Molecular Oncology最新文献

{"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":"Endoglin mediates the tumor- and metastasis-promoting traits of stromal myofibroblasts in human breast carcinomas.","authors":"Shoki Okubo, Yoshihiro Mezawa, Zixu Wang, Ahmet Acar, Yasuhiko Ito, Atsushi Takano, Yohei Miyagi, Tomoyuki Yokose, Yamashita Toshinari, Yataro Daigo, Takuya Shirakihara, Akira Orimo","doi":"10.1002/1878-0261.70074","DOIUrl":"https://doi.org/10.1002/1878-0261.70074","url":null,"abstract":"<p><p>Carcinoma-associated fibroblasts (CAFs), which are abundant in the tumor microenvironment, influence cancer hallmarks. We previously described transforming growth factor-β (TGF-β)-Smad2/3 signaling as being activated in myofibroblastic CAFs (myCAFs) in an autocrine fashion by increasing TGF-β production. However, factors regulating such autocrine TGF-β signaling remain poorly understood. Herein, we show that the abundance of endoglin (ENG), a TGF-β superfamily coreceptor expressed on human breast myCAFs, is significantly associated with poorer outcomes of breast cancer patients. Inhibition of ENG expression on myCAFs not only suppressed the TGF-β-Smad2/3 pathway and TGF-β1 expression but also attenuated the ability of myCAF to promote primary tumor growth and metastasis. Mechanistically, ENG facilitates TGF-β-Smad2/3 signaling in myCAFs, presumably through association with a TGF-β ligand-receptor complex, leading to self-stimulating TGF-β1 production. Stromal TGF-β1, in turn, induces partial epithelial-mesenchymal transition in cancer cells in a paracrine manner, resulting in suppression of primary tumor growth and promotion of invasion and metastasis. ENG-primed TGF-β autocrine signaling also produces other factors that could mediate primary tumor growth promotion by myCAFs. Collectively, these findings suggest that ENG-primed TGF-β autocrine and paracrine signaling mediates tumor- and metastasis-promoting abilities of myCAFs.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144612217","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}

{"title":"Raphin-1 mediates the survival and sensitivity to radiation of pediatric-type diffuse high-grade glioma via phosphorylated eukaryotic initiation factor 2α-dependent and -independent processes.","authors":"Karin Eytan, Moshe Leitner, Amos Toren, Shoshana Paglin, Michal Yalon","doi":"10.1002/1878-0261.70081","DOIUrl":"https://doi.org/10.1002/1878-0261.70081","url":null,"abstract":"<p><p>The primary treatment for fatal pediatric-type diffuse high-grade glioma (PED-DHGG) which harbor the H3K27M or H3G34R/V mutation is radiation, but it provides only short-term relief. Inhibitors of phosphorylated eIF2α (PeIF2α) phosphatase-namely raphin-1 and salubrinal-decrease survival of PED-DHGG cell lines and sensitize them to radiation. However, although both drugs increase PeIF2α, they have different effects on common targets and different targets altogether. Here, we aimed to identify PeIF2α-phosphatase-dependent and PeIF2α-phosphatase-independent molecular targets. Raphin-1 but not salubrinal, decreased the level of BiP and CReP and increased that of DR5, in an ISRIB-independent manner. Raphin-1 induced similar changes in MEF^S51A cells and in irradiated PED-DHGG, suggesting a PeIF2α-independent contribution to raphin-1's radiosensitizing effect. Importantly, while the expression of [S51D] eIF2α decreased the survival of PED-DHGG and both raphin-1 and salubrinal decreased the survival of MEF^WT cells, only raphin-1 decreased the survival of mutant MEF^S51A cells. Our results suggest that the sensitivity of PED-DHGG to raphin-1 is mediated by both PeIF2α-dependent and PeIF2α-independent processes. Elucidating these processes could reveal targets for the development of drugs to overcome radiotherapy resistance of PED-DHGG.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144601019","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":"Expression of Concern: Activation of protein phosphatase 2A tumor suppressor as potential treatment of pancreatic cancer.","authors":"","doi":"10.1002/1878-0261.70087","DOIUrl":"https://doi.org/10.1002/1878-0261.70087","url":null,"abstract":"","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144584317","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":"The critical role of DNA damage-inducible transcript 4 (DDIT4) in stemness character of leukemia cells and leukemia initiation.","authors":"Yishuang Li, Zhijie Cao, Haiyan Xing, Zhenya Xue, Wenbing Liu, Jiayuan Chen, Yihan Mei, Runxia Gu, Hui Wei, Shaowei Qiu, Min Wang, Qing Rao, Jianxiang Wang","doi":"10.1002/1878-0261.70090","DOIUrl":"https://doi.org/10.1002/1878-0261.70090","url":null,"abstract":"<p><p>Leukemia stem cells (LSCs) are critical for leukemia initiation, and the stemness properties of LSCs are related to disease relapse. Stemness properties, including quiescence, self-renewal, and chemoresistance, are maintained through an interplay between leukemia cells and the bone marrow (BM) niche. Here, we demonstrated that DNA damage-inducible transcript 4 (DDIT4) can be induced in a hypoxic BM niche and is required for the quiescence and self-renewal of AML1-ETO9a (AE9a)-transformed leukemia cells in vitro. More importantly, analysis of publicly available transcriptional data from adult acute myeloid leukemia (AML) patients revealed that elevated DDIT4 expression correlates with poor prognosis. Furthermore, DDIT4 knockout markedly suppressed leukemia initiation, quiescence, chemoresistance, and self-renewal of AE9a-transformed leukemia cells in vivo. Mechanistically, DDIT4 upregulates the expression of HOXA gene cluster, and re-expression of HOXA6 in DDIT4 knockout AE9a cells can rescue the impaired leukemia initiation. Our findings demonstrate the critical role of DDIT4 in the stemness of AE9a leukemia cells and elucidate its underlying mechanism, suggesting that targeting DDIT4 may represent a promising therapeutic strategy for eliminating LSCs in AML1-ETO leukemia.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144575919","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":"Unveiling unique protein and phosphorylation signatures in lung adenocarcinomas with and without ALK, EGFR, and KRAS genetic alterations.","authors":"Fanni Bugyi, Mirjam Balbisi, Simon Sugár, Lóránd Váncza, Eszter Regős, Ilona Kovalszky, Ibolya Laczó, Tünde Harkó, Gábor Kecskeméti, Zoltán Szabó, Judit Moldvay, László Drahos, Lilla Turiák","doi":"10.1002/1878-0261.70091","DOIUrl":"https://doi.org/10.1002/1878-0261.70091","url":null,"abstract":"<p><p>Genetic alterations in key oncogenes have been frequently identified in lung adenocarcinoma (LUAD), including genes encoding epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), and anaplastic lymphoma kinase (ALK). In this pilot study, we aimed to characterize the differences in enriched biological pathways and phosphorylation events between LUAD tumors harboring EGFR, KRAS, or echinoderm microtubule-associated protein-like 4 (EML4)-ALK oncogenic alterations and triple wild-type LUAD tumors (WT, without EML4-ALK, KRAS, or EGFR alterations) by mass spectrometry (MS)-based quantitative proteomics and phosphoproteomics. We analyzed tumor regions of 82 formalin-fixed paraffin-embedded (FFPE) tissue sections with 6, 23, 31, and 22 samples from the EML4-ALK, EGFR, KRAS, and WT sample groups, respectively. A total of 1377 to 2189 proteins and 73 to 1781 phosphosites were quantified in these analyses. Based on the results, the samples clustered according to their genetic alteration type, and EGFR-mutated samples showed unique protein expression patterns. Membrane organization, vesicle organization, and vesicle-mediated transport Gene Ontology Biological Process (GOBP) terms were significantly downregulated in EGFR-mutated samples compared to the other sample groups. Changes in 36 proteins and 52 phosphosites were also identified as potentially specific to a given genetic alteration. Many of these proteins have previously been linked to EGFR or KRAS mutations [e.g., cathepsin L, stimulator of interferon genes protein (STING)], whereas several phosphoproteins are associated with RNA splicing [e.g., serine/arginine-rich splicing factor 1 (SRSF1), SRSF2, and SRSF7 proteins]. Kinase-substrate enrichment analysis indicated altered activities of 10 kinases, including mitogen-activated protein kinases (MAPKs) and cyclin-dependent kinases (CDKs). For example, CDK2 activity was elevated in EML4-ALK samples compared to the other sample groups. Our results could provide significant insights into further studies that could contribute to developing improved diagnostic and therapeutic strategies for LUAD.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144575920","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":"Correction to \"The polyamine transporter ATP13A3 mediates difluoromethylornithine-induced polyamine uptake in neuroblastoma\".","authors":"","doi":"10.1002/1878-0261.70088","DOIUrl":"https://doi.org/10.1002/1878-0261.70088","url":null,"abstract":"","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553992","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":"Surfaceome: a new era in the discovery of immune evasion mechanisms of circulating tumor cells.","authors":"Doryan Masmoudi, Jérome Vialaret, Christophe Hirtz, Catherine Alix-Panabières","doi":"10.1002/1878-0261.13665","DOIUrl":"10.1002/1878-0261.13665","url":null,"abstract":"<p><p>Circulating tumor cells (CTCs) are cancer cells that detach from the original site and reach the bloodstream. The most aggressive CTCs survive various immune system attacks and initiate metastasis formation. Importantly, CTCs are not specifically targeted by the current immunotherapies due to the limited knowledge on specific targets. Proteomic profiling can be a powerful tool for understanding some of the immune evasion mechanisms used by cancer cells and particularly CTCs. These mechanisms are generally linked to the expression of specific surface proteins/peptides (i.e. the surfaceome). The study of the peptides that bind to class I molecules of the major histocompatibility complex (MHC-I) and of the various glycoproteins expressed on CTC surface may open a completely new avenue for the discovery of novel mechanisms of immune evasion. In this review, we discuss how immunopeptidomic and glycoproteomic studies of CTCs that interact with immune cells could help to better understand how metastasis-initiator CTCs escape the host immune response. We also describe how immunopeptidomic and glycoproteomic studies are carried out.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"1979-1997"},"PeriodicalIF":6.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12234394/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141076258","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}