAC develop resistance, significantly limiting treatment efficacy. This study aims to screen and validate key genes associated with gemcitabine resistance in advanced PDAC using bioinformatics analysis and clinical sample validation, thereby providing potential noninvasive biomarkers and therapeutic targets for overcoming chemoresistance.
View Article and Find Full Text PDFJ Gastrointest Oncol
December 2024
Department of Gastroenterology, Yijishan Hospital of Wannan Medical College, Wuhu, China.
Background: The impact of prolonged surgical waiting time (SWT) on the prognosis of pancreatic ductal adenocarcinoma (PDAC) remains controversial. This study aimed to explore the impact of prolonged SWT on PDAC-specific mortality (PSM).
Methods: The data of patients with stage I-II primary PDAC who received radical resection were obtained from the Surveillance, Epidemiology, and End Results database.
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