Issues
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The genomic landscape of pancreatic ductal adenocarcinoma (PDAC) has been an active area of research, but the evolutionary dynamics that lead to late-stage PDAC are not well understood, in part because challenges in sampling metastatic disease hinder comprehensive genomic assessment. To this end, Mullen and colleagues performed multiregion genomic profiling of PDAC tumor samples derived from research autopsies or surgical resection specimens, comprised of over 600 primary or metastatic samples from 91 patients with different stages of disease and treatment status. Phylogenetic analysis in the context of clinicopathologic features demonstrated that high truncal density, a measure of the accumulation of somatic mutations in the most recent common ancestor, was significantly associated with worse survival. In addition, evolutionary features corresponded with different disease manifestations, as samples from patients with less than five metastatic lesions had fewer driver alterations, a lower fractional allelic loss, and increased chance of being monoclonal, whereas samples from advanced stage or treated tumors were more often polyclonal. These findings provide important insight into pancreatic tumor evolution. For more information, see the article by Mullen and colleagues on page 329. Artwork by Bianca Dunn. - PDF Icon PDF LinkTable of Contents
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In This Issue
In the Spotlight
Science in Society
Review
The Hallmarks of Predictive Oncology
Research Brief
Predisposition Footprints in the Somatic Genome of Wilms Tumors
Predisposition mutations may forge and constrain the somatic evolution of the childhood kidney cancer, Wilms tumor.
Research Articles
Glioblastoma Cortical Organoids Recapitulate Cell-State Heterogeneity and Intercellular Transfer
Glioblastoma-cortical organoids recreate intercellular mRNA transfer between heterogeneous cell populations, providing a scalable platform for interrogating state-specific communication dynamics in glioblastoma.
CTR-FAPI PET Enables Precision Management of Medullary Thyroid Carcinoma
Covalent targeted radioligand–engineered FAPI potentiates an improved patient-based detection rate, tumor uptake, and diagnostic accuracy of medullary thyroid carcinoma, thereby facilitating precision management of this disease.
The Evolutionary Forest of Pancreatic Cancer
Multiregion-sampled pancreatic cancers representing the full spectrum of clinical presentations reveal distinct genetic differences in pancreatic cancers with indolent features versus those with aggressive metastatic spread.
Tumor-Intrinsic Kinome Landscape of Pancreatic Cancer Reveals New Therapeutic Approaches
Tumor-intrinsic subtypes of pancreatic cancer are characterized by distinct kinomes that shed light on subtype-specific vulnerabilities such as receptor tyrosine kinases, including EGFR, in basal-like tumors.
The UBA1–STUB1 Axis Mediates Cancer Immune Escape and Resistance to Checkpoint Blockade
UBA1 is a potential cancer biomarker and therapeutic target that mediates immune evasion through JAK1 degradation, and targeted UBA1 inhibition synergizes with immune checkpoint blockade to enhance antitumor immunity and survival.
DNAJB1-PRKACA Fusion Drives Fibrolamellar Liver Cancer through Impaired SIK Signaling and CRTC2/p300-Mediated Transcriptional Reprogramming
The DNAJB1–PRKACA fusion in fibrolamellar carcinoma drives tumorigenesis by suppressing SIKs and activating CRTC2/p300-mediated transcription, defining a core oncogenic mechanism that suggests therapeutic targets in this rare type of liver cancer.
Copper Drives Remodeling of Metabolic State and Progression of Clear Cell Renal Cell Carcinoma
Copper promotes metabolic remodeling in clear cell renal cell carcinoma by enhancing mitochondrial respiration, biosynthesis, and detoxification, fueling tumor progression and offering a target for therapeutic strategies.
Survivin Promotes Stem Cell Competence for Skin Cancer Initiation
Survivin is preferentially expressed by epidermal stem cells and confers the competence to initiate skin cancer formation following oncogenic Hedgehog signaling.
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