Cancer research最新文献

{"title":"Abstract B020: Preclinical investigation of FGFR inhibitors in pediatric low-grade gliomas","authors":"April A Apfelbaum, Sangita Pal, Sarah W Lamson, Eric Morin, Georges Ayoub, Sher Bahadur, Jeromy DiGiacomo, Margaret M Cusick, Prem Prabhakar, Connor C Bossi, Sehee Oh, Hyesung Jeon, Jinhua Wang, Hong Yue, Yuan Xiong, Amy Cameron, Patrick Rechter, Quang-De Nguyen, Sara J. Buhrlage, Eric S Fischer, Michael J Eck, Keith L Ligon, Pratiti Bandopadhayay","doi":"10.1158/1538-7445.pediatric25-b020","DOIUrl":"https://doi.org/10.1158/1538-7445.pediatric25-b020","url":null,"abstract":"Pediatric brain cancers are the leading cause of cancer-related deaths in children. We (and others) have reported that close to 10% of all pediatric gliomas, encompassing low-grade and high-grade gliomas, harbor recurrent drive alterations in Fibroblast Growth Factor Receptor proteins (FGFR). In pediatric low-grade gliomas FGFR1 alterations are the most common and occur as structural variants, including kinase duplications and fusion proteins, or kinase-activating single nucleotide variants. Recurrent FGFR1 alterations and the existence of multiple FDA-approved (for adult) pan-FGFR inhibitors represent an attractive therapeutic target for precision medicine approaches, however a challenge with FGFR inhibitors has been the toxicities associated with them and the lack of clinical trials in children. A major aim of this project is to identify the best preclinical FGFR inhibitor candidates for these patients. To address this, we have generated isogenic mouse and human neural stem cells models driven by FGFR1 and BRAF alterations found in pLGGS. We have found that these models grow independent of growth factor and form tumors in mice. The FGFR1-altered models exhibit sensitivity to MEK inhibitors. They also exhibit efficacy to panFGFR inhibitors in vitro and in vivo. We are currently testing the PK characteristics and blood brain barrier efficacy of all available FGFR inhibitors to inform the best candidate for early phase clinical trials. Overall, this project aims to perform preclinical testing using our novel isogenic models to determine a candidate FGFR inhibitor for patients with pLGGs. Citation Format: April A Apfelbaum, Sangita Pal, Sarah W Lamson, Eric Morin, Georges Ayoub, Sher Bahadur, Jeromy DiGiacomo, Margaret M Cusick, Prem Prabhakar, Connor C Bossi, Sehee Oh, Hyesung Jeon, Jinhua Wang, Hong Yue, Yuan Xiong, Amy Cameron, Patrick Rechter, Quang-De Nguyen, Sara J. Buhrlage, Eric S Fischer, Michael J Eck, Keith L Ligon, Pratiti Bandopadhayay. Preclinical investigation of FGFR inhibitors in pediatric low-grade gliomas [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Breakthrough Therapies; 2025 Sep 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_2): nr B020.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"44 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140542","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":"Abstract B028: MicroRNA-mediated reconstruction of the tumor microenvironment: Enhancing CAR T-cell therapy for Diffuse Intrinsic Pontine Glioma","authors":"Kaleem L Coleman, Ryan Corbett, Bicna Song, Alex Sickler, Jo Lynne Rokita, Dalia Haydar","doi":"10.1158/1538-7445.pediatric25-b028","DOIUrl":"https://doi.org/10.1158/1538-7445.pediatric25-b028","url":null,"abstract":"Diffuse Intrinsic Pontine Glioma (DIPG) is a universally fatal pediatric brain tumor with median survival of less than 12 months. While chimeric antigen receptor (CAR) T-cell therapy shows promise, its efficacy in DIPG is limited by a profoundly immunosuppressive tumor microenvironment (TME). MicroRNAs (miRs), small non-coding RNAs that regulate gene expression, play critical roles in both gliomagenesis and immune regulation. Given their expression in both tumor and immune cells, miRs represent a novel, underexplored strategy to modulate the TME and enhance immunotherapy. We hypothesize that targeting dysregulated miR expression in DIPG can reprogram the TME to support CAR T-cell activation and persistence. To investigate the role of miRs in DIPG, we performed small RNA sequencing on post-mortem DIPG tumors, matched normal brain tissue, and healthy brain controls. We identified significant dysregulation of multiple miRs in DIPG, including upregulation of immune-regulatory miRNAs miR[SB1] -135b[SB2] , miR-455[SB3] , and miR-301b[SB4] , which have been previously reported to play roles in macrophage polarization and T-cell exhaustion. miRNA target prediction and Gene Ontology Enrichment Analysis[SB5] confirmed association of upregulated miRs with immune system processes, including T-cell differentiation and myeloid cell regulation. Bulk RNA sequencing of the same samples revealed elevated expression of immunosuppressive genes, such as IL10RA, CD53, CD44, and LGALS9, and downregulation of SIRPA, suggesting impaired immune cell clearance. Notably, fourteen predicted targets of miR-135b were significantly downregulated in DIPG/DMG, and nine of these targets – including MEF2C, STAT6, APC, and KLF4 – are involved in immune-related processes, supporting the role of miR-135b in modulating immune regulatory networks in the TME.[SB6] To assess therapy-induced changes in miR expression, we treated glioma-bearing mice with B7-H3 CAR T cells, control CARs, or left them untreated. Tumors harvested at defined timepoints were profiled for miRs. Principal Component Analysis revealed distinct clustering in B7-H3 CAR–treated tumors. Differential expression analysis identified therapy-associated miRs (including miR-344, let-7d, miR-155, and miR-30c) implicated macrophage polarization and T-cell dysfunction. Together, our data suggests that miRs contribute to DIPG immune suppression and are dynamically regulated by CAR T-cell therapy. Ongoing studies aim to define how targeting specific miRs can enhance CAR T-cell function, offering a new avenue to improve outcomes in DIPG. Citation Format: Kaleem L Coleman, Ryan Corbett, Bicna Song, Alex Sickler, Jo Lynne Rokita, Dalia Haydar. MicroRNA-mediated reconstruction of the tumor microenvironment: Enhancing CAR T-cell therapy for Diffuse Intrinsic Pontine Glioma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Breakthrough Therapies; ","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"27 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140876","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":"Abstract A037: CDK12 – A druggable dependency and potential therapeutic target of desmoplastic small round cell tumor","authors":"Shruthi Sanjitha Sampath, Justin W Magrath, Dane A Flinchum, Sean B Lee","doi":"10.1158/1538-7445.pediatric25-a037","DOIUrl":"https://doi.org/10.1158/1538-7445.pediatric25-a037","url":null,"abstract":"Desmoplastic small round cell tumor (DSRCT) is a pediatric tumor driven by the fusion oncoprotein EWSR1-WT1 formed as a result of a recurrent translocation event between chromosomes 11 and 22. It is a rare malignancy with a 5-year survival rate of 15-20%. Owing to the difficulties in developing targeted therapies for specific oncogenic transcription factors, there is a need to identify DSRCT-specific dependencies. We performed a CRISPR-Cas9 drop-out screen against the human genome and identified Cyclin-dependent Kinase CDK12 to be a selective DSRCT dependency. To validate this finding, doxycycline(dox)-inducible shRNA system was used to establish a stable knockdown of CDK12 expression in JN-DSRCT-1 and BER-DSRCT cell lines. Dox-dependent knockdown of CDK12 was validated by Western blot and quantitative RT-PCR. Consistent with our CRISPR screen, silencing CDK12 decreased DSRCT cell proliferation as indicated by colony formation assays. CDK12 complexes with Cyclin K to phosphorylate the C-terminal domain (CTD) of RNA Polymerase II, which is required for transcription initiation and elongation. THZ531, a CDK12/13 selective inhibitor, binds to the CDK12/Cyclin K complex to inhibit its activity. THZ531 treatment significantly reduced cell viability with IC50 values of 59.25 nM and 51.31 nM in JN-DSRCT-1 and BER-DSRCT, respectively. In contrast, the normal mesothelial cell line LP9 showed a much lower susceptibility to THZ531 with an IC50 of 183.8 nM. THZ531 led to a significant reduction in the phosphorylation of Ser2 of the CTD of RNA polymerase II after 6 hours of treatment, demonstrating effective inhibition of CDK12 activity. A prolonged treatment of THZ531 (24h) significantly increased PARP cleavage in JN-DSRCT-1 and BER-DSRCT cell lines and CDK12 inhibition causes downregulation of large DNA damage response genes. These results indicate that CDK12 inhibition decreases transcription initiation and elongation and induces apoptosis in DSRCT cell lines, making it a potential therapeutic target for DSRCT. Furthermore, co-treatment of DSRCT cell lines with THZ531 and DNAPK inhibitor KU-57788 synergistically reduced DSRCT cell growth and proliferation. These findings indicate that CDK12 is a critical dependency and therapeuic target in DSRCT suggesting that combinatorial inhibition strategies may enhance antitumor efficacy. Citation Format: Shruthi Sanjitha Sampath, Justin W Magrath, Dane A Flinchum, Sean B Lee. CDK12 – A druggable dependency and potential therapeutic target of desmoplastic small round cell tumor [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Breakthrough Therapies; 2025 Sep 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_2): nr A037.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"319 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140933","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":"Abstract A034: PRKG1 hinders myogenic differentiation and predicts response to AKT inhibitor ipatasertib in Rhabdomyosarcoma","authors":"Estela Prada, Pablo Taboas, Angel Montero, Alexandra Avgustinova, Inmaculada Hernandez, Jaume Mora","doi":"10.1158/1538-7445.pediatric25-a034","DOIUrl":"https://doi.org/10.1158/1538-7445.pediatric25-a034","url":null,"abstract":"Rhabdomyosarcoma (RMS) is marked by a myogenesis differentiation blockade, and while the AKT/mTOR pathway is universally activated, its pharmacological inhibition has shown limited success. This study stems from an effort to understand the failure to translate preclinical findings to clinical application. We evaluated the activity of two pan-AKT inhibitors: ipatasertib, an ATP-competitive inhibitor, and miransertib, an allosteric AKT inhibitor. In vitro and in vivo efficacy assessment was conducted in RMS cell lines and fusion-positive/negative patient-derived xenografts (PDX). Unlike miransertib, ipatasertib showed significant antitumor activity against a subset of RMS. Besides AKT, another kinase target of ipatasertib, but not of miransertib, is PRKG1, a cGMP-dependent protein kinase that shares the ATP binding pocket with AKT. The role of PRKG1 in RMS was investigated in PRKG1-depleted RMS cells and in xenograft models by transcriptomic approaches. PRKG1 silencing in RMS cells reduced tumor formation in xenograft models and induced a differentiated myogenic transcriptome. RMS showed higher PRKG1 expression compared to any other developmental cancer, akin to fetal skeletal muscle. Importantly, PRKG1 expression in RMS correlates with mesodermal transcriptional signature and enhanced sensitivity to ipatasertib, regardless of the fusion oncogene status. The antitumor activity of ipatasertib is dose-dependent, reaching an effective intra-tumor concentration when administered at 25 mg/kg daily. This study unveils the role of PRKG1 in myogenesis and highlights the potential of PRKG1 as a clinical biomarker for ipatasertib therapy in RMS. Citation Format: Estela Prada, Pablo Taboas, Angel Montero, Alexandra Avgustinova, Inmaculada Hernandez, Jaume Mora. PRKG1 hinders myogenic differentiation and predicts response to AKT inhibitor ipatasertib in Rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Breakthrough Therapies; 2025 Sep 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_2): nr A034.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"18 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140938","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":"Abstract A013: Multi-omic profiling of plasma circulating tumor DNA (ctDNA) detects and differentiates Wilms tumors and malignant rhabdoid tumors of the kidney","authors":"Nensi M Ruzgar, Cora Ricker, Kelly Klega, Catherine Clinton, Aleksi Halme, Natalie Greenwood, Laura Madanat-Harjuoja, Elizabeth A Mullen, Brian D Crompton","doi":"10.1158/1538-7445.pediatric25-a013","DOIUrl":"https://doi.org/10.1158/1538-7445.pediatric25-a013","url":null,"abstract":"Purpose: Pediatric renal tumors (RT) represent a range of histologies with varying prognoses and therapy recommendations, complicating initial treatment decisions without a histologic diagnosis when surgery or biopsy are contraindicated. In these cases, non-invasive diagnostic assays could guide disease-specific therapy. We previously showed that circulating tumor DNA (ctDNA) is detectable in patients with Wilms tumor (WT) and can identify somatic features when tumor tissue is unavailable. However, conventional ctDNA profiling methods, such as copy number alteration (CNA) detection, are unlikely to distinguish RT histologies. For example, malignant rhabdoid tumors of the kidney (MRTK) are driven by biallelic INI1 loss which is difficult to detect in ctDNA and typically lack other somatic events. Recent advances now allow whole-genome methylation sequencing (WGMS) on samples with low DNA input, such as cell-free DNA. Here, we examined if methylation and fragment features could improve ctDNA detection and differentiate diagnoses in patients with WT and MRTK as proof of concept for liquid biopsy diagnostics. Methods: Pretreatment plasma and tumor tissue from patients with WT (14 matched pairs) and MRTK (7 pairs, 8 unmatched plasma), and plasma from 20 healthy donors were profiled by enzymatic WGMS at 30X target coverage. ichorCNA was used to detect ctDNA based on CNAs. Differentially methylated regions (DMRs) were identified using R methylKit. Fragment length and end motif frequencies were analyzed in WT and healthy plasma. Machine learning prediction models were built using cross-validation to classify healthy, WT and MRTK plasma. Results: ctDNA was detected based on aneuploidy in 8/14 (53%) patients with WT and only 3/15 (20%) with MRTK. Matched WT plasma and tumors had 85.7% agreement in detecting 1p loss, and 71.4% agreement in detecting 1q gain or 16q loss. For matched MRTK samples, 5/7 tumor and 1/7 plasma had detectable INI1 loss. Compared to healthy donor plasma, WT tissue had 2146 DMRs and MRTK tissue had 65 DMRs. Separate unsupervised analyses using these DMRs clustered WT and MRTK plasma with their respective tumor types compared to healthy controls, including 3 WT and 7 MRTK plasma where ctDNA was not detected based on aneuploidy. Generalized linear models (GLM) were trained to differentiate WT and MRTK tissue based on these DMRs and classified 12/14 WT and 11/15 MRTK plasma as their assigned diagnoses. WT cell-free DNA also had higher frequency of short fragments and distinct end motif profiles than healthy plasma (p<0.01). GLMs that were trained to differentiate WT from healthy plasma using DMRs, fragment lengths and end motifs predicted tumor signals in 14/14 WT plasma. Conclusions: Methylation profiling improves ctDNA detection in WT and MRTK and can differentiate these diagnoses in most cases. For WT, using fragment data improved sensitivity of ctDNA detection in cases where detecting aneuploidy was insufficient. Our findings","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"91 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140990","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":"Abstract A040-PR008: Characterization of cytotoxic cell abundance and genetic variants in immune related genes in pediatric acute lymphoblastic leukemia patients","authors":"Ignacio Gomez Mercado, Daniel Avendaño, Sabrina Ledesma Bazan, Pablo Sanchis, Maria Cecilia Riccheri, Geraldine Gueron, Javier Cotignola, Maria Sol Ruiz","doi":"10.1158/1538-7445.pediatric25-a040-pr008","DOIUrl":"https://doi.org/10.1158/1538-7445.pediatric25-a040-pr008","url":null,"abstract":"Acute lymphoblastic leukemia (ALL) is the leading cause of cancer-related mortality in pediatrics. Between 15-30% of patients relapse, and current treatments are associated with acute and long-term toxicity. The immune component of the tumor microenvironment is an under-explored factor that could play a role in the establishment or progression of the disease, as well as modulate response to chemo- and immunotherapies. We characterized the molecular profile of leukemias from 32 patients with pediatric ALL treated under the ALLIC-GATLA 2010 clinical protocol in Argentina by transcriptome sequencing (Illumina). We estimated the immune component through digital cytometry (MIXTURE) and a cytolytic score based on the expression of five genes. We searched for single nucleotide variants (SNV) in the transcriptome (CTAT-Mutations) that could alter the interaction with immune cells in the tumor microenvironment. For this, we analyzed 843 genes from Reactome collections associated with the immune system. Variants were filtered and annotated using publicly available germline and somatic variant databases. The group of patients with higher abundance of cytotoxic cells (Z-score>1) was associated with an increased risk of relapse/death (HR=4.5; p=0.05), and higher levels of CX3CR1 (q-val<0.05) and TIM-3 (q-val=0.06). Analysis of an independent high-risk cohort (TARGET B-ALL phase II, N=88), confirmed that a higher cytolytic score was associated with the risk of relapse in an univariate (HR=2.66, p=0.001) and multivariate model including cytolytic score (p<0.006), protocol (p=0,07), ETV6::RUNX1 (p:>0.05) and TCF3::PBX1 status (p<0.001). Cytolytic score was not associated with molecular subtype, age, sex or early response to treatment (p>0.05). For SNV analysis, we developed a threshold value for the QUAL parameter to select for high-confidence variants, establishing a specificity of 95%. Eleven variants were found in nine patients, being 8/11 classified by Franklin as TIER3 in CEP290, UBE3B, CPNE3, DUSP4, DAPP1, RNF135, TBC1D10C and TLR1; 2/11 as TIER1 in TP53, KRAS; and 1/11 as TIER4 in BTN3A3. Patient harboring variants in these genes were significantly associated with a lower GSVA score in the Reactome dataset “MHC_Class_II_Antigen_Presentation” (q-val<0.01). We found a variant in UBE3B, located in the active site of the E3 ubiquitin ligase, and associated with a low GSVA score in the Reactome “Antigen presentation through MHC class I” pathway. A novel variant in CPNE3 gene was found, located in a highly conserved residue and predicted to be deleterious by multiple tools. Conclusion: the abundance of cytotoxic cells was independent of molecular subtype and associated with a worse prognosis in independent cohorts. Further analysis of the variants found in this study has the potential to identify novel mechanisms modulating the interaction between the immune system and leukemic cells in ALL. Citation Format: Igna","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"73 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140991","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":"ZNF296 Drives Immune Evasion in Epithelial Cancers by Repressing Immune Stimulatory Genes.","authors":"Hefei Wang,Fangting Zhao,Yao Li,Peiyu Wang,Yixue Wang,Pengfei Ren,Changhe Li,Hanqiu Zheng,Zexian Zeng,Deng Pan","doi":"10.1158/0008-5472.can-25-0153","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-0153","url":null,"abstract":"Resistance to immune-mediated destruction is a fundamental hallmark of cancer. Although several mechanisms have been identified that facilitate immune evasion, the transcriptional programs that orchestrate this process remain poorly understood. Here, through a genome-wide CRISPR activation screen in human cancer cells subjected to natural killer (NK) cell-mediated killing, we identified ZNF296, a transcription factor highly expressed in epithelial cancers, as a key driver of tumor resistance to both NK and cytotoxic T cell (CTL)-mediated immunity. In mouse models, inhibition of ZNF296 significantly enhanced both NK and T cell-mediated anti-tumor immunity, leading to a marked reduction in metastasis and increased infiltration of immune cells into the tumor microenvironment. Mechanistically, ZNF296 induced strong transcriptional repression of interferon-stimulated genes and key immunostimulatory ligands critical for NK and T cell-mediated cytotoxicity. At the molecular level, ZNF296 directly interacted with and recruited the NuRD chromatin remodeling and deacetylase complex to the promoters of its target genes to suppress expression. Notably, treatment with low-dose romidepsin, an FDA-approved inhibitor targeting HDAC1, a core component of the NuRD complex, effectively restored NK and T cell-mediated killing in cancer cells with high ZNF296 expression. Collectively, these findings establish ZNF296 as a key regulator of immune evasion, driving resistance to both NK and T cell-mediated antitumor immunity, and highlight its potential as a therapeutic target to overcome immune resistance in epithelial cancers.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"24 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145127130","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":"Mismatch Repair as a Dynamic and Clinically Actionable Vulnerability in Cancer","authors":"Eleonora Piumatti, Pietro Paolo Vitiello, Vito Amodio, Alberto Bardelli, Giovanni Germano","doi":"10.1158/0008-5472.can-25-2255","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-2255","url":null,"abstract":"DNA mismatch repair (MMR) preserves genomic integrity by correcting replication errors. Deficiency in MMR (MMRd) results in microsatellite instability, increased tumor mutational burden, neoantigen generation, and activation of immune response. In this review, we first outlined how MMR loss promotes immune activation and responsiveness to immune checkpoint blockade (ICB), establishing MMRd status as the first tumor-agnostic biomarker for ICB therapy. Subsequently, we summarized the compelling evidence that defines MMR status as a dynamic, context-dependent process influenced by environmental and therapeutic pressures, rather than a fixed, binary trait. Accordingly, we discussed the implications of spatial and temporal heterogeneity of MMR status for both the diagnosis and treatment of cancer, the differential response of MMRd tumors to ICB, as well as the occasional benefits observed in MMR-proficient (MMRp) immune-cold cancers. We then explored strategies to exploit MMR dynamics and mimic MMRd-like phenotypes through alkylating agents, pharmacological MMR inhibition, and stress-mediated modulation, with the aim of sensitizing refractory tumors to immunotherapy. Finally, we reported emerging therapeutic opportunities in MMRd tumors, including Werner helicase inhibition, nonsense-mediated decay blockade, and neoantigen-targeted vaccines. Altogether, reframing MMR as a dynamic and targetable axis may broaden immunotherapy applicability and advance precision immune oncology across different tumor types.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"12 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145133562","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":"Stress Promotes Lung Metastasis in Breast Cancer by Altering Neutrophil Differentiation.","authors":"Pengfei Liu,Jie Zheng,Wenjing Ma,Jinhui Lü,Qian Zhao,Danni Li,Xiaoyan Jiang,Haikun Wang,Haiyun Wang,Zuoren Yu","doi":"10.1158/0008-5472.can-25-1763","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-1763","url":null,"abstract":"Mental stress is widely recognized as a significant risk factor for breast cancer, exerting detrimental effects on both progression and prognosis. Herein, we investigated the role of stress in regulating breast cancer metastasis. In genetically engineered and transplantation breast cancer mouse models, chronic stress stimulation increased tumor growth and lung metastasis. Single-cell RNA-sequencing analysis of the pre-metastatic lung microenvironment revealed induction of a previously unrecognized subtype of cancer stress-primed (CSP) neutrophils, characterized by the overexpression of Ccl3, Ccl4, Cxcl2, Il1r2, and Cebpb. Pseudotime trajectory analysis demonstrated that chronic stress caused a shift of neutrophils from the cancer-primed (CP) neutrophil subtype to the CSP subtype in the lung. Activation of the glucocorticoid receptor NR3C1 by the stress hormone corticosterone induced expression of Cebpb in neutrophils, which then promoted transcription of Ccl3 and Ccl4. The differentiation of neutrophils into the CSP subtype promoted lung metastasis of CCR1+ breast cancer cells via CCL3/CCL4-mediated recruitment. Targeting this axis using an anti-Ly6G antibody to deplete neutrophils, a CRISPR/Cas9-mediated approach to conditionally knockout Ccl3/Ccl4 in neutrophils, and BX471 treatment to inhibit CCR1 in cancer cells all significantly reduced breast cancer lung metastasis. Together, this study not only demonstrates a stress-neutrophil-cancer axis that promotes lung metastasis in breast cancer but also provides potential strategies for reducing lung metastasis by targeting CSP neutrophils or CCR1+ breast cancer cells.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"156 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145127031","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":"MEN1 Promotes Ferroptosis by Disrupting CD44 Alternative Splicing to Suppress Lung Cancer.","authors":"Ting Pan,Jiamei Zhu,Xuyan Wang,Dekun Tang,Ziming Wang,Yunqiao Yang,Yin Teng,Qianting Tian,Guixue Dan,Chaochun Chen,Dafang Yu,Mengyuan Liu,Houmei Wang,Tuo Zhang,Bing Guo,Tengxiang Chen,Bangming Jin","doi":"10.1158/0008-5472.can-25-0021","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-0021","url":null,"abstract":"Ferroptosis is a characteristic form of cell death triggered by excessive iron-dependent reactive oxygen species (ROS) that plays an important role in suppressing tumor development. Here, we identified MEN1 as a driver of ferroptosis in lung cancer. MEN1 facilitated lipid ROS generation and sensitized lung cancer cells to ferroptosis by perturbing CD44 precursor messenger RNA (pre-mRNA) splicing. CD44 variant isoforms were highly expressed and correlated with poor prognosis in human lung cancers. Loss of Men1 profoundly accelerated the progression of mutant Kras driven lung adenocarcinoma (LUAD) and promoted the accumulation of CD44 variant isoforms. Mechanistically, MEN1 maintained a relatively slow RNA polymerase II (Pol II) elongation by controlling the release of PAF1 from the CD44 pre-mRNA, which in turn prevented the inclusion of CD44 variable exons (CD44v). Furthermore, CD44v6-interfering peptides effectively abrogated the growth and metastasis of established MEN1 deficient tumors by activating ferroptosis. Collectively, this study unveils a mechanism of tumor suppression based on MEN1 regulation of CD44 alternative splicing, ROS production, and ferroptosis induction.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"19 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145127030","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}