Oncogenesis最新文献

{"title":"Extracellular matrix stiffness determines the phenotypic behavior of dedifferentiated melanoma cells through a DDR1/2-dependent YAP mechanotransduction pathway.","authors":"Margaux Lecacheur, Ilona Berestjuk, Alexandrine Carminati, Mira Rabbaa, Océane Bouvet, Serena Diazzi, Pierric Biber, Christopher Rovera, Marie Irondelle, Frédéric Larbret, Virginie Prod'homme, Christophe A Girard, Marcel Deckert, Sophie Tartare-Deckert","doi":"10.1038/s41389-026-00636-y","DOIUrl":"10.1038/s41389-026-00636-y","url":null,"abstract":"<p><p>Extracellular matrix (ECM) stiffening is a biophysical hallmark of solid tumors. Cutaneous melanoma is an aggressive malignancy characterized by high heterogeneity and phenotypic plasticity in which melanoma cells switch from a proliferative and differentiated phenotype to an invasive, dedifferentiated and therapy-resistant state. However, the impact of ECM stiffness on the diverse cellular phenotypes of melanoma remains poorly defined. Here, we show that melanoma cell subpopulations differ in their responses to mechanical signals. Compared to melanocytic/transitory cells, dedifferentiated cells exhibited heightened sensitivity to stiff collagen matrices, characterized by increased cell spreading, focal adhesion maturation, YAP nuclear translocation and contractility. ECM stiffening enhanced proliferation, migration and invasion in dedifferentiated cells, whereas highly proliferative and poorly migratory melanocytic/transitory cells were less affected by collagen stiffness. Importantly, a soft ECM sensitized dedifferentiated cells, but not melanocytic/transitory cells, to BRAF/MEK inhibition. Mechanistically, the mechanosensitivity of dedifferentiated cells relies on collagen receptors DDR1 and DDR2, which control cytoskeleton reorganization and YAP mechanosignaling. Genetic or pharmacological inhibition of DDR, actomyosin contractility, or YAP suppressed stiffness-induced proliferation and migration, reduced traction forces, and restored sensitivity to targeted therapy in dedifferentiated cells. Conversely, ectopic DDR1/DDR2 expression confers mechanosensitive properties to melanocytic cells. Our results thus reveal that phenotypic plasticity endows dedifferentiated melanoma cells with increased addiction to mechanical cues and implicate DDR1/2-YAP-dependent signaling in this aggressive behavior.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13490450/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148252700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Testican-1 activates Wnt/β-Catenin signaling to drive colorectal cancer progression.","authors":"Yi Li, Chuying Huang, Chu Zhang, Lian Feng, Huiyun Lin, Jiannan Yao, Shu Luo, Jinsen Shi, Yuping Yang, Zhiyun Cao, Nathaniel Weygant","doi":"10.1038/s41389-026-00635-z","DOIUrl":"10.1038/s41389-026-00635-z","url":null,"abstract":"<p><p>Colorectal cancer (CRC) ranks second in cancer-related mortality worldwide. Its clinical intractability and chemoresistance pose significant challenges, often driven by cancer stem cells (CSCs). Wnt/β-catenin signaling is a lynchpin of CSC self-renewal, but targetable upstream drivers remain elusive. Using bioinformatics, we identified the proteoglycan SPOCK1 (encoding the protein Testican-1) as a Wnt-associated marker. High SPOCK1 gene expression predicted poor patient prognosis and reduced progression-free survival following first-line chemotherapy. In vitro assays demonstrated that Testican-1 levels modulated Wnt/β-catenin activity. Testican-1 downregulation inhibited β-catenin nuclear translocation and TCF/LEF-mediated transcription, leading to concurrent suppression of CRC proliferation and spheroid-forming potential. Conversely, Testican-1 overexpression promoted β-catenin nuclear translocation and TCF/LEF-mediated transcription, which enhanced CRC malignant properties. This Testican-1-driven pro-tumorigenic effect was reversed by the β-catenin/TCF/LEF inhibitor iCRT3, demonstrating Testican-1's dependence on Wnt transcriptional activation. We validated this functional role in vivo using a Testican-1-overexpressing xenograft model and ex vivo using patient-derived organoids (PDOs), both confirming increased growth and β-catenin nuclear localization. Furthermore, data-independent acquisition (DIA) mass spectrometry of Testican-1-overexpressing tumors showed enrichment in Wnt/β-catenin and pro-tumorigenic pathways, including c-Myc and oxidative phosphorylation. Notably, Testican-1 expression was associated with remodeling of the tumor microenvironment, characterized by desmoplastic features. In summary, our findings establish a novel Testican-1/Wnt/β-catenin axis driving CRC tumorigenesis and progression, positioning it as a promising therapeutic target to overcome Wnt-mediated progression and resistance.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13487164/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148239652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CAF-derived PTGDS drives pancreatic cancer neuroendocrine differentiation and chemoresistance via PAQR9-MAPK.","authors":"Jingwen Liang, Wang Peng, Zhou Luan, Luyao Liu, Hai Huang, Haochen Cui, Mengdie Cao, Shiru Chen, Si Xiong, Shuya Bai, Wei Chen, Bin Cheng, Yuchong Zhao","doi":"10.1038/s41389-026-00634-0","DOIUrl":"10.1038/s41389-026-00634-0","url":null,"abstract":"<p><p>The tumor microenvironment, particularly cancer-associated fibroblasts (CAFs), critically influences pancreatic ductal adenocarcinoma (PDAC) progression. Neuroendocrine differentiation (NED) is associated with aggressive tumor behavior and therapy resistance in multiple malignancies, yet its regulation within the PDAC environment is poorly characterized. Through integrated analysis of clinical specimens and transcriptomic datasets, we identified significant enrichment of NED markers correlating with poor patient outcomes. Single-cell RNA sequencing further identified Glycoprotein prostaglandin D2 synthase (PTGDS) as a CAF-derived factor potentially driving NED. Functional studies demonstrated that PTGDS secreted by CAFs robustly induced NED while enhancing proliferation, invasion, migration, and gemcitabine resistance in pancreatic cancer cells. Mechanistically, we established that PTGDS activates MAPK signaling through its membrane receptor PAQR9, and the pharmacological inhibition of MAPK signaling or knockdown of PAQR9 effectively reversed PTGDS-induced malignant phenotypes. These findings reveal a novel CAFs/PTGDS-PAQR9-MAPK signaling axis that promotes NED and drives PDAC progression, offering new therapeutic opportunities to overcome stromal-mediated chemoresistance.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13482867/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148227516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-apoptotic BCL-2 family proteins: from regulatory networks to therapeutic targeting.","authors":"Zhe Wang, Mutian Tang, Marina Konopleva","doi":"10.1038/s41389-026-00632-2","DOIUrl":"10.1038/s41389-026-00632-2","url":null,"abstract":"<p><p>The BCL-2 protein family controls the intrinsic apoptotic pathway through a delicate balance of pro- and anti-apoptotic members acting at the mitochondrial outer membrane. Anti-apoptotic proteins BCL-2, BCL-XL, MCL-1, BCL-W, and BCL2A1 (BFL-1) function as critical survival factors whose dysregulation contributes to cancer development and therapeutic resistance. This review systematically examines the multilayered regulatory mechanisms governing these proteins, including transcriptional control by NF-κB, STAT3/5, and HIF-1α; post-transcriptional regulation through alternative splicing and microRNAs; and post-translational modifications that determine protein stability and function. The clinical success of venetoclax, a selective BCL-2 inhibitor, has established BCL-2 family targeting as an effective therapeutic strategy and fundamentally changed the management of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). However, therapeutic challenges persist: resistance emerges through MCL-1 upregulation, BCL-2 mutations, and metabolic reprogramming; BCL-XL inhibition causes dose-limiting thrombocytopenia; and MCL-1 inhibitors face class-wide cardiac toxicity. Emerging strategies to overcome these limitations include tissue-selective proteolysis-targeting chimeras (PROTACs) and antibody-drug conjugates (ADCs) enabling tumor-targeted delivery, next-generation inhibitors that overcome resistance mutations, and biomarker-guided patient selection. This review provides an integrated overview of the regulatory mechanisms and evolving therapeutic strategies targeting anti-apoptotic BCL-2 family proteins, outlining both prominent successes and unresolved challenges.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13448827/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148157615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The emerging role of disulfidptosis in metabolic synergistic death and cancer immunotherapy.","authors":"Zheng Wu, Rong Tang, Jin Xu, Yufeng Wang, Liquan Jin, Yingna Liao, Dingru Li, Cheng Zu, Chengkai Yang, Xianjun Yu, Si Shi","doi":"10.1038/s41389-026-00633-1","DOIUrl":"10.1038/s41389-026-00633-1","url":null,"abstract":"<p><p>Disulfidptosis is an emerging form of regulated cell death (RCD) that is mechanistically distinct from, yet closely interconnected with, classical cell death modalities such as apoptosis, ferroptosis, and cuproptosis. It is typically triggered in cells with high expression of solute carrier family 7 member 11 (SLC7A11, also known as xCT) under glucose-deprived conditions. In this context, nicotinamide adenine dinucleotide phosphate (NADPH) becomes depleted, and consequently the level of reduced glutathione (GSH) declines, which in turn compromises the cellular capacity to efficiently resolve aberrantly accumulated intracellular disulfide bonds. As a result, disulfide stress progressively builds up and ultimately promotes abnormal crosslinking, aggregation, and functional disruption of cytoskeletal proteins, thereby driving catastrophic cytoskeletal collapse and cell death. Because SLC7A11 overexpression represents a key metabolic hallmark across multiple cancer types, disulfidptosis provides a novel conceptual framework for exploiting tumor-specific metabolic vulnerabilities. Moreover, accumulating evidence across diverse malignancies suggests that disulfidptosis contributes to tumor progression. Meanwhile, recent studies have increasingly highlighted evolving drug delivery strategies and metabolic synergistic approaches that integrate disulfidptosis with other RCD programs, and, importantly, its impact on the tumor immune microenvironment is gradually being elucidated. In this review, we systematically summarize the definition, molecular mechanisms, and biological functions of disulfidptosis, emphasize recent advances in its synergistic interplay with other cell death modalities, and discuss its implications for cancer immunotherapy. Finally, we outline emerging drug delivery strategies designed to induce disulfidptosis in tumor cells, aiming to facilitate further exploration and translational development of disulfidptosis-based anticancer therapies.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13443501/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148150686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tipping the balance: NRF2's dual role in ferroptotic fate.","authors":"Izadora de Souza, Ana Beatriz da Silva Teixeira, Ancely Ferreira Dos Santos, José Pedro Friedmann Angeli, Clarissa Ribeiro Reily Rocha","doi":"10.1038/s41389-026-00630-4","DOIUrl":"10.1038/s41389-026-00630-4","url":null,"abstract":"<p><p>The NRF2 pathway has emerged as a central regulator of cellular redox homeostasis, coordinating the expression of a broad array of genes that protect cells from oxidative and electrophilic stress. In the context of cancer, NRF2 has been recognized as a key driver of chemoresistance, as its sustained activation enhances antioxidant defenses, detoxification pathways, and metabolic adaptation, thereby promoting tumor cell survival under therapeutic stress. Beyond its canonical role in redox regulation, NRF2 also orchestrates the expression of multiple genes involved in ferroptosis, a non-apoptotic, iron-dependent form of cell death that has recently gained attention as a promising strategy to overcome drug resistance. Mechanistically, NRF2 modulates ferroptosis through several interconnected pathways, including the regulation of glutathione biosynthesis, lipid metabolism, and iron homeostasis, yet its impact is highly context-dependent and can vary according to cell type and metabolic state. In this review, we provide an overview of the interplay between NRF2 and ferroptosis, tracing the historical development of this network and highlighting the pivotal roles of specific NRF2 targets in controlling ferroptotic susceptibility. Finally, we discuss how targeted modulation of NRF2 may influence ferroptosis, offering a potential avenue for the design of innovative therapies aimed at selectively eradicating resistant tumors.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"15 1","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13222347/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148101641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The central precocious puberty-associated gene MKRN3 is a tumor suppressor regulating CSDE1 ubiquitination in ovarian cancer.","authors":"Fengrui Zhang, Chang Yuan, Yumei Cheng, Chun Chen, Luyao Guan, Xiaofang Wang, Yuxiang Luo, Chunling Zeng, Yangjie Xiong, Haoqi Lan, Yue Dong, Xiaona Jia, Simin Wang, Qi Cao, Yuexiang Wang, Yuan Lu","doi":"10.1038/s41389-026-00631-3","DOIUrl":"10.1038/s41389-026-00631-3","url":null,"abstract":"<p><p>Earlier age at menarche has long been known to be associated with an increased risk of ovarian cancer (OC). However, the underlying mechanisms are not completely understood. Here, we report a paternally inherited imprinted gene, MKRN3, that is associated with central precocious puberty (CPP) and that plays a tumor suppressive role in OC. We found that genomic MKRN3 mutations are significantly more common in OC patients. Genomic mutations in MKRN3 and low MKRN3 expression levels are correlated with poor patient survival. The restoration of MKRN3 in MKRN3-inactivated OC cells significantly suppresses tumor growth and proliferation in vitro and in vivo. Ovary-specific knockout of endogenous MKRN3 accelerates P53 inactivation-induced tumorigenesis in mice. Mechanistically, CSDE1 was identified as a major substrate for MKRN3 in OC via mass spectrometry-based proteomics screens. MKRN3 regulates OC cell proliferation through proteolytic ubiquitination of CSDE1. Our comprehensive data reveal that the CPP-associated gene MKRN3 is a tumor suppressor in human OC. We propose that germline mutations in the MKRN3 gene might partially explain the association between precocious puberty and the risk of OC.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13396335/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148043261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Catestatin peptide impedes melanoma progression and drug resistance by reprogramming oncogenic signaling pathways.","authors":"Satadeepa Kal, Suborno Jati, Kechun Tang, Nicholas J G Webster, Angelo Corti, Sushil K Mahata","doi":"10.1038/s41389-026-00628-y","DOIUrl":"10.1038/s41389-026-00628-y","url":null,"abstract":"<p><p>Melanoma remains one of the most aggressive and therapy-resistant cancers, underscoring the need for innovative therapeutic strategies. In our current study we report a peptide-based approach as potential therapeutic. Here we report for the first time the involvement of Catestatin (CST) peptide in carcinogenesis, with melanoma identified as unexplored and therapeutically relevant context. The expression and role of CST, a Chromogranin A (CgA)-derived peptide with immunomodulatory and reparative properties in skin injury, led us to examine its connection to melanoma. Analysis of human melanoma tissues revealed that CST expression decreases with advancing disease stage, suggesting a potential tumor-suppressive function. Restoration of CST in patient-derived melanoma cells and established melanoma cell lines (A375, B16F10, and SKMEL28) induced apoptosis and suppressed proliferation and migratory capacity, while normal skin fibroblasts remained unaffected, indicating tumor-selective activity. In vivo, CST administration significantly reduced tumor growth and tumor weight in the B16F10 melanoma mouse model, with no detectable systemic toxicity. Transcriptomic profiling of CST-treated melanoma cells and tumors revealed downregulation of pathways involved in hypoxia signaling, extracellular-matrix remodeling, epithelial-to-mesenchymal transition (EMT), and stress-adaptive responses, key drivers of melanoma invasion and progression. Consistent with these findings, CST suppressed several mediators of tumor progression. CST also reduced the viability and migration of Vemurafenib-resistant A375 cells, accompanied by the downregulation of multiple resistance-associated genes. Together, these findings establish catestatin as a novel regulator of melanoma growth and therapeutic resistance and provide a mechanistic rationale for the development of CST-based peptide therapeutics targeting both treatment-naive and drug-resistant melanoma. Catestatin Suppresses Tumor Progression and Metastasis by Inducing Apoptosis and Inhibiting Pro-tumorigenic Signaling. Catestatin (CST), a Chromogranin A-derived peptide, exhibits potent anti-tumor activity by suppressing cancer progression across multiple stages. CST levels decline with advancing tumor stage, suggesting a loss of endogenous tumor restraint during progression to metastasis. In patient-derived melanoma cells and tumor models (A375 and B16F10), CST treatment induces apoptotic cell death. Mechanistically, CST downregulates key pro-tumorigenic and pro-fibrotic signaling molecules, including LOXL2, PDGFRB, CCN2, and DDIT4, which are associated with extracellular-matrix remodeling, growth factor signaling, and cellular stress adaptation. These findings identify CST as a novel regulator of tumor survival and metastatic potential, supporting its therapeutic potential as a peptide-based anti-cancer agent.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13369845/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147988504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic vulnerabilities in pleural mesothelioma.","authors":"Sílvia Plans-Marin, Cristina Muñoz-Pinedo, Ernest Nadal","doi":"10.1038/s41389-026-00625-1","DOIUrl":"10.1038/s41389-026-00625-1","url":null,"abstract":"<p><p>Mesothelioma is a rare tumour of mesothelial origin that is often diagnosed at advanced stages. Despite recent approval of immunotherapy, the prognosis of mesothelioma remains dismal. Growing evidence links tumour metabolism to the molecular mechanisms driving mesothelioma's aggressiveness, therapeutic resistance and poor outcomes. Mesothelioma-specific metabolic alterations may be derived from asbestos-induced chronic inflammation, the mesothelial origin, the pleural microenvironment and tumour-stroma interactions, as well as recurrent genomic alterations that distinguish mesothelioma from malignancies of the lung parenchyma. Elucidating these metabolic alterations is therefore crucial for identifying exploitable vulnerabilities and improving therapeutic strategies. Key metabolic pathways, including glycolysis, the pentose phosphate pathway, nucleotide biosynthesis and amino acid and lipid metabolism, are tightly interconnected within a dynamic network that regulates cell survival and proliferation. Metabolism also shapes tumour microenvironment by regulating redox homoeostasis, signalling and nutrient exchange. Considering these pathways in isolation provides an incomplete picture, and instead, studying them as a whole, and building a coherent metabolic map is essential for revealing context-specific dependencies. In this review, we summarise current knowledge of mesothelioma metabolism, highlighting how recurrent genetic alterations including CDKN2A, MTAP, BAP1, NF2 and TP53 influence metabolic phenotypes. We discuss experimental and therapeutic efforts that target individual metabolic branches and evaluate how these insights can inform a unified strategy to exploit metabolic weaknesses and guide the rational development of combination therapies.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13365598/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147982745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-omics analysis reveals LARP1 as a key integrator of translation and metabolism in AML.","authors":"Dominik A Nahotko, Brian Lee, Emely Lopez Fajardo, Aneta H Baran, Szymon K Filip, Peter A Faull, Elizabeth T Bartom, Masha Kocherginsky, Peng Gao, Jason Miska, Diana Saleiro, Elspeth M Beauchamp, Leonidas C Platanias","doi":"10.1038/s41389-026-00623-3","DOIUrl":"10.1038/s41389-026-00623-3","url":null,"abstract":"<p><p>La-related protein 1 (LARP1) is an RNA-binding protein and downstream effector of mTOR and CDK9 signaling that regulates translation of mRNAs containing a 5'-terminal oligopyrimidine motif. While elevated LARP1 expression has been linked to poor prognosis in acute myeloid leukemia (AML), its mechanistic role remains unclear. Using CRISPR/Cas9-mediated LARP1 knockout and multi-omics analyses, we investigated LARP1's role in AML. LARP1 loss impaired proliferation, clonogenicity, and tumor growth in xenografts, and enhanced sensitivity of AML cells to 5-azacytidine and cytarabine. Polysome profiling and RNA sequencing revealed that LARP1 modulates a distinct set of transcripts involved in mitochondrial function, amino acid metabolism, and cell cycle regulation, independently of mTOR and CDK9. Proteomics analysis uncovered additional effects of LARP1 loss on immune signaling, lysosomal pathways, and protein stability, including changes not evident at the RNA level. Metabolomic profiling showed reprogramming of arginine/creatine metabolism and depletion of pyrimidine biosynthesis intermediates. Cytidine deaminase, a known resistance factor, was downregulated across omics layers upon LARP1 loss. These findings define LARP1 as a key integrator of translational regulation and metabolic control in AML, supporting leukemic cell survival and promoting drug resistance. Targeting LARP1 may uncover vulnerabilities in leukemia cells, not addressed by current therapies.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13346483/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147960173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}