Issues
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Cover Image
Cover Image
Dysregulated expression or mutations in oncogenic splicing factors, including the serine/arginine-rich (SR) protein family, can support tumor development. One such family member, SRSF1, is overexpressed in many tumor types in which it promotes oncogenic transformation, but its role in pancreatitis and the development of pancreatic ductal adenocarcinoma (PDAC) remains undetermined. Wan and colleagues demonstrated that SRSF1 expression is high in pancreatitis, PDAC precursor lesions, as well as PDAC tumors, with this elevated expression being sufficient to promote pancreatitis and accelerate KRASG12D-mutated PDAC. Mechanistically, SRSF1 is able to activate the MAPK pathway, in part, through the alternative splicing of the interleukin 1 receptor type 1. Additionally, in phenotypically normal KRASG12D-expressing epithelial cells, a negative feedback mechanism controls SRSF1 protein destabilization and pancreatic cell homeostasis, but hyperactive MYC inhibits this regulation and supports PDAC tumorigenesis. For more information, see the article by Wan and colleagues on page 1678. Artwork by Bianca Dunn. - PDF Icon PDF LinkTable of Contents
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In This Issue
In the Spotlight
Cancer Hallmarks Review
Review
Research Articles
Comutations and KRASG12C Inhibitor Efficacy in Advanced NSCLC
Genetic coalterations in KEAP1, SMARCA4, and CDKN2A were revealed as major independent determinants of KRASG12C inhibitor clinical outcomes in advanced non–small cell lung cancer that together allow for patient segregation into prognostic subgroups.
Integrative Analysis of a Large Real-World Cohort of Small Cell Lung Cancer Identifies Distinct Genetic Subtypes and Insights into Histologic Transformation
A genomic investigation of 3,600 small cell lung cancer (SCLC) tumors reveals novel rare cohorts with potential therapeutic importance, biopsy site–specific heterogeneity, and new insights into SCLC histologic transformation.
A Compendium of Syngeneic, Transplantable Pediatric High-Grade Glioma Models Reveals Subtype-Specific Therapeutic Vulnerabilities
Models of pediatric high-grade glioma reveal genotype–phenotype associations, differences in cell type composition, and sensitivity to targeted and combination therapy approaches, making preclinical evaluation of a precision therapy approach possible.
Early Infiltration of Innate Immune Cells to the Liver Depletes HNF4α and Promotes Extrahepatic Carcinogenesis
Metabolic rewiring of liver metabolism by extrahepatic tumors via innate immune cells occurs at the early disease stage, promoting tumor progression and cancer-related systemic manifestations, such as weight loss.
Type I Interferon Signaling via the EGR2 Transcriptional Regulator Potentiates CAR T Cell–Intrinsic Dysfunction
Continuous type I interferon signaling that is mediated by the transcriptional regulator EGR2 fuels CAR T-cell dysfunction and points to the EGR2–type I interferon axis as a therapeutic vulnerability to improve efficacy of CAR T-cell therapy.
Mitophagy Promotes Resistance to BH3 Mimetics in Acute Myeloid Leukemia
Mitophagy modulators like MFN2 drive BH3-mimetic resistance in acute myeloid leukemia (AML), and genetic or pharmacologic inhibition of MFN2 improved leukemia cell elimination both in vitro and in preclinical AML patient-derived models.
Splicing Factor SRSF1 Promotes Pancreatitis and KRASG12D-Mediated Pancreatic Cancer
The expression of splicing factor SRSF1 is tightly regulated to maintain pancreas homeostasis, and dysregulated SRSF1 induces pancreatitis and accelerates KRASG12D-mediated tumor progression through alternative splicing.
An African-Specific Variant of TP53 Reveals PADI4 as a Regulator of p53-Mediated Tumor Suppression
The epigenetic modifier PADI4, which has a role in the immune recognition of proteins, is not transactivated by several p53 hypomorphs, including the African-specific genetic variant Y107H, but plays a key role in tumor suppression by p53.
C/EBPα Confers Dependence to Fatty Acid Anabolic Pathways and Vulnerability to Lipid Oxidative Stress–Induced Ferroptosis in FLT3-Mutant Leukemia
FLT3 mutations in acute myeloid leukemia drive an aggressive phenotype, but a critical vulnerability mediated by C/EBPα regulation of lipid metabolism offers new avenues for targeted therapies that leverage the synthetic lethality of ferroptosis induction and FLT3 inhibition.
News in Brief
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Prostate Cancer
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Disease Progression
Barrett Esophagus
Metastasis
Bladder Cancer
RNA Stability
Immune Evasion
Clinical Trial
Glioblastoma
Breast Cancer
Immunology
Immunosuppression
Immunotherapy
Cell Plasticity
Neuroblastoma
Cachexia
Splicing
Correction
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