Molecular Oncology最新文献

{"title":"NanoCMSer: a consensus molecular subtype stratification tool for fresh-frozen and paraffin-embedded colorectal cancer samples.","authors":"Arezo Torang, Simone van de Weerd, Veerle Lammers, Sander van Hooff, Inge van den Berg, Saskia van den Bergh, Miriam Koopman, Jan N IJzermans, Jeanine M L Roodhart, Jan Koster, Jan Paul Medema","doi":"10.1002/1878-0261.13781","DOIUrl":"10.1002/1878-0261.13781","url":null,"abstract":"<p><p>Colorectal cancer (CRC) is a significant contributor to cancer-related mortality, emphasizing the need for advanced biomarkers to guide treatment. As part of an international consortium, we previously categorized CRCs into four consensus molecular subtypes (CMS1-CMS4), showing promise for outcome prediction. To facilitate clinical integration of CMS classification in settings where formalin-fixed paraffin-embedded (FFPE) samples are routinely used, we developed NanoCMSer, a NanoString-based CMS classifier using 55 genes. NanoCMSer achieved high accuracy rates, with 95% for fresh-frozen samples from the MATCH cohort and 92% for FFPE samples from the CODE cohort, marking the highest reported accuracy for FFPE tissues to date. Additionally, it demonstrated 96% accuracy across a comprehensive collection of 23 RNAseq-based datasets, compiled in this study, surpassing the performance of existing models. Classifying with only 55 genes, the CMS predictions were still biologically relevant, recognizing CMS-specific biology upon enrichment analysis. Additionally, we observed substantial differences in recurrence-free survival curves when comparing CMS2/3 patients in stage III versus II. Probability of recurrence after 5 years increased by 21% in CMS2 and 31% in CMS3 for patients in stage III, whereas this difference was less pronounced for CMS1 and CMS4, with 11% and 10%, respectively. We posit NanoCMSer as a robust tool for subtyping CRCs for both tumor biology and clinical practice, accessible via nanocmser r package (https://github.com/LEXORlab/NanoCMSer) and Shinyapp (https://atorang.shinyapps.io/NanoCMSer).</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"1332-1346"},"PeriodicalIF":6.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077266/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886113","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":"Germline variants in CDKN2A wild-type melanoma prone families.","authors":"Gjertrud T Iversen, Marie Loeng, Amalie Lund Holth, Per E Lønning, Jürgen Geisler, Stian Knappskog","doi":"10.1002/1878-0261.70020","DOIUrl":"10.1002/1878-0261.70020","url":null,"abstract":"<p><p>Germline pathogenic variants in CDKN2A are well established as an underlying cause of familial malignant melanoma. While pathogenic variants in other genes have also been linked to melanoma, most familial cases remain unexplained. We assessed pathogenic germline variants in 360 cancer-related genes in 56 Norwegian melanoma-prone families. The index cases were selected based on familial history of melanoma and/or multiple primary melanomas, along with previous negative tests for pathogenic CDKN2A variants. We found 6 out of 56 index individuals to carry germline pathogenic or likely pathogenic variants in BRCA2, MRE11, ATM, MSH2, CHEK2, and AR. One family member with melanoma (not index case) carried a pathogenic variant in MAP3K6. In addition, we found a high fraction of variants previously considered benign and/or as variants of uncertain significance in xeroderma pigmentosum-related genes. In particular, XPC^L48F was found in 8 indexes; thus, the allele fraction (0.07) was significantly higher than in comparable healthy populations (0.02-0.03; P-values from 0.007 to 0.014). In conclusion, we found that several melanoma-prone families have pathogenic variants in genes not usually linked to melanoma.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"1493-1507"},"PeriodicalIF":6.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077288/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143605327","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":"Polyfunctional CD8⁺CD226⁺RUNX2^hi effector T cells are diminished in advanced stages of chronic lymphocytic leukemia.","authors":"Maryam Rezaeifar, Shima Shahbaz, Anthea C Peters, Spencer B Gibson, Shokrollah Elahi","doi":"10.1002/1878-0261.13793","DOIUrl":"10.1002/1878-0261.13793","url":null,"abstract":"<p><p>CD8⁺ T cells, a subset of T cells identified by the surface glycoprotein CD8, particularly those expressing the co-stimulatory molecule CD226, play a crucial role in the immune response to malignancies. However, their role in chronic lymphocytic leukemia (CLL), an immunosuppressive disease, has not yet been explored. We studied 64 CLL patients and 25 age- and sex-matched healthy controls (HCs). We analyzed the proportion of CD226-expressing cells among different CD8⁺ T cell subsets (including naïve, central memory, effector memory, and effectors) in CLL patients, stratified by Rai stage and immunoglobulin heavy-chain variable region gene (IgHV) mutation status. Additionally, we compared the effector functions of CD8⁺CD226⁺ cells and their CD226^- counterparts. We also quantified cytokine and chemokine levels in the plasma of CLL and HCs. Furthermore, we reanalyzed the publicly available bulk RNA-seq on CD226⁺ and CD226^-CD8⁺ T cells. Finally, we evaluated the impact of elevated cytokines/chemokines on CD226 expression. Our results showed that CD226-expressing cells were significantly decreased within the effector memory and effector CD8⁺ T cell subsets in CLL patients with advanced Rai stages and unmutated IgHV, a marker of poor prognosis. These cells displayed robust effector functions, including cytokine production, cytolytic activity, degranulation, proliferation, and migration capacity. In contrast, CD8⁺CD226^- T cells displayed an exhausted phenotype with reduced Runt-related transcription factor 2 (RUNX2) expression. Elevated levels of interleukin-6 (IL-6) and macrophage inflammatory protein-1 beta (MIP-1β) were inversely correlated with the frequency of CD8⁺CD226⁺ T cells and may contribute to the downregulation of CD226, possibly leading to T cell dysfunction in CLL. Our findings highlight the critical role of CD8⁺CD226⁺RUNX2^hi T cells in CLL and suggest that their reduction is associated with disease progression and poor clinical outcomes. This study also underscores the potential of targeting IL-6 and MIP-1β to preserve polyfunctional CD8⁺CD226⁺ T cells as a promising immunotherapy strategy.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"1347-1370"},"PeriodicalIF":6.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077284/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951231","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 roles and applications of extracellular vesicles in cancer.","authors":"Clotilde Théry, Daniel Louvard","doi":"10.1002/1878-0261.70007","DOIUrl":"10.1002/1878-0261.70007","url":null,"abstract":"<p><p>Extracellular vesicles (EVs) have been studied for several decades and are attracting growing interest among life scientists and oncologists. Understanding the extent of diversity of their cellular origins, structure, molecular composition, and consequently functions is still under progress. EVs offer numerous diagnostic and therapeutic possibilities, but many fundamental questions about their functions need to be resolved in order to effectively and safely implement their applications in the treatment of human diseases.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"1287-1290"},"PeriodicalIF":6.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077283/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483660","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":"Microglial reprogramming: a potential new frontier in enhancing immunotherapy for melanoma brain metastasis.","authors":"Noam Savion-Gaiger, Dorin Bar-Ziv, Harriet Kluger","doi":"10.1002/1878-0261.70028","DOIUrl":"10.1002/1878-0261.70028","url":null,"abstract":"<p><p>The brain is a common site of metastatic dissemination in advanced melanoma. Due to limited access to samples from human brain metastases, our understanding of the tumor microenvironment in the brain lags behind that of other sites, and murine studies are therefore highly informative. Rodriguez-Baena et al. conducted elegant studies of myeloid cells within melanoma brain metastases, demonstrating their plasticity and changes before and after colonization by melanoma cells. The immune-inhibitory changes in microglial cells may be reversed or mitigated by inhibition of RelA/NF-κB.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"1291-1294"},"PeriodicalIF":6.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077281/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662715","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":"Clinical significance of stratifying prostate cancer patients through specific circulating genes.","authors":"Seta Derderian, Edouard Jarry, Arynne Santos, Quentin Vesval, Lucie Hamel, Rafael Sanchez-Salas, Alexis Rompré-Brodeur, Wassim Kassouf, Raghu Rajan, Fadi Brimo, Marie Duclos, Armen Aprikian, Simone Chevalier","doi":"10.1002/1878-0261.13805","DOIUrl":"10.1002/1878-0261.13805","url":null,"abstract":"<p><p>Patient stratification remains a challenge for optimal treatment of prostate cancer (PCa). This clinical heterogeneity implies intra-tumoural heterogeneity, with different prostate epithelial cell subtypes not all targeted by current treatments. We reported that such cell subtypes are traceable in liquid biopsies through representative transcripts. Expanding on this concept, we included 57 genes representing cell subtypes, drug targets and relevant to resistance as non-invasive biomarkers for stratification. This panel was tested by RT-qPCR (quantitative reverse transcription polymerase chain reaction) in blood of controls and different categories of PCa patients. Overall, circulating transcripts showed predictive value throughout the disease. Those with aggressive pathological features such as intra-ductal carcinoma at diagnosis showed more genes over-expressed. In metastatic patients, signatures of subtypes or resistance were associated with treatments, progression-free survival and overall survival. Altogether, testing markers of cell diversity, an intrinsic feature of tumours, and drug targets via liquid biopsies represents a valuable means to stratify patients and predict responses to current or new therapeutic modalities. Over-expressed drug target genes suggest potential benefit from targeted treatments, justifying new clinical trials to offer patient-tailored strategies to eventually impact on PCa mortality.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"1310-1331"},"PeriodicalIF":6.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077267/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008667","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 PTTG1/VASP axis promotes oral squamous cell carcinoma metastasis by modulating focal adhesion and actin filaments.","authors":"Suyeon Park, Sang Shin Lee, Shihyun Kim, Yeonjun Lee, Gyeonwon Park, Jung Oh Kim, Jongho Choi","doi":"10.1002/1878-0261.13779","DOIUrl":"10.1002/1878-0261.13779","url":null,"abstract":"<p><p>The dynamics of focal adhesions (FAs) are essential physiological processes involved in cell spreading, metastasis, and regulation of the actin cytoskeleton. FAs are complex structures comprising proteins, such as paxillin and zyxin, which interact with extracellular membranes and influence cell motility and morphology. Although related studies have been reported in various cancers, the function and molecular mechanisms of oral squamous cell carcinoma (OSCC) remain unknown. We investigated the coordination between the actin cytoskeleton and FA proteins, specifically introducing pituitary tumor-transforming gene 1 (PTTG1; also known as PTTG1 regulator of sister chromatid separation, securin) into OSCC. Furthermore, we explored the co-localization of several FAs and PTTG1 through small interfering RNA (siRNA) control or siRNA-vasodilator-stimulated phosphoprotein (VASP) and -PTTG1, examining the mechanisms mediated by the induced changes in OSCC both in vitro and in vivo. The knockdown of VASP and PTTG1 regulates the dynamic actin cytoskeleton, restricting cell protrusion and motility from the front to the rear of OSCC cells. Our findings may provide new insights into how cells interact with each other on the surface of FAs in OSCC, influencing metastatic properties.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"1517-1531"},"PeriodicalIF":6.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077276/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142962195","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":"Targeting PRAME directly or via EZH2 inhibition overcomes retinoid resistance and represents a novel therapy for keratinocyte carcinoma.","authors":"Brandon Ramchatesingh, Amelia Martinez Villarreal, Philippe Lefrançois, Jennifer Gantchev, Sriraam Sivachandran, Samy Abou Setah, Ivan V Litvinov","doi":"10.1002/1878-0261.13820","DOIUrl":"10.1002/1878-0261.13820","url":null,"abstract":"<p><p>Retinoids have demonstrated efficacy as preventative/treatment agents for keratinocyte carcinomas (KCs): basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (SCC). However, retinoid resistance mechanisms limit the efficacy of these compounds. A subset of KCs expresses Preferentially Expressed Antigen in Melanoma (PRAME): a retinoid signaling corepressor. PRAME is proposed to repress retinoid signaling by guiding enhancer of zeste homolog 2 (EZH2) to retinoic acid response elements (RARE) in promoters. We investigated the effects of PRAME on KC pathogenesis and retinoid response. High-PRAME expression in tumors was negatively correlated with epidermal differentiation gene signatures. PRAME overexpression downregulated epidermal differentiation gene signatures and impaired differentiation in 3D culture. PRAME overexpression attenuated retinoid-induced RARE activation, growth suppression, and differentiation responses. Conversely, low-PRAME tumors and PRAME-depleted KC cells demonstrated enriched epidermal differentiation gene signatures. PRAME downregulation restored retinoid-induced RARE activation, growth suppression, keratinization in SCC, and cell death signaling in BCC. Furthermore, combined retinoid and EZH2 inhibitor treatment augmented RARE activation and suppressed PRAME-expressing KC cell growth. Hence, PRAME confers retinoid resistance in KC, which may be overcome by EZH2 inhibition.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"1471-1492"},"PeriodicalIF":6.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077289/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657823","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":"Impact of molecular diagnostics and targeted cancer therapy on patient outcomes (MODIFY): a retrospective study of the implementation of precision oncology.","authors":"Michaël Dang, Anna Schritz, Nikolai Goncharenko, Guy Berchem","doi":"10.1002/1878-0261.13785","DOIUrl":"10.1002/1878-0261.13785","url":null,"abstract":"<p><p>High-throughput genomic analyses are being implemented in clinical practice. MODIFY is a retrospective study of the first introduction of genomic profiling and molecular tumor boards in the country of Luxembourg. The primary objective was to assess whether patients derived a clinical benefit by measuring the percentage of patients who presented a progression-free survival (PFS) on matched therapy (PFS2) 1.3-fold longer than PFS on previous therapy (PFS1). A total of 94 patients were included. In total, 45 patients (53.57% of patients with successful next-generation sequencing [NGS] analysis) were found to have an actionable mutation. Of these, 11 patients received the treatment recommended by the molecular tumor board, another 12 received best-supportive care, and 20 were treated with conventional therapy. PFS2 and PFS1 data were available for eight patients. The PFS2/PFS1 ratio was ≥ -1.3 in 62.5% (n = 5/8; CI [30.38, 86.51]) of patients; three patients showed a partial response, and median overall survival (OS) was 7.3 months. Although the examined population was small, this study further supports evidence indicating that patients with advanced cancer benefit from molecular profiling and targeted therapy.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"1508-1516"},"PeriodicalIF":6.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077269/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813700","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":"Cystatin A promotes the antitumor activity of T helper type 1 cells and dendritic cells in murine models of pancreatic cancer.","authors":"Alessandro Nasti, Shingo Inagaki, Tuyen Thuy Bich Ho, Akihiro Seki, Keiko Yoshida, Kosuke Satomura, Yoshio Sakai, Shuichi Kaneko, Taro Yamashita","doi":"10.1002/1878-0261.13796","DOIUrl":"10.1002/1878-0261.13796","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) is a disease with poor prognosis due to diagnostic and therapeutic limitations. We previously identified cystatin A (CSTA) as a PDAC biomarker and have conducted the present study to investigate the antitumor effects of CSTA. PDAC murine models were established with genetically modified PAN02 tumor cell lines to evaluate the antitumor immune response. PDAC mouse survival was significantly longer with CSTA, and its antitumor effect was mediated mainly by CD4+ cells and partly by CD8+ cells. We also observed an increased infiltration of CD4+ and CD8+ cells in tumors of mice overexpressing CSTA. Phenotypically, we confirmed higher T helper type 1 (Th1) cell activity and increased frequency and activity of M1 macrophages and dendritic cells (DCs) in CSTA-overexpressing mice. Gene expression analysis highlighted pathways related to interferon gamma (IFN-γ) induction and Th1 lymphocyte activation that were induced by CSTA. Macrophages and DCs shifted toward proinflammatory antitumor phenotypes. Furthermore, activated splenocytes of PDAC model mice expressing CSTA had increased proapoptotic activity. CSTA also promoted the selective migration of CD4+ and CD11c+ immune cells in an in vitro migration assay. In conclusion, CSTA exerts antitumor effects by enhancing Th1-mediated antitumor effects through promotion of DC and M1 macrophage activity, thereby increasing immune cell chemotaxis. CSTA could be a novel therapeutic candidate for PDAC.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"1452-1470"},"PeriodicalIF":6.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077287/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142962194","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}