Molecular Oncology最新文献

Dose-dependent induction of epithelial-mesenchymal transition in 3D melanoma models by non-thermal plasma treatment. 非热等离子体治疗3D黑色素瘤模型中上皮-间质转化的剂量依赖性诱导。

IF 6.6 2区医学

Molecular Oncology Pub Date : 2025-05-29 DOI: 10.1002/1878-0261.70055

Eline Biscop, Edgar Cardenas De La Hoz, Hanne Verswyvel, Joey De Backer, Ho Wa Lau, Angela Privat-Maldonado, Wim Vanden Berghe, Steve Vanlanduit, Evelien Smits, Annemie Bogaerts, Abraham Lin

{"title":"Dose-dependent induction of epithelial-mesenchymal transition in 3D melanoma models by non-thermal plasma treatment.","authors":"Eline Biscop, Edgar Cardenas De La Hoz, Hanne Verswyvel, Joey De Backer, Ho Wa Lau, Angela Privat-Maldonado, Wim Vanden Berghe, Steve Vanlanduit, Evelien Smits, Annemie Bogaerts, Abraham Lin","doi":"10.1002/1878-0261.70055","DOIUrl":"https://doi.org/10.1002/1878-0261.70055","url":null,"abstract":"Despite the promising results of non-thermal plasma (NTP) devices for cancer therapy, the potential adverse effects of NTP irradiation have remained unexplored, including the effects on epithelial-mesenchymal transition (EMT) and subsequent cancer metastasis. In this study, we investigate NTP-induced EMT initiation and progression. A microsecond-pulsed dielectric barrier discharge plasma device was used for NTP treatment, and chicken chorioallantoic membrane (CAM) and spheroids were used as 3D tumor models. NTP treatment reduced tumor volume in the CAM model, but a shift towards a mesenchymal-like phenotype was also measured in melanoma tumors via analysis of the six EMT biomarkers, though changes in cancer cell migration to other organs were not significant. In the spheroid model, molecular analysis also indicated an EMT response following NTP treatment, and enhanced cell migration was measured in one cell line. EMT induction with NTP was dose-dependent and transient; high NTP treatments caused significant EMT response and enhanced migration, but low NTP doses did not. Our findings highlight the important role of NTP parameters for cancer treatment and consequential EMT responses. The insights obtained here further build the foundation for clinical optimization, harnessing the cancer-killing potential of NTP while safeguarding against undesirable EMT-related outcomes.","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144182860","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}

引用次数: 0

Therapeutic applications of a novel humanized monoclonal antibody targeting chemokine receptor CCR9 in pancreatic cancer. 一种靶向趋化因子受体CCR9的新型人源化单克隆抗体在胰腺癌中的治疗应用。

IF 6.6 2区医学

Molecular Oncology Pub Date : 2025-05-28 DOI: 10.1002/1878-0261.70062

Hannah G McDonald, Anna M Reagan, Charles J Bailey, Mei Gao, Muqiang Gao, Angelica L Solomon, Michael J Cavnar, Prakash K Pandalai, Mautin T Barry-Hundeyin, Megan M Harper, Justin A Rueckert, Ángela Turrero, Araceli Tobio, Anxo Vidal, Daniel Roca-Lema, Elia Álvarez-Coiradas, Pablo Garrido, Laureano Simón, Joseph Kim

{"title":"Therapeutic applications of a novel humanized monoclonal antibody targeting chemokine receptor CCR9 in pancreatic cancer.","authors":"Hannah G McDonald, Anna M Reagan, Charles J Bailey, Mei Gao, Muqiang Gao, Angelica L Solomon, Michael J Cavnar, Prakash K Pandalai, Mautin T Barry-Hundeyin, Megan M Harper, Justin A Rueckert, Ángela Turrero, Araceli Tobio, Anxo Vidal, Daniel Roca-Lema, Elia Álvarez-Coiradas, Pablo Garrido, Laureano Simón, Joseph Kim","doi":"10.1002/1878-0261.70062","DOIUrl":"https://doi.org/10.1002/1878-0261.70062","url":null,"abstract":"The relative failure of immune checkpoint inhibitors in pancreatic ductal adenocarcinoma (PDAC) despite having a dense, immunosuppressive tumor microenvironment highlights the need to target alternate/escape pathways. We have previously examined C-C chemokine receptor type 9 (CCR9) as a candidate immune checkpoint and developed a targeted, humanized monoclonal antibody (SRB2). Cytotoxicity of SRB2 was evaluated in vitro and in vivo. CCR9 expression on PDAC cells/tissues, immune components of patient-derived organoids (PDOs), and antibody-dependent cell-mediated cytotoxicity were examined. In PANC-1 and MIA PaCa-2 cell lines, we demonstrated highest CCR9 expression; however, no direct cytotoxic effect was observed with SRB2 treatment. In PANC-1 cells, NK cell-mediated cytotoxicity was promoted by SRB2. Dose-dependent SRB2 cytotoxicity was observed in PDAC PDOs. In patient-derived xenograft mouse models, cytotoxicity of SRB2 monotherapy and in combination with oxaliplatin was also shown. In humanized immune-competent mouse models, SRB2 efficacy was similar to other drugs, but two mice in this cohort had complete tumor regression. Our current studies suggest that therapeutic targeting of CCR9 may improve PDAC outcomes, and additional studies are underway to evaluate SRB2 for clinical use.","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144174177","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}

引用次数: 0

BMP antagonist CHRDL2 enhances the cancer stem-cell phenotype and increases chemotherapy resistance in colorectal cancer. BMP拮抗剂CHRDL2增强结直肠癌肿瘤干细胞表型，增加化疗耐药。

IF 6.6 2区医学

Molecular Oncology Pub Date : 2025-05-28 DOI: 10.1002/1878-0261.70064

Eloise Clarkson, Annabelle Lewis

{"title":"BMP antagonist CHRDL2 enhances the cancer stem-cell phenotype and increases chemotherapy resistance in colorectal cancer.","authors":"Eloise Clarkson, Annabelle Lewis","doi":"10.1002/1878-0261.70064","DOIUrl":"https://doi.org/10.1002/1878-0261.70064","url":null,"abstract":"Bone morphogenetic protein (BMP) antagonists have been increasingly linked to the development of colorectal cancer (CRC). BMP signalling operates in opposition to the WNT signalling pathway, which sustains stem-cell maintenance and self-renewal of the normal intestinal epithelium. Reduced BMP and elevated WNT signalling lead to expansion of the stem-cell compartment and the hyperproliferation of epithelial cells, a defining characteristic of CRC. Chordin-like-2 (CHRDL2) is a secreted BMP antagonist, with overexpression linked to poor prognosis and variants in the gene shown to be associated with an elevated CRC risk. However, the detailed mechanism by which CHRDL2 contributes to CRC is unknown. In this study, we explored the impact of CHRDL2 overexpression on CRC cells to investigate whether CHRDL2's inhibition of BMP signalling intensifies WNT signalling and enhances the cancer stem-cell phenotype and response to treatment. Our research approach combines 2D cancer cell lines engineered to inducibly overexpress CHRDL2 and 3D organoid models treated with extrinsic CHRDL2, complemented by RNA sequencing analysis. CHRDL2 was found to enhance the survival of organoids and CRC cells during chemotherapy and irradiation treatment due to activation of DNA damage response pathways. Organoids treated with secreted CHRDL2 exhibited elevated levels of stem-cell markers and reduced differentiation, as evidenced by diminished villi budding. RNA-seq analysis revealed that CHRDL2 increased the expression of stem-cell markers, WNT signalling and other well-established cancer-associated pathways through BMP inhibition. These findings collectively suggest that CHRDL2 overexpression could affect response to CRC therapy by enhancing DNA repair and the stem-cell potential of cancer cells, and its role as a biomarker should be further explored.","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144174172","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}

引用次数: 0

Molecular imaging predicts trastuzumab-deruxtecan (T-DXd) response in head and neck cancer xenograft models. 分子成像预测头颈癌异种移植模型中的曲妥珠单抗-德鲁西替康（T-DXd）反应。

IF 6.6 2区医学

Molecular Oncology Pub Date : 2025-05-28 DOI: 10.1002/1878-0261.70056

Abdullah Bin Naveed, Lucas Mani, Muhammad Bilal Mirza, Ashtyn McAdoo, Takahito Kondo, Hidenori Tanaka, Nicole Meeks, Eben Rosenthal, Marisa Hom

{"title":"Molecular imaging predicts trastuzumab-deruxtecan (T-DXd) response in head and neck cancer xenograft models.","authors":"Abdullah Bin Naveed, Lucas Mani, Muhammad Bilal Mirza, Ashtyn McAdoo, Takahito Kondo, Hidenori Tanaka, Nicole Meeks, Eben Rosenthal, Marisa Hom","doi":"10.1002/1878-0261.70056","DOIUrl":"https://doi.org/10.1002/1878-0261.70056","url":null,"abstract":"Erb-b2 receptor tyrosine kinase 2 (ERBB2; also known as HER2) expression is observed in 25-40% of head and neck squamous cell carcinomas (HNSCC), yet there are no anti-HER2 therapies under evaluation for HNSCC, as conventional cytostatic anti-HER2 antibodies have had limited effectiveness and levels of HER2 overexpression are lower in HNSCC tumors compared to breast cancer. Trastuzumab-deruxtecan (T-DXd; Enhertu) is a HER2-targeting antibody-drug conjugate (ADC) comprising an anti-HER2 monoclonal antibody, a cleavable linker, and a potent topoisomerase I inhibitor payload, and has shown promising results in very low HER2-expressing tumors. We compare the efficacy of T-DXd, trastuzumab-emtansine (ADC comprising an anti-HER2 antibody and microtubule inhibitor, T-DM1; Kadcyla) and trastuzumab (Herceptin) therapy in HNSCC with low and absent HER2 expression in vitro and in vivo. In vitro treatment of a low HER2-expressing human HNSCC cell line (FaDu) with T-DXd resulted in dose-dependent cell death (IC50 values of 9856 ng·mL-1). T-DXd treatment of FaDu and UMSCC-47 (low HER2-expressing cell line) mouse xenografts displayed antitumor activity (P = 0.0001 and 0.015 respectively). When comparing T-DXd to other approved anti-HER2 therapies, only FaDu mice treated with T-DXd showed a reduction in tumor growth (P = 0.0012). In UMSCC-1 cells (absent HER2 expression), the drug failed to accumulate in tumors and showed no measurable antitumor effect, in contrast to FaDu xenografts, where drug accumulation in the tumor correlated with a therapeutic response. T-DXd treatment yielded antitumor activity in FaDu and UMSCC-47 tumors, highlighting the potential for T-DXd efficacy in low HER2-expressing tumors.","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144174176","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}

引用次数: 0

Circulating tumor DNA monitoring and blood tumor mutational burden in patients with metastatic solid tumors treated with atezolizumab. atezolizumab治疗的转移性实体瘤患者循环肿瘤DNA监测和血液肿瘤突变负担。

IF 6.6 2区医学

Molecular Oncology Pub Date : 2025-05-28 DOI: 10.1002/1878-0261.70054

Charles Swanton, Russell W Madison, Candice Francheska B Tambaoan, Funda Meric-Bernstam, Christopher J Sweeney, Razelle Kurzrock, Howard A Burris, David R Spigel, Hanna Tukachinsky, Jason Hughes, Julia Malato, Bongin Yoo, Tania Szado, Cheryl Schwab, Lincoln W Pasquina, Amaya Gasco, Katja Schulze, Claire F Friedman

{"title":"Circulating tumor DNA monitoring and blood tumor mutational burden in patients with metastatic solid tumors treated with atezolizumab.","authors":"Charles Swanton, Russell W Madison, Candice Francheska B Tambaoan, Funda Meric-Bernstam, Christopher J Sweeney, Razelle Kurzrock, Howard A Burris, David R Spigel, Hanna Tukachinsky, Jason Hughes, Julia Malato, Bongin Yoo, Tania Szado, Cheryl Schwab, Lincoln W Pasquina, Amaya Gasco, Katja Schulze, Claire F Friedman","doi":"10.1002/1878-0261.70054","DOIUrl":"https://doi.org/10.1002/1878-0261.70054","url":null,"abstract":"Immune checkpoint inhibitors are important for treatment across tumor types but are not universally effective in controlling disease. Early understanding of tumor response, or lack thereof, can inform treatment decisions. This study evaluates changes in circulating tumor DNA (ctDNA) and blood tumor mutational burden (bTMB) for associations with response to programmed cell death 1 ligand 1 (PD-L1) blockade. We sequenced cell-free DNA collected at the start of therapy, on treatment, and at the end of therapy for 153 patients treated with atezolizumab as part of the pan-tumor MyPathway study (NCT02091141). ctDNA tumor fraction (TF) and bTMB were assessed for correlation with progression-free survival (PFS) and overall survival (OS). We found that molecular response (MR, ≥50% decrease in TF at cycle 3 day 1) was associated with improved PFS (9.7 vs 1.5 months from C3D1; HR = 0.27) and OS (21.1 vs 14.3 months from C3D1; HR = 0.44). These findings were consistent when limited to patients with stable disease (SD; PFS HR = 0.55; OS HR = 0.39). bTMB was correlated with tissue-based TMB (tTMB) when TF was high (≥1%), but not with OS in this cohort. In total, 61% of baseline samples had predicted clonal hematopoiesis (CH) variants. No correlation between maximum variant allele frequency (maxVAF) of predicted CH and TF was seen. In summary, MR is associated with outcomes for patients treated with atezolizumab and could stratify patients with SD. While CH was common, maxVAF for CH variants was not associated with ctDNA TF. Quantification of ctDNA enables therapy response monitoring and is critical for interpretation of bTMB as a proxy for tTMB.","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144174175","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}

引用次数: 0

Genomics-led approach to drug testing in models of undifferentiated pleomorphic sarcoma. 以基因组学为主导的未分化多形性肉瘤模型药物测试方法。

IF 6.6 2区医学

Molecular Oncology Pub Date : 2025-05-26 DOI: 10.1002/1878-0261.70059

Piotr J Manasterski, Molly R Danks, John P Thomson, Morwenna Muir, Martin Lee, John C Dawson, Ana T Amaral, Juan Diaz-Martin, David S Moura, Javier Martin-Broto, Ali Alsaadi, Donald M Salter, Ailsa J Oswald, Graeme Grimes, Larry Hayward, Ted R Hupp, Karen Sisley, Paul H Huang, Neil O Carragher, Valerie G Brunton

{"title":"Genomics-led approach to drug testing in models of undifferentiated pleomorphic sarcoma.","authors":"Piotr J Manasterski, Molly R Danks, John P Thomson, Morwenna Muir, Martin Lee, John C Dawson, Ana T Amaral, Juan Diaz-Martin, David S Moura, Javier Martin-Broto, Ali Alsaadi, Donald M Salter, Ailsa J Oswald, Graeme Grimes, Larry Hayward, Ted R Hupp, Karen Sisley, Paul H Huang, Neil O Carragher, Valerie G Brunton","doi":"10.1002/1878-0261.70059","DOIUrl":"https://doi.org/10.1002/1878-0261.70059","url":null,"abstract":"Undifferentiated pleomorphic sarcoma (UPS) is a rare cancer with limited systemic treatment options and poor outcomes. To seek novel therapeutic interventions, we undertook mutational analysis of 20 UPS patient tumours, four established UPS cell lines and three patient-derived xenograft (PDX) models. Frequently mutated genes were uncommon; in contrast, copy number (CN) events were common with CN gain frequently observed at genes including JUN, EGFR and CDK6 and loss at WNT8B, RB1 and PTEN. Analysis of overlapping genomic changes between patient tumours and PDX models or cell lines revealed druggable events. A selected panel of drugs targeting these was analysed in in vitro UPS models demonstrating that the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib is synergistic in combination with the fibroblast growth factor receptor (FGFR) inhibitor infigratinib. This was further confirmed to be efficacious in an ex vivo tumour slice model. Taken together, our results demonstrate the rationale for utilising genomic data to identify drug classes targeting druggable events in low-prevalence cancers and indicate that trametinib alone or in combination with infigratinib should be further explored for clinical UPS management.","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144143107","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}

引用次数: 0

The subcellular distribution of phosphorylated Y-box-binding protein-1 at S102 in colorectal cancer patients, stratified by KRAS mutational status and clinicopathological features. 基于KRAS突变状态和临床病理特征的结直肠癌患者S102位点磷酸化y -box结合蛋白1亚细胞分布

IF 6.6 2区医学

Molecular Oncology Pub Date : 2025-05-26 DOI: 10.1002/1878-0261.70060

Konstanze Lettau, Stephan Forchhammer, Birgit Fehrenbacher, Lejla Mahmutovic, Marcus Scharpf, Gunnar Blumenstock, Martin Schaller, Irina Bonzheim, Shayan Khozooei, Mahmoud Toulany

{"title":"The subcellular distribution of phosphorylated Y-box-binding protein-1 at S102 in colorectal cancer patients, stratified by KRAS mutational status and clinicopathological features.","authors":"Konstanze Lettau, Stephan Forchhammer, Birgit Fehrenbacher, Lejla Mahmutovic, Marcus Scharpf, Gunnar Blumenstock, Martin Schaller, Irina Bonzheim, Shayan Khozooei, Mahmoud Toulany","doi":"10.1002/1878-0261.70060","DOIUrl":"https://doi.org/10.1002/1878-0261.70060","url":null,"abstract":"Oncoprotein Y-box-binding protein-1 (YB-1) is involved in all cancer hallmarks. One of the most studied post-translational modifications of YB-1 is phosphorylation on Serine 102 (S102), which is involved in cancer progression. KRAS mutations are frequent, have been associated with poor prognosis and therapy resistance, and they are considered a major stimulator of S102 YB-1 in vitro. In this study, a relationship between S102 YB-1 phosphorylation in subcellular fractions and KRAS mutation was investigated in CRC tissues, and its association with clinicopathological parameters was analyzed. Immunohistochemistry on 36 patient samples and 5 normal tissue samples highlighted nuclear S102 YB-1 was specific to cancer tissues. Nuclear S102 YB-1 was expressed in 47.2% of tumor tissues, which was positively correlated with KRAS mutation (P = 0.017). There was no significant association between cytoplasmic S102 YB-1 with KRAS mutation status (P = 0.391). Further studies in larger cohorts are needed to validate the observed results. The significant association between S102 YB-1 in the nucleus and KRAS mutation may suggest YB-1 as an effective target to improve survival of CRC patients with KRAS-mutated tumors.","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144151261","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}

引用次数: 0

Landscape of BRAF transcript variants in human cancer. 人类癌症中BRAF转录变异体的景观。

IF 6.6 2区医学

Molecular Oncology Pub Date : 2025-05-25 DOI: 10.1002/1878-0261.70043

Maurizio S Podda, Danilo Tatoni, Gianluca Mattei, Alberto Magi, Romina D'Aurizio, Laura Poliseno

{"title":"Landscape of BRAF transcript variants in human cancer.","authors":"Maurizio S Podda, Danilo Tatoni, Gianluca Mattei, Alberto Magi, Romina D'Aurizio, Laura Poliseno","doi":"10.1002/1878-0261.70043","DOIUrl":"https://doi.org/10.1002/1878-0261.70043","url":null,"abstract":"The BRAFV600E mutant kinase is widely studied as a cancer driver and therapeutic target. Here, we investigated how the annotation of the BRAF-reference (ref) and BRAF-X1 variants has evolved in public databases and addressed challenges posed by their discrimination and quantification from short-read sequencing. We built IsoWorm, a bioinformatic pipeline tailored to discriminate and quantify BRAF variants, and employed it to analyze > 600 cancer cell lines and > 1000 cancer tissue samples. Using FLIBase, we reanalyzed TCGA data from > 9000 cancer tissue samples. We consistently found that BRAF-X1 (now BRAF-204) is very abundant in human cancer and its expression is 1.5-75 times greater than that of BRAF-ref (now BRAF-220). Crucially, we identified KIRP-kidney renal papillary cell carcinoma as a cancer subtype in which a high BRAF-204/BRAF-220 ratio is an independent prognostic factor of poor outcome. Our in silico analyses establish BRAF as a mix of two protein-coding transcript variants, with BRAF-204 being more highly expressed than BRAF-220. These findings prompt us to undertake the systematic benchmarking of BRAF-204 against BRAF-220 in terms of molecular mechanisms, biological activities, druggability, and clinical relevance.","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144143153","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}

引用次数: 0

Simultaneous inhibition of TRIM24 and TRIM28 sensitises prostate cancer cells to antiandrogen therapy, decreasing VEGF signalling and angiogenesis. 同时抑制TRIM24和TRIM28使前列腺癌细胞对抗雄激素治疗敏感，减少VEGF信号传导和血管生成。

IF 6.6 2区医学

Molecular Oncology Pub Date : 2025-05-24 DOI: 10.1002/1878-0261.70065

Damien A Leach, Nilesh Chatterjee, Kellie Spahr, Gilberto Serrano de Almeida, Anabel Varela-Carver, Taimur T Shah, Mathias Winkler, Hashim U Ahmed, Charlotte L Bevan

{"title":"Simultaneous inhibition of TRIM24 and TRIM28 sensitises prostate cancer cells to antiandrogen therapy, decreasing VEGF signalling and angiogenesis.","authors":"Damien A Leach, Nilesh Chatterjee, Kellie Spahr, Gilberto Serrano de Almeida, Anabel Varela-Carver, Taimur T Shah, Mathias Winkler, Hashim U Ahmed, Charlotte L Bevan","doi":"10.1002/1878-0261.70065","DOIUrl":"https://doi.org/10.1002/1878-0261.70065","url":null,"abstract":"Castrate-resistant prostate cancer (CRPC) is a likely outcome of hormone treatment for advanced prostate cancer. Although no longer dependent on androgen levels, CRPC remains driven by the androgen receptor (AR). One proposed progression mechanism is altered repertoires of coregulator proteins possessing the ability to alter AR activity. Increased expression of tripartite motif-containing 24 (TRIM24) and TRIM28-two members of a distinct bromodomain-containing subfamily of Tripartite motif (TRIM) coregulators-occurs in CRPC. Endogenous TRIM24 and TRIM28 interact with each other and AR, bind to chromatin and regulate genes such as the angiogenic factor vascular endothelial growth factor A (VEGFA) and oncogene MYC. Silencing of TRIM24 and TRIM28 simultaneously, but not either alone, sensitised CRPC model cell lines to the antiandrogen enzalutamide and bicalutamide. This re-sensitisation to antiandrogen therapeutics could then be reversed by addition of VEGF. Furthermore, both TRIM24 and TRIM28 expression associated with angiogenesis signatures in tumour samples, and conditioned media from TRIM24 and TRIM28-silenced cancer cells inhibited endothelial cell proliferation and formation of vascular tube structures. Our data suggest that TRIM24 and TRIM28 proteins interact, in gene-specific manners, to regulate AR activity, increase VEGF signalling and angiogenesis, and that targeting these coregulators may increase the effectiveness of antiandrogen therapy.","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144136346","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}

引用次数: 0

Systematic profiling of cancer-fibroblast interactions reveals drug combinations in ovarian cancer. 癌症-成纤维细胞相互作用的系统分析揭示了卵巢癌的药物组合。

IF 6.6 2区医学

Molecular Oncology Pub Date : 2025-05-24 DOI: 10.1002/1878-0261.70051

Greta Gudoityte, Osheen Sharma, Laura Leuenberger, Emelie Wallin, Josefin Fernebro, Päivi Östling, Rebecka Bergström, Johan Lindberg, Ulrika Joneborg, Olli Kallioniemi, Brinton Seashore-Ludlow

{"title":"Systematic profiling of cancer-fibroblast interactions reveals drug combinations in ovarian cancer.","authors":"Greta Gudoityte, Osheen Sharma, Laura Leuenberger, Emelie Wallin, Josefin Fernebro, Päivi Östling, Rebecka Bergström, Johan Lindberg, Ulrika Joneborg, Olli Kallioniemi, Brinton Seashore-Ludlow","doi":"10.1002/1878-0261.70051","DOIUrl":"https://doi.org/10.1002/1878-0261.70051","url":null,"abstract":"Ovarian cancer (OC) is a leading cause of death of gynecological cancers in women. Poor patient response to treatment highlights the need to better understand how the tumor microenvironment affects OC progression. Growing evidence indicates the crucial role of non-cancerous components, such as cancer-associated fibroblasts, in establishing a complex network of cellular and molecular interactions, influencing cancer progression and response to treatment. Therefore, in this study, we sought to characterize the impact of fibroblasts on OC cell behavior and drug response. Using both direct and indirect cell co-culture systems, we observed distinct changes in cancer cell proliferation, morphology, and secretome in the presence of fibroblasts. Furthermore, an imaging-based high-throughput drug screen of 528 oncology compounds revealed multiple drugs that showed altered efficacy in the co-culture conditions, demonstrating the role of fibroblasts in driving cancer cell resistance to treatment. Most importantly, our data identified the two drug combinations of Birinapant or Vorinostat with Carboplatin as promising treatments, exploiting the altered cancer cell phenotype in co-cultures. These findings were supported by the increased sensitivity of ex vivo cultures to these combinations.","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144136350","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}

引用次数: 0