Molecular Oncology最新文献

{"title":"ITGAV and SMAD4 influence the progression and clinical outcome of pancreatic ductal adenocarcinoma.","authors":"Daniel K C Lee, Keyue Chen, Ryan Loke, Xiang Li, David Liubart, Golam T Saffi, Jonathan T S Chow, Ché M P Melo, Lydia To, Leonardo Salmena","doi":"10.1002/1878-0261.70080","DOIUrl":"https://doi.org/10.1002/1878-0261.70080","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive and lethal malignancy with limited treatment options, a fact that underscores the urgent need for more effective therapies to improve patient outcomes. Preclinical studies have shown promise for αV integrin-targeted therapies; however, clinical trials have been disappointing, highlighting the need for further research. In this study, we demonstrate that integrin subunit alpha V (ITGAV) signals through both mothers against decapentaplegic homolog 4 (SMAD4)-dependent or SMAD4-independent pathways, depending on the genetic context. In SMAD4-positive PDAC cells, ITGAV contributes to the transforming growth factor-beta (TGF-β) signaling pathway to regulate proliferation, migration, and invasion. Conversely, in SMAD4-negative PDAC cells, ITGAV influences only proliferation and migration via activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-related kinase (ERK) pathway. High levels of ITGAV are also associated with poor prognostic outcomes in SMAD4 wild-type patients but are not prognostic in SMAD4 mutant patients. Thus, ITGAV contributes to different patterns of PDAC progression. These findings suggest that stratifying PDAC patients based on both SMAD4 status and ITGAV expression could inform more effective integrin-targeted treatment strategies.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144753853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"β-TrCP overexpression enhances cisplatin sensitivity by depleting BRCA1.","authors":"Rocío Jiménez-Guerrero, Alejandro Belmonte-Fernández, Mónica González-Moreno, Laura Rodríguez-Cordero, Begoña Pérez-Valderrama, Joaquín Herrero-Ruíz, Francisco Romero, Carmen Sáez, Miguel Á Japón","doi":"10.1002/1878-0261.70089","DOIUrl":"https://doi.org/10.1002/1878-0261.70089","url":null,"abstract":"<p><p>Cisplatin is one of the most used anticancer chemotherapy agents; however, over time, patients develop resistance to the treatment, and survival rates drop dramatically. Investigation of tumor cell resistance mechanisms could increase sensitivity and prevent cancer progression. Here, we investigated the role of the E3 ubiquitin ligase SCF (β-TrCP) in cisplatin resistance in different tumor cell lines, analyzing its role in the stability of BRCA1 and CtIP, proteins involved in DNA damage repair by homologous recombination. We showed that SCF(β-TrCP) plays a key role in cisplatin response, as overexpression of wild-type β-TrCP increased DNA damage and cisplatin-induced apoptosis, while overexpression of a dominant-negative mutant or siRNA-mediated downregulation of β-TrCP decreased the damage and conferred treatment resistance. Furthermore, we demonstrated that BRCA1 and CtIP interacted with β-TrCP in vivo, and their levels changed when β-TrCP expression was modulated. We also described that β-TrCP-mediated BRCA1 degradation involves both lysosomal and proteasomal pathways. Mechanistically, the failure of β-TrCP to regulate the degradation of BRCA1 enables a more efficient DNA damage repair and thereby the acquisition of cisplatin resistance. Overall, β-TrCP overexpression sensitizes cisplatin-induced DNA damage by depleting BRCA1.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RKIP overexpression reduces lung adenocarcinoma aggressiveness and sensitizes cells to EGFR-targeted therapies.","authors":"Ana Raquel-Cunha, Joana Pinheiro, Rui F Marques, Patrícia Fontão, Diana Cardoso-Carneiro, Adriana Mendes, Izabela N F Gomes, Ana Carolina Laus, Renato J da Silva-Oliveira, Rui Manuel Reis, Olga Martinho","doi":"10.1002/1878-0261.70096","DOIUrl":"https://doi.org/10.1002/1878-0261.70096","url":null,"abstract":"<p><p>Lung adenocarcinoma (LUAD), the most common subtype of non-small-cell lung cancer (NSCLC), is often driven by mutations, particularly in epidermal growth factor receptor (EGFR), that guide targeted therapy choices. However, resistance to these treatments remains a major clinical challenge. Raf kinase inhibitory protein (RKIP), encoded by the PEBP1 gene, a metastasis suppressor, modulates key oncogenic pathways and may influence tumor aggressiveness and therapy response. Yet, its specific role in NSCLC remains unclear. This study investigates the influence of RKIP expression on NSCLC aggressiveness and explores its impact on therapy response, particularly to EGFR-targeted therapies. In silico analyses revealed that lower RKIP mRNA expression correlates with poorer survival outcomes in LUAD patients but not in other NSCLC subtypes. Genetic modulation of RKIP expression in LUAD cell lines demonstrated that its overexpression reduced migration, spheroid integrity, and suppressed tumor growth, whereas RKIP knockout had opposite effects, particularly in vivo. Expression profiling showed that RKIP overexpression impacts the activation of mitogen-activated protein kinase (MAPK), RAC serine/threonine-protein kinase (AKT), and signal transducer and activator of transcription 3 (STAT3) pathways, as well as processes related to extracellular matrix regulation and inflammatory responses. Importantly, in vitro and in vivo experiments demonstrated that RKIP overexpression sensitizes cells to anti-EGFR treatments, whereas RKIP knockout diminished their sensitivity. Overall, our findings indicate that RKIP modulates LUAD progression and response to EGFR-targeted therapies, although its clinical value as a biomarker requires further validation. These findings highlight RKIP's potential in overcoming therapeutic resistance and the need for further investigation into its regulatory mechanisms.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decrypting cancer's spatial code: from single cells to tissue niches.","authors":"Cenk Celik, Shi Pan, Eloise Withnell, Hou Wang Lam, Maria Secrier","doi":"10.1002/1878-0261.70100","DOIUrl":"https://doi.org/10.1002/1878-0261.70100","url":null,"abstract":"<p><p>Spatial transcriptomics (ST) has emerged as a powerful tool to map gene expression patterns to the local tissue structure in cancer, enabling unprecedented insights into cellular heterogeneity and tumour microenvironments. As the technology matures, developing new, spatially informed analytical frameworks will be essential to fully leverage its potential to elucidate the complex organisation and emerging properties of cancer tissues. Here, we highlight key challenges in cancer spatial transcriptomics, focusing on three emerging topics: (a) defining cell states, (b) delineating cellular niches and (c) integrating spatial data with other modalities that can pave the way towards clinical translation. We discuss multiple analytical approaches that are currently implemented or could be adapted in the future in order to tackle these challenges, including classical biostatistics methods as well as methods inherited from geospatial analytics or artificial intelligence. In the rapidly expanding landscape of ST, such methodologies lay the foundation for biological discoveries that conceptualise cancer as an evolving system of interconnected niches.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144715150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nicotinamide N-methyltransferase promotes drug resistance in lung cancer, as revealed by nascent proteomic profiling.","authors":"Zhanwu Hou, Zhen Wang, Fei Yang, Xiao Han, Lei Li, Huadong Liu","doi":"10.1002/1878-0261.70097","DOIUrl":"https://doi.org/10.1002/1878-0261.70097","url":null,"abstract":"<p><p>Kinase inhibitors have achieved great success in targeted cancer therapy, yet the evident limitations in their effectiveness persist due to therapeutic resistance. To gain insight into the molecular mechanisms and thwart resistance, we profiled the time-resolved nascent protein perturbations in response to drug therapy using metabolic labeling and facilitated the identification of 2238 proteins via liquid chromatography tandem mass spectrometry (LC-MS/MS). Among these, 51 proteins exhibited upregulation, whereas 105 proteins showed downregulation following a 24-h drug treatment. Clustering analysis revealed that the differential proteins were mainly enriched in metabolic-related pathways. Combined with changes in whole-protein levels, we noticed significant fluctuations in the metabolism-related protein nicotinamide N-methyltransferase (NNMT). Additionally, NNMT overexpression diminished drug effectiveness, whereas its inhibition enhanced therapeutic efficacy. An increase in NNMT was also found in drug-resistant cells, and the NNMT inhibitor JBSNF-000088 inhibited the proliferation of resistant cells. Subsequent phosphoproteomic analysis indicated that the effects of NNMT overexpression on transcription factors, proteins involved in the Rho GTPases cycle, and cell-cycle-related proteins may be related to tumor resistance. In summary, our study provides unique insights into nascent protein perturbations during the initial stages of drug therapy and identified NNMT as a promising target for delaying and overcoming therapeutic resistance.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144663967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the role of cyclin D1 in the pathogenesis of multiple myeloma beyond cell cycle regulation.","authors":"Ignacio J Cardona-Benavides, Sara Cristobal-Vargas, Cristina De Ramón, Elizabeta A Rojas, Irena Misiewicz-Krzeminska, Isabel Isidro, José Juan Pérez, Bruno Paiva, Noemi Puig, Miguel Alcoceba, María-Victoria Mateos, Luis A Corchete, Myriam Cuadrado, Norma C Gutiérrez","doi":"10.1002/1878-0261.70085","DOIUrl":"https://doi.org/10.1002/1878-0261.70085","url":null,"abstract":"<p><p>Cyclins D could be a unifying event in multiple myeloma (MM), even though MM is not typically considered a proliferative disease. In this study, we hypothesized that cyclins D might have additional roles in the pathogenesis of MM beyond cell cycle control. We showed that overexpression of CCND1 and CCND2 in MM cell lines lacking these proteins revealed a mutually exclusive expression pattern, with both cyclins D localized in the cytoplasm and no impact on proliferation. To investigate non-canonical roles of cyclin D1, we performed transcriptome analysis and multidimensional flow cytometry. Cyclin D1 overexpression led to upregulation of several key cell adhesion pathway proteins, including STAT1 and ZO-1, along with alterations in the actin cytoskeleton and decreased adhesion to certain matrices. Immunophenotypic analysis showed a significant reduction in CD56 expression following cyclin D1 overexpression, validated in a cohort of 85 MM patients, in which 73% with high cyclin D1 were CD56-negative. High cyclin D1 was also associated with increased circulating tumor cells (CTCs) (P < 0.001). Overall, we revealed novel functions of cyclin D1 in MM pathogenesis, particularly in cell adhesion and dissemination.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144659676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting of PTP4A3 overexpression sensitises HGSOC cells towards chemotherapeutic drugs.","authors":"Ana López-Garza, David James, Emma Creagh, James T Murray","doi":"10.1002/1878-0261.70092","DOIUrl":"https://doi.org/10.1002/1878-0261.70092","url":null,"abstract":"<p><p>Ovarian cancer (OC) has the highest mortality rate of all gynaecological malignancies, partly attributable to its propensity for chemotherapy resistance. The most common subtype of OC is serous, of which high-grade serous ovarian cancer (HGSOC) is the most lethal subtype. Protein tyrosine phosphatase 4A3 (PTP4A3) overexpression is implicated in tumour cell invasion and metastasis by upregulating the PI3K/Akt/mTORC1 axis. Previously, we reported that PTP4A3 increased the survival of non-serous OC cells by activating the autophagy pathway. Here, we investigated the impact of PTP4A3 on cell proliferation, autophagy and chemoresistance in HGSOC cells and whether targeting PTP4A3 in HGSOC cells that overexpress this phosphatase would sensitise them to existing chemotherapeutic drugs. Gene silencing of PTP4A3 resulted in the upregulation of compensatory mechanisms that overcame the loss of PTP4A3 expression, but this was mitigated by pan-PTP4A inhibition with JMS-053 in HGSOC cells. Moreover, shRNA-mediated silencing of PTP4A3 sensitised HGSOC cells to clinically relevant chemotherapeutic drugs. Overall, we show that compensatory mechanisms from PTP4A1 and PTP4A2 can arise when specifically targeting PTP4A3 in HGSOC and that pan-PTP4A inhibition can overcome those effects.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144626633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Olaparib synergy screen reveals Exemestane induces replication stress in triple-negative breast cancer.","authors":"Nur Aininie Yusoh, Liping Su, Suet Lin Chia, Xiaohe Tian, Haslina Ahmad, Martin R Gill","doi":"10.1002/1878-0261.70093","DOIUrl":"https://doi.org/10.1002/1878-0261.70093","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) remains the breast cancer subtype with the poorest prognosis. While PARP inhibitors (PARPi) effectively target BRCA1/2-mutant TNBCs via synthetic lethality, most TNBCs are BRCA1/2 wild-type. Synergistic drug combinations may expand PARPi efficacy to BRCA-proficient TNBC. To identify new PARPi combinations, we screened a library of 166 FDA-approved oncology drugs for synergy with Olaparib in TNBC cells. We found that Exemestane, an aromatase inhibitor, synergized with Olaparib, significantly decreasing IC₅₀ values and clonogenicity while increasing DNA damage and apoptosis. The mechanistic basis for this synergy was rationalized by the previously unreported ability of Exemestane to induce replication stress via reactive oxygen species (ROS) generation and oxidative stress. This combination had low cytotoxicity toward normal breast epithelial cells, and Exemestane has no reported severe toxicity as a monotherapy. The combination of Olaparib and Exemestane was able to achieve enhanced tumor growth inhibition in a murine xenograft model, greater than either drug employed as a single agent, and GO and KEGG enrichment analysis indicated alterations in pathways associated with cell death in response to Exemestane and Olaparib treatment.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144626632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-omic characterization of consensus molecular subtype 1 (CMS1) colorectal cancer with dampened immune response improves precision medicine.","authors":"Livia Concetti, Manuel Scimeca, Julia Bischof, Jonathan Woodsmith, Massimiliano Agostini, Cristina Fiorani, Yufang Shi, Eleonora Candi, Gerry Melino, Alessandro Mauriello, Giuseppe S Sica","doi":"10.1002/1878-0261.70023","DOIUrl":"https://doi.org/10.1002/1878-0261.70023","url":null,"abstract":"<p><p>Colorectal cancer (CRC) is a heterogenous disease with distinct biological and clinical subgroups, each with different prognoses and responses to therapy. In this case report, taking inspiration from a case of locally advanced CRC with serine/threonine-protein kinase B-raf (BRAF) V600E mutation, we highlight an atypical consensus molecular subtype 1 (CMS1). Deep multi-omic analyses showed a limited expression of programmed cell death protein 1 (PD-1) and reduced T-cell infiltration, including CD8⁺ and natural killer (NK) cells, in the analyzed CMS1 tumor. In parallel, a reduced activation of the JAK/STAT pathway was detected, suggesting a lack of clinical response to immunotherapy with checkpoint inhibitors. Furthermore, the finding of up-regulated expression of WEE1 G2 checkpoint kinase (WEE1), checkpoint kinase 1 (CHK1), and checkpoint kinase 2 (CHK2), poly(ADP-ribose) polymerase (PARP), and heat shock protein 90 (HSP90) suggests a potential alternative therapeutic approach using inhibitors of the cell cycle, HSP90, or PARP in combination with conventional chemotherapy, targeted agents, or immunotherapy. This paradigmatic case should stimulate a regular deep omics analysis to improve precision medicine. We therefore suggest that full mutational and expression profiling analyses of CRC subtypes should be undertaken to improve therapeutic strategies in CRC treatment.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive profiling of lncRNAs and mRNAs enriched in small extracellular vesicles for early noninvasive detection of colorectal cancer: diagnostic panel assembly and extensive validation.","authors":"Petra Vychytilova-Faltejskova, Marketa Pavlikova, Lucie Pifkova, Robin Jugas, Tana Machackova, Lenka Radova, Milana Sachlova, Renata Bartosova, Tetiana Samoilenko, Zuzana Feckova, Jana Orlickova, Erika Slamova, Elleni Ponechal Michu, Dagmar Al Tukmachi, Michaela Ruckova, Martina Vodinska, Jan Kotoucek, Tina Catela Ivkovic, Marie Boudna, Lucia Bohovicova, Teodor Stanek, Jana Halamkova, Martin Svoboda, Vladimir Prochazka, Tomas Grolich, Zdenek Kala, Ondrej Slaby","doi":"10.1002/1878-0261.70086","DOIUrl":"https://doi.org/10.1002/1878-0261.70086","url":null,"abstract":"<p><p>Early diagnosis of colorectal cancer (CRC) is crucial for successful treatment and mortality reduction. In this regard, blood-based tests play an indispensable role. Current research is focused on molecules actively secreted by tumor cells into small extracellular vesicles (EVs). This four-phase study included 613 CRC patients, 446 controls, and 120 precancerous lesions. High-throughput transcriptome profiling of small EVs was performed on samples from 100 CRC patients and 50 controls, followed by extensive validation using reverse transcription quantitative polymerase chain reaction. Diagnostic panels were developed via logistic regression and further characterized by enrolling samples from gastric cancer patients, CRC patients before/after surgery, and samples of tumor tissues/adjacent mucosa. We identified 17 molecules significantly elevated in CRC, with the highest levels in metastatic cases. Additionally, seven of them differentiated controls from precancerous lesions. Two diagnostic panels were developed, enabling early CRC detection with high sensitivity and specificity, outperforming the fecal occult blood test. Furthermore, six molecules were differentially expressed between tumor tissue and mucosa, while seven EV-enriched molecules decreased significantly after surgery. These findings highlight EVs as key reservoirs of CRC-associated molecules and a promising source of biomarkers.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144601018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}