Issues
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Cover Image
Cover Image
The Hippo signaling pathway regulates development and tissue regeneration, and the tumor-suppressive function of this pathway is commonly dysregulated in human tumors. In the absence of upstream inhibitory phosphorylation mediated by the kinases LATS1/2, the transcriptional co-activators YAP/TAZ enter the nucleus and induce TEAD-dependent expression of transcriptional programs that govern proliferation and lineage plasticity. Through a unique CRISPR screening approach, Klingbeil and colleagues demonstrated that YAP/TAZ-driven cancers were dependent on the kinase paralogs MARK2/3. Moreover, biochemical studies mapped the role of MARK2/3 in directly supporting YAP/TAZ function through the inhibitory phosphorylation of NF2 and activating phosphorylation of YAP. Notably, inducible expression of a protein-based, catalytic inhibitor of MARK2/3 suppressed tumor growth in YAP/TAZ-dependent organoid and xenograft tumor models, providing proof-of-concept for MARK2/3 as promising therapeutic targets to reactivate the Hippo signaling pathway in human cancers. For more information, see the article by Klingbeil and colleagues on page 2471. Artwork by Bianca Dunn. - PDF Icon PDF LinkTable of Contents
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In This Issue
In the Spotlight
Science in Society
In Focus
Commentary
Research Brief
TREM2-Expressing Multinucleated Giant Macrophages Are a Biomarker of Good Prognosis in Head and Neck Squamous Cell Carcinoma
Keratin-rich granulomas composed of multinucleated giant cells, a subtype of TREM2-expressing tumor-associated macrophages, are a biomarker of good prognosis in patients with head and neck squamous cell carcinoma.
Research Articles
NVL-655 Is a Selective and Brain-Penetrant Inhibitor of Diverse ALK-Mutant Oncoproteins, Including Lorlatinib-Resistant Compound Mutations
By combining potent targeting of ALK oncoproteins and resistant mutants with brain penetrance and selectivity for ALK over TRK, the ALK inhibitor NVL-655 addresses key limitations of approved ALK inhibitors.
Identification and Characterization of Chemotherapy-Resistant High-Risk Neuroblastoma Persister Cells
MYC(N) suppression and NFκB activation, the latter triggered by both tumor cell–intrinsic and –extrinsic factors, mediate cellular persistence in high-risk neuroblastoma and reveal new therapeutic approaches to prevent relapse.
Botensilimab, an Fc-Enhanced Anti–CTLA-4 Antibody, Is Effective against Tumors Poorly Responsive to Conventional Immunotherapy
Fc-enhanced anti-CTLA-4 leverages novel FcγR-dependent mechanisms to potentiate antitumor immunity and overcomes limitations of conventional anti-CTLA-4, effectively treating poorly immunogenic and refractory cancers.
Epigenetic and Oncogenic Inhibitors Cooperatively Drive Differentiation and Kill KRAS-Mutant Colorectal Cancers
EZH2 inhibitors dramatically enhance the effects of RAS pathway inhibitors by cooperatively suppressing the WNT pathway, thereby driving differentiation and enhancing apoptosis and tumor regression of colorectal cancer.
TCR-Engineered T Cells Directed against Ropporin-1 Constitute a Safe and Effective Treatment for Triple-Negative Breast Cancer
ROPN1 is a highly expressed intracellular antigen in triple-negative breast cancer, and a T-cell receptor targeting ROPN1 enables sensitive and selective cancer cell recognition, supporting use as a safe and potent T-cell therapy.
MARK2/MARK3 Kinases Are Catalytic Codependencies of YAP/TAZ in Human Cancer
The kinases MARK2 and MARK3 are identified as requirements for the function of the YAP and TAZ oncogenes, thus providing a druggable vulnerability in Hippo-dysregulated carcinomas and sarcomas.
A Targetable Secreted Neural Protein Drives Pancreatic Cancer Metastatic Colonization and HIF1α Nuclear Retention
Neuronal pentraxin 1 (NPTX1) is identified as a therapeutically druggable driver of pancreatic cancer metastatic colonization through its action on the receptor AMIGO2, which promotes HIF-1α nuclear retention and hypoxic growth.
RNA Shielding of p65 Is Required to Potentiate Oncogenic Inflammation in TET2-Mutated Clonal Hematopoiesis
TET2 loss of function drives overexpression of the lncRNA MALAT1 in terminally differentiated myeloid cells, which is both necessary and sufficient for sustained inflammation that drives oncogenesis in myeloid neoplasms.
Increased RNA and Protein Degradation Is Required for Counteracting Transcriptional Burden and Proteotoxic Stress in Human Aneuploid Cells
Aneuploid cells adapt to transcriptional and proteotoxic stress by enhancing RNA and protein degradation pathways, making them more sensitive to disruptions in these processes and presenting potential therapeutic targets.
Correction
Correction: St. Jude Survivorship Portal: Sharing and Analyzing Large Clinical and Genomic Datasets from Pediatric Cancer Survivors
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