Activating KRAS mutations are found in nearly all cases of pancreatic ductal adenocarcinoma (PDAC), yet effective clinical targeting of oncogenic KRAS remains elusive. Understanding of KRAS-dependent PDAC-promoting pathways could lead to the identifi cation of vulnerabilities and the development of new treatments. We show that oncogenic KRAS induces BNIP3L /NIX expression and a selective mitophagy program that restricts glucose fl ux to the mitochondria and enhances redox capacity. Loss of Nix restores functional mitochondria to cells, increasing demands for NADPH reducing power and decreasing proliferation in glucose-limited conditions. Nix deletion markedly delays progression of pancreatic cancer and improves survival in a murine (KPC) model of PDAC. Although conditional Nix ablation in vivo initially results in the accumulation of mitochondria, mitochondrial content eventually normalizes via increased mitochondrial clearance programs, and pancreatic intraepithelial neoplasia (PanIN) lesions progress to PDAC. We identify the KRAS-NIX mitophagy program as a novel driver of glycolysis, redox robustness, and disease progression in PDAC. SIGNIFICANCE: NIX-mediated mitophagy is a new oncogenic KRAS effector pathway that suppresses functional mitochondrial content to stimulate cell proliferation and augment redox homeostasis. This pathway promotes the progression of PanIN to PDAC and represents a new dependency in pancreatic cancer.

Recent studies implicated the RNA-binding protein with multiple splicing (RBPMS) family of proteins in oocyte, retinal ganglion cell, heart, and gastrointestinal smooth muscle development. These RNA-binding proteins contain a single RNA recognition motif (RRM), and their targets and molecular function have not yet been identified. We defined transcriptome-wide RNA targets using photoactivatable-ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) in HEK293 cells, revealing exonic mature and intronic pre-mRNA binding sites, in agreement with the nuclear and cytoplasmic localization of the proteins. Computational and biochemical approaches defined the RNA recognition element (RRE) as a tandem CAC trinucleotide motif separated by a variable spacer region. Similar to other mRNA-binding proteins, RBPMS family of proteins relocalized to cytoplasmic stress granules under oxidative stress conditions suggestive of a support function for mRNA localization in large and/or multinucleated cells where it is preferentially expressed.

Background The prognostic impact of margin status is reported with conflicting results after pancreatic cancer resection. While some studies validated an uninvolved resection margin (R0) 1 mm or more of tumour clearance, others have failed to show benefit. This systematic review and meta-analysis aimed to investigate the effects of margin definitions on median overall survival (OS). Methods MEDLINE, Web of Science, and the Cochrane Central Register of Controlled Trials were searched for studies reporting associations between resection margins and OS between 2010 and 2021. Data regarding margin status (R0 circumferential resection margin (CRM) negative (CRM–), R0 CRM positive (CRM+), R0 direct, and R1 and OS were extracted. Hazard ratios (HRs) were pooled with a random-effects model. The risk of bias was evaluated with the Quality in Prognosis Studies (QUIPS) tool. Results The full texts of 774 studies were screened. In total, 21 studies compromising 6056 patients were included in the final synthesis. In total, 188 (24 per cent) studies were excluded due to missing margin definitions. The R0 (CRM+) rate was 50 per cent (95 per cent confidence interval (c.i.) 0.40 to 0.61) and the R0 (CRM−) rate was 38 per cent (95 per cent c.i. 0.29 to 0.47). R0 (CRM−) resection was independently associated with improved OS compared to combined R1 and R0 (CRM+; HR 1.36, 95 per cent c.i. 1.23 to 1.56). Conclusion The revised R status was confirmed as an independent prognosticator compared to combined R0 (CRM+) and R1. The limited number of studies, non-standardized pathology protocols, and the varying number of margins assessed hamper comparability.