Cancer research最新文献

{"title":"Editor's Note: Low-Dose Paclitaxel Reduces S100A4 Nuclear Import to Inhibit Invasion and Hematogenous Metastasis of Cholangiocarcinoma.","authors":"Massimiliano Cadamuro, Gaia Spagnuolo, Luisa Sambado, Stefano Indraccolo, Giorgia Nardo, Antonio Rosato, Simone Brivio, Chiara Caslini, Tommaso Stecca, Marco Massani, Nicolò Bassi, Eugenio Novelli, Carlo Spirli, Luca Fabris, Mario Strazzabosco","doi":"10.1158/0008-5472.CAN-24-3017","DOIUrl":"10.1158/0008-5472.CAN-24-3017","url":null,"abstract":"","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"84 22","pages":"3909"},"PeriodicalIF":12.5,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inflammasome-Activating Nanovaccine for Cancer Immunotherapy.","authors":"Wenyao Zhen, Xiaoyuan Chen","doi":"10.1158/0008-5472.CAN-24-2905","DOIUrl":"10.1158/0008-5472.CAN-24-2905","url":null,"abstract":"<p><p>A range of advanced nanovaccines (NV) combined with immunotherapies has recently emerged for treating malignant tumors and has demonstrated promising tumor-suppressive effects. Nevertheless, their effectiveness is often limited by immunosuppression within the tumor microenvironment. To overcome this challenge, new approaches for NV development are required to improve antigen cross-presentation and to remodel the tumor microenvironment. In this issue of Cancer Research, Zhou and colleagues have developed a photo-enhanceable inflammasome-activating nanovaccine (PIN) designed for precise, in situ delivery of a tumor antigen and a hydrophobic small molecule that activates the NLRP3 inflammasome pathway. Near infrared light exposure enables the accumulation of PINs at tumor sites by inducing a photo-triggered charge reversal in the BODIPY-modified PAMAM nanocarrier. Systemic administration of PINs resulted in effective intratumoral activation of the NLRP3 inflammasome and antigen cross-presentation in antigen-presenting cells upon light exposure, leading to enhanced immune responses through increased proinflammatory cytokine production without significant systemic toxicity. Importantly, PINs also enhanced the efficacy of immune checkpoint blockade and promoted the development of long-term immune memory in mouse models of melanoma and hepatocellular carcinoma. Overall, inflammasome-activating NVs represent a cancer immunotherapy strategy by harnessing the innate immune system to achieve robust responses against tumors. Ongoing research and development are crucial to addressing current limitations and advancing this innovative technology toward clinical application. See related article by Zhou et al., p. 3834.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"84 22","pages":"3709-3711"},"PeriodicalIF":12.5,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Scavenger Receptor CD36 in Tumor-Associated Macrophages Promotes Cancer Progression by Dampening Type I Interferon Signaling.","authors":"Ziyan Xu, Alexandra Kuhlmann-Hogan, Shihao Xu, Hubert Tseng, Dan Chen, Shirong Tan, Ming Sun, Victoria Tripple, Marcus Bosenberg, Kathryn Miller-Jensen, Susan M Kaech","doi":"10.1158/0008-5472.CAN-23-4027","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-23-4027","url":null,"abstract":"<p><p>Tumor-associated macrophages (TAMs) are a heterogenous population of myeloid cells that dictate the inflammatory tone of the tumor microenvironment (TME). In this study, we unveiled a mechanism by which scavenger receptor CD36 suppresses TAM inflammatory states. CD36 was upregulated in TAMs and associated with immunosuppressive features, and myeloid-specific deletion of CD36 significantly reduced tumor growth. Moreover, CD36-deficient TAMs acquired inflammatory signatures including elevated type-I interferon (IFN-I) production, mirroring the inverse correlation between CD36 and IFN-I response observed in cancer patients. IFN-I, especially IFNβ, produced by CD36-deficient TAMs directly induced tumor cell quiescence and delayed tumor growth. Mechanistically, CD36 acted as a natural suppressor of IFN-I signaling in macrophages through p38 activation downstream of oxidized lipid signaling. These findings establish CD36 as a critical regulator of TAM function and the tumor inflammatory microenvironment, providing additional rationale for pharmacological inhibition of CD36 to rejuvenate anti-tumor immunity.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor heterogeneity and cooperating cancer hallmarks driven by divergent EMT programs.","authors":"Phoebe Carter, Yibin Kang","doi":"10.1158/0008-5472.CAN-24-4309","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-24-4309","url":null,"abstract":"<p><p>Epithelial-to-mesenchymal transition (EMT) is known to play roles in orchestrating cellular plasticity across many physiological and pathological contexts. Partial EMT, wherein cells maintain both epithelial and mesenchymal features, is gaining recognition for its functional importance in cancer in recent years. There are many factors regulating both partial and full EMT, and the precise mechanisms underlying these processes vary depending on the biological context. Furthermore, how different EMT states cooperate to create a heterogeneous tumor population and promote different pro-malignant features remains largely undefined. In a recent study published in Nature Cancer, Youssef and colleagues described how two disparate EMT programs, active in either organ fibrosis or embryonic development, are utilized within different cells within the same murine mammary tumor model. This work provides mechanistic insight into the development of intratumoral heterogeneity, providing evidence for the cooperation between the two EMT trajectories.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Communal Coping Intervention for Couples Managing Chronic Illness: Proof-of-Concept Study.","authors":"Melissa Zajdel, Vicki S Helgeson","doi":"10.1037/cfp0000234","DOIUrl":"10.1037/cfp0000234","url":null,"abstract":"<p><strong>Introduction: </strong>Communal coping is an interpersonal coping strategy defined as the appraisal of a problem as shared and collaboration to manage it. Despite evidence establishing links of communal coping to health, few interventions have involved communal coping. This study seeks to establish proof of concept that an intervention rooted in communal coping theory can impact couple members' communal coping and intermediary outcomes.</p><p><strong>Methods: </strong>Couples (<i>n</i> = 40) in which one person has type 2 diabetes were randomly assigned to intervention versus control in a parallel randomized trial with 1:1 allocation. The intervention consisted of a single session focused on discussion of shared stressors, communal coping education, and collaborative implementation intentions followed by 7 days of text message reinforcement. Couples were interviewed in-person, received the intervention or active control, and completed 7 daily questionnaires. Communal coping and intermediary outcomes associated with communal coping were assessed daily. Feasibility and acceptability were also assessed.</p><p><strong>Results: </strong>The intervention increased reports of both patient and partner shared appraisal and collaboration and impacted some intermediary outcomes of communal coping. Compared to control, intervention participants reported greater perceived partner responsiveness, patient support receipt, and partner confidence in patient illness self-efficacy.</p><p><strong>Discussion: </strong>This study provides initial proof of concept that an intervention based on communal coping theory can increase couples' communal coping-both shared appraisal and collaboration. Additionally, the intervention was able to impact some intermediary outcomes that may be linked to downstream health outcomes for both patients and partners.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"75 1","pages":"188-201"},"PeriodicalIF":1.9,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11361721/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86380137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mag-Net: Rapid enrichment of membrane-bound particles enables high coverage quantitative analysis of the plasma proteome.","authors":"Christine C Wu, Kristine A Tsantilas, Jea Park, Deanna Plubell, Justin A Sanders, Previn Naicker, Ireshyn Govender, Sindisiwe Buthelezi, Stoyan Stoychev, Justin Jordaan, Gennifer Merrihew, Eric Huang, Edward D Parker, Michael Riffle, Andrew N Hoofnagle, William S Noble, Kathleen L Poston, Thomas J Montine, Michael J MacCoss","doi":"10.1101/2023.06.10.544439","DOIUrl":"10.1101/2023.06.10.544439","url":null,"abstract":"<p><p>Membrane-bound particles in plasma are composed of exosomes, microvesicles, and apoptotic bodies and represent ~1-2% of the total protein composition. Proteomic interrogation of this subset of plasma proteins augments the representation of tissue-specific proteins, representing a \"liquid biopsy,\" while enabling the detection of proteins that would otherwise be beyond the dynamic range of liquid chromatography-tandem mass spectrometry of unfractionated plasma. We have developed an enrichment strategy (Mag-Net) using hyper-porous strong-anion exchange magnetic microparticles to sieve membrane-bound particles from plasma. The Mag-Net method is robust, reproducible, inexpensive, and requires <100 μL plasma input. Coupled to a quantitative data-independent mass spectrometry analytical strategy, we demonstrate that we can collect results for >37,000 peptides from >4,000 plasma proteins with high precision. Using this analytical pipeline on a small cohort of patients with neurodegenerative disease and healthy age-matched controls, we discovered 204 proteins that differentiate (q-value < 0.05) patients with Alzheimer's disease dementia (ADD) from those without ADD. Our method also discovered 310 proteins that were different between Parkinson's disease and those with either ADD or healthy cognitively normal individuals. Using machine learning we were able to distinguish between ADD and not ADD with a mean ROC AUC = 0.98 ± 0.06.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"72 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11014469/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86271795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Epigenetic Evolution of Glioma Is Determined by the IDH1 Mutation Status and Treatment Regimen.","authors":"Tathiane M Malta, Thais S Sabedot, Natalia S Morosini, Indrani Datta, Luciano Garofano, Wies Vallentgoed, Frederick S Varn, Kenneth Aldape, Fulvio D'Angelo, Spyridon Bakas, Jill S Barnholtz-Sloan, Hui K Gan, Mohammad Hasanain, Ann-Christin Hau, Kevin C Johnson, Simona Cazacu, Ana C deCarvalho, Mustafa Khasraw, Emre Kocakavuk, Mathilde C M Kouwenhoven, Simona Migliozzi, Simone P Niclou, Johanna M Niers, D Ryan Ormond, Sun Ha Paek, Guido Reifenberger, Peter A Sillevis Smitt, Marion Smits, Lucy F Stead, Martin J van den Bent, Erwin G Van Meir, Annemiek Walenkamp, Tobias Weiss, Michael Weller, Bart A Westerman, Bauke Ylstra, Pieter Wesseling, Anna Lasorella, Pim J French, Laila M Poisson, Roel G W Verhaak, Antonio Iavarone, Houtan Noushmehr","doi":"10.1158/0008-5472.CAN-23-2093","DOIUrl":"10.1158/0008-5472.CAN-23-2093","url":null,"abstract":"<p><p>Tumor adaptation or selection is thought to underlie therapy resistance in glioma. To investigate longitudinal epigenetic evolution of gliomas in response to therapeutic pressure, we performed an epigenomic analysis of 132 matched initial and recurrent tumors from patients with IDH-wildtype (IDHwt) and IDH-mutant (IDHmut) glioma. IDHwt gliomas showed a stable epigenome over time with relatively low levels of global methylation. The epigenome of IDHmut gliomas showed initial high levels of genome-wide DNA methylation that was progressively reduced to levels similar to those of IDHwt tumors. Integration of epigenomics, gene expression, and functional genomics identified HOXD13 as a master regulator of IDHmut astrocytoma evolution. Furthermore, relapse of IDHmut tumors was accompanied by histologic progression that was associated with survival, as validated in an independent cohort. Finally, the initial cell composition of the tumor microenvironment varied between IDHwt and IDHmut tumors and changed differentially following treatment, suggesting increased neoangiogenesis and T-cell infiltration upon treatment of IDHmut gliomas. This study provides one of the largest cohorts of paired longitudinal glioma samples with epigenomic, transcriptomic, and genomic profiling and suggests that treatment of IDHmut glioma is associated with epigenomic evolution toward an IDHwt-like phenotype.</p><p><strong>Significance: </strong>Standard treatments are related to loss of DNA methylation in IDHmut glioma, resulting in epigenetic activation of genes associated with tumor progression and alterations in the microenvironment that resemble treatment-naïve IDHwt glioma.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"741-756"},"PeriodicalIF":12.5,"publicationDate":"2024-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10911804/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138797274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adipose Triglyceride Lipase Is a Therapeutic Target in Advanced Prostate Cancer That Promotes Metabolic Plasticity.","authors":"Dominik Awad, Pham Hong Anh Cao, Thomas L Pulliam, Meredith Spradlin, Elavarasan Subramani, Tristen V Tellman, Caroline F Ribeiro, Riccardo Muzzioli, Brittany E Jewell, Hubert Pakula, Jeffrey J Ackroyd, Mollianne M Murray, Jenny J Han, Mei Leng, Antrix Jain, Badrajee Piyarathna, Jingjing Liu, Xingzhi Song, Jianhua Zhang, Albert R Klekers, Justin M Drake, Michael M Ittmann, Cristian Coarfa, David Piwnica-Worms, Mary C Farach-Carson, Massimo Loda, Livia S Eberlin, Daniel E Frigo","doi":"10.1158/0008-5472.CAN-23-0555","DOIUrl":"10.1158/0008-5472.CAN-23-0555","url":null,"abstract":"<p><p>Lipid metabolism plays a central role in prostate cancer. To date, the major focus has centered on de novo lipogenesis and lipid uptake in prostate cancer, but inhibitors of these processes have not benefited patients. A better understanding of how cancer cells access lipids once they are created or taken up and stored could uncover more effective strategies to perturb lipid metabolism and treat patients. Here, we identified that expression of adipose triglyceride lipase (ATGL), an enzyme that controls lipid droplet homeostasis and a previously suspected tumor suppressor, correlates with worse overall survival in men with advanced, castration-resistant prostate cancer (CRPC). Molecular, genetic, or pharmacologic inhibition of ATGL impaired human and murine prostate cancer growth in vivo and in cell culture or organoids under conditions mimicking the tumor microenvironment. Mass spectrometry imaging demonstrated that ATGL profoundly regulates lipid metabolism in vivo, remodeling membrane composition. ATGL inhibition induced metabolic plasticity, causing a glycolytic shift that could be exploited therapeutically by cotargeting both metabolic pathways. Patient-derived phosphoproteomics identified ATGL serine 404 as a target of CAMKK2-AMPK signaling in CRPC cells. Mutation of serine 404 did not alter the lipolytic activity of ATGL but did decrease CRPC growth, migration, and invasion, indicating that noncanonical ATGL activity also contributes to disease progression. Unbiased immunoprecipitation/mass spectrometry suggested that mutation of serine 404 not only disrupts existing ATGL protein interactions but also leads to new protein-protein interactions. Together, these data nominate ATGL as a therapeutic target for CRPC and provide insights for future drug development and combination therapies.</p><p><strong>Significance: </strong>ATGL promotes prostate cancer metabolic plasticity and progression through both lipase-dependent and lipase-independent activity, informing strategies to target ATGL and lipid metabolism for cancer treatment.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"703-724"},"PeriodicalIF":12.5,"publicationDate":"2024-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10939928/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138457982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phospholipase PLCE1 Promotes Transcription and Phosphorylation of MCM7 to Drive Tumor Progression in Esophageal Cancer.","authors":"Qi Shi, Guixuan Xu, Yuliang Jiang, Ju Yang, Xueping Han, Qian Wang, Ya Li, Zhiyu Zhang, Kaige Wang, Hao Peng, Fangfang Chen, Yandi Ma, Linyue Zhao, Yunzhao Chen, Zheng Liu, Lan Yang, Xingyuan Jia, Tao Wen, Zhaohui Tong, Xiaobin Cui, Feng Li","doi":"10.1158/0008-5472.CAN-23-1633","DOIUrl":"10.1158/0008-5472.CAN-23-1633","url":null,"abstract":"<p><p>Phospholipase C epsilon 1 (PLCE1) is a well-established susceptibility gene for esophageal squamous cell carcinoma (ESCC). Identification of the underlying mechanism(s) regulated by PLCE1 could lead to a better understanding of ESCC tumorigenesis. In this study, we found that PLCE1 enhances tumor progression by regulating the replicative helicase MCM7 via two pathways. PLCE1 activated PKCα-mediated phosphorylation of E2F1, which led to the transcriptional activation of MCM7 and miR-106b-5p. The increased expression of miR-106b-5p, located in intron 13 of MCM7, suppressed autophagy and apoptosis by targeting Beclin-1 and RBL2, respectively. Moreover, MCM7 cooperated with the miR-106b-25 cluster to promote PLCE1-dependent cell-cycle progression both in vivo and in vitro. In addition, PLCE1 potentiated the phosphorylation of MCM7 at six threonine residues by the atypical kinase RIOK2, which promoted MCM complex assembly, chromatin loading, and cell-cycle progression. Inhibition of PLCE1 or RIOK2 hampered MCM7-mediated DNA replication, resulting in G1-S arrest. Furthermore, MCM7 overexpression in ESCC correlated with poor patient survival. Overall, these findings provide insights into the role of PLCE1 as an oncogenic regulator, a promising prognostic biomarker, and a potential therapeutic target in ESCC.</p><p><strong>Significance: </strong>PLCE1 promotes tumor progression in ESCC by activating PKCα-mediated phosphorylation of E2F1 to upregulate MCM7 and miR-106b-5p expression and by potentiating MCM7 phosphorylation by RIOK2.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"560-576"},"PeriodicalIF":11.2,"publicationDate":"2024-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138797269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"R-Loop Accumulation in Spliceosome Mutant Leukemias Confers Sensitivity to PARP1 Inhibition by Triggering Transcription-Replication Conflicts.","authors":"Zhiyan Silvia Liu, Sayantani Sinha, Maxwell Bannister, Axia Song, Erica Arriaga-Gomez, Alexander J McKeeken, Elizabeth A Bonner, Benjamin K Hanson, Martina Sarchi, Kouhei Takashima, Dawei Zong, Victor M Corral, Evan Nguyen, Jennifer Yoo, Wannasiri Chiraphapphaiboon, Cassandra Leibson, Matthew C McMahon, Sumit Rai, Elizabeth M Swisher, Zohar Sachs, Srinivas Chatla, Derek L Stirewalt, H Joachim Deeg, Tomasz Skorski, Eirini P Papapetrou, Matthew J Walter, Timothy A Graubert, Sergei Doulatov, Stanley C Lee, Hai Dang Nguyen","doi":"10.1158/0008-5472.CAN-23-3239","DOIUrl":"10.1158/0008-5472.CAN-23-3239","url":null,"abstract":"<p><p>RNA splicing factor (SF) gene mutations are commonly observed in patients with myeloid malignancies. Here we showed that SRSF2- and U2AF1-mutant leukemias are preferentially sensitive to PARP inhibitors (PARPi), despite being proficient in homologous recombination repair. Instead, SF-mutant leukemias exhibited R-loop accumulation that elicited an R-loop-associated PARP1 response, rendering cells dependent on PARP1 activity for survival. Consequently, PARPi induced DNA damage and cell death in SF-mutant leukemias in an R-loop-dependent manner. PARPi further increased aberrant R-loop levels, causing higher transcription-replication collisions and triggering ATR activation in SF-mutant leukemias. Ultimately, PARPi-induced DNA damage and cell death in SF-mutant leukemias could be enhanced by ATR inhibition. Finally, the level of PARP1 activity at R-loops correlated with PARPi sensitivity, suggesting that R-loop-associated PARP1 activity could be predictive of PARPi sensitivity in patients harboring SF gene mutations. This study highlights the potential of targeting different R-loop response pathways caused by spliceosome gene mutations as a therapeutic strategy for treating cancer.</p><p><strong>Significance: </strong>Spliceosome-mutant leukemias accumulate R-loops and require PARP1 to resolve transcription-replication conflicts and genomic instability, providing rationale to repurpose FDA-approved PARP inhibitors for patients carrying spliceosome gene mutations.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"577-597"},"PeriodicalIF":12.5,"publicationDate":"2024-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10922727/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134648494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}