Molecular Oncology最新文献_第3页

TRPM8 levels determine tumor vulnerability to channel agonists. TRPM8水平决定肿瘤对通道激动剂的易感性。

IF 4.5 2区医学

Molecular Oncology Pub Date : 2025-10-01 Epub Date: 2025-05-22 DOI: 10.1002/1878-0261.70049

Alessandro Alaimo, Francesco Giuseppe Carbone, Kristi Buzo, Nicole Annesi, Sacha Genovesi, Annalisa Lorenzato, Karen Widmann, Michela Libergoli, Elisa Marmocchi, Giovanni Bertalot, Alberto Brolese, Mauro Giulio Papotti, Luca Molinaro, Orazio Caffo, Mattia Barbareschi, Alberto Bardelli, Alessandro Romanel, Sabrina Arena, Andrea Lunardi

{"title":"TRPM8 levels determine tumor vulnerability to channel agonists.","authors":"Alessandro Alaimo, Francesco Giuseppe Carbone, Kristi Buzo, Nicole Annesi, Sacha Genovesi, Annalisa Lorenzato, Karen Widmann, Michela Libergoli, Elisa Marmocchi, Giovanni Bertalot, Alberto Brolese, Mauro Giulio Papotti, Luca Molinaro, Orazio Caffo, Mattia Barbareschi, Alberto Bardelli, Alessandro Romanel, Sabrina Arena, Andrea Lunardi","doi":"10.1002/1878-0261.70049","DOIUrl":"10.1002/1878-0261.70049","url":null,"abstract":"Targeted therapies have pervasively enhanced clinical protocols and significantly improved survival and quality of life of cancer patients. Mostly grounded on small molecules and antibodies targeting deregulated mechanisms in cancer cells, precision oncology approaches are limited to a few tumor types because of the paucity of clinically actionable targets. Here, we report a comparative analysis of the cation channel transient receptor potential melastatin 8 (TRPM8; also known as transient receptor potential cation channel subfamily M member 8) in lung, breast, colorectal, and prostate cancers. Our findings reveal high levels of channel expression in cores of all four carcinomas, irrespective of reduced expression of its RNA. Importantly, cancer cell lines that represent the various tumor types consistently show that sub-lethal chemotherapy dosages combined with the TRPM8 agonist D-3263 have a synergistic lethal effect. In addition, administration of D-3263 increases the cytotoxicity of 5-FU/Oxaliplatin in patient-derived colorectal cancer organoids, depending on the levels of TRPM8. Overall, our study strengthens the candidacy of TRPM8 as a molecular target for precision oncology approaches and paves the way for the design of basket trials for its clinical testing in TRPM8-high tumors.","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2905-2920"},"PeriodicalIF":4.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12515718/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144128018","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}

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 4.5 2区医学

Molecular Oncology Pub Date : 2025-10-01 Epub 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":"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":"2936-2950"},"PeriodicalIF":4.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12515716/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The tumor-microbe connection. 肿瘤与微生物的联系。

IF 4.5 2区医学

Molecular Oncology Pub Date : 2025-10-01 Epub Date: 2025-09-03 DOI: 10.1002/1878-0261.70115

Gerlanda Vella, Maria Rescigno

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 4.5 2区医学

Molecular Oncology Pub Date : 2025-10-01 Epub 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":"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":"2797-2821"},"PeriodicalIF":4.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12515719/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

SensRORing cholesterol to drive protumoral myelopoiesis. 感知胆固醇驱动原瘤性骨髓形成。

IF 4.5 2区医学

Molecular Oncology Pub Date : 2025-10-01 Epub Date: 2025-08-20 DOI: 10.1002/1878-0261.70113

Sara Gennari, Luigi Nezi, Teresa Manzo

引用次数: 0

Evaluation of KRAS and NRAS mutations in metastatic colorectal cancer: an 8-year study of 10 754 patients in Turkey. KRAS和NRAS突变在转移性结直肠癌中的评估：土耳其一项为期8年的10754例患者研究

IF 4.5 2区医学

Molecular Oncology Pub Date : 2025-10-01 Epub Date: 2025-05-23 DOI: 10.1002/1878-0261.70042

Gozde Kavgaci, Izzet Akiva, Yavuz Hakan Ozon, Hakan Berkil, Huseyin Karadayi, Omer Dizdar, Suayib Yalcin

{"title":"Evaluation of KRAS and NRAS mutations in metastatic colorectal cancer: an 8-year study of 10 754 patients in Turkey.","authors":"Gozde Kavgaci, Izzet Akiva, Yavuz Hakan Ozon, Hakan Berkil, Huseyin Karadayi, Omer Dizdar, Suayib Yalcin","doi":"10.1002/1878-0261.70042","DOIUrl":"10.1002/1878-0261.70042","url":null,"abstract":"This study aimed to evaluate KRAS and NRAS mutations over an eight-year period to provide a comprehensive understanding of the genetic landscape of metastatic colorectal cancer (mCRC) in Turkish patients. Tumor tissue samples were collected from 10 754 patients with mCRC between January 2015 and June 2023 from multiple centers across Turkey, and all genetic analyses were performed at a single facility. DNA was analyzed for mutations in codons 12, 13, 59, 61, 117, and 146 of the KRAS and NRAS genes using nested PCR and multiplex minisequencing techniques. Among the conclusive results from 10 681 patients, 46.6% (4982) had KRAS mutations, and 53.4% (5699) were wild-type. The most common KRAS mutations were G12D (30.3%), G12V (20.1%), G13D (18.4%), and G12C (7.0%). Results from the 5699 KRAS wild-type patients revealed that 480 (8.5%) had NRAS mutations, while 91.5% were NRAS wild-type. The most frequent NRAS mutations were Q61K (19.7%), G12D (19.1%), and G12V (12%). This study provides a large-scale, real-world dataset of KRAS and NRAS mutation profiles in Turkish mCRC patients, contributing significantly to the understanding of the genetic characteristics of mCRC in this population.","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2967-2977"},"PeriodicalIF":4.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12515694/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144136370","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}

引用次数: 0

Hypomethylating agents increase L1 retroelement expression without inducing novel insertions in myeloid malignancies. 在髓系恶性肿瘤中，低甲基化药物增加L1逆转录因子的表达而不诱导新的插入。

IF 4.5 2区医学

Molecular Oncology Pub Date : 2025-10-01 Epub Date: 2025-09-04 DOI: 10.1002/1878-0261.70111

Šárka Pavlová, Hana Svozilová, Marcela Krzyžánková, Radim Sonnek, Anastasiya Volakhava, Anastasia Smirnova, Tatiana Grigoreva, Zuzana Jašková, Hana Synáčková, Dennis Wahl, Michaela Bilčíková, Libor Červinek, Šárka Pospíšilová, Ilgar Mamedov, Karla Plevová

{"title":"Hypomethylating agents increase L1 retroelement expression without inducing novel insertions in myeloid malignancies.","authors":"Šárka Pavlová, Hana Svozilová, Marcela Krzyžánková, Radim Sonnek, Anastasiya Volakhava, Anastasia Smirnova, Tatiana Grigoreva, Zuzana Jašková, Hana Synáčková, Dennis Wahl, Michaela Bilčíková, Libor Červinek, Šárka Pospíšilová, Ilgar Mamedov, Karla Plevová","doi":"10.1002/1878-0261.70111","DOIUrl":"10.1002/1878-0261.70111","url":null,"abstract":"Retroelements in the human genome are silenced via multiple mechanisms, including DNA methylation, to prevent their potential mutagenic effect. Retroelement activity, demonstrated by their expression and somatic retrotransposition events, was shown to be deregulated in multiple tumors but not yet in leukemia. We hypothesized that treatment with hypomethylating agents, commonly used in myelodysplastic syndromes and acute myeloid leukemia, could lead to increased retroelement activity and somatic retrotranspositions, thus contributing to disease progression. To address this hypothesis, we induced the expression of ORF1p protein with hypomethylating agents in DAMI and HL-60 myeloid cell lines. To study whether long-term hypomethylating agent therapy induces somatic retrotranspositions, we analyzed (i) both cell lines treated for 4 weeks, and (ii) sequential samples from 17 patients with myelodysplastic syndrome treated with hypomethylating agents. Using a sensitive next-generation sequencing (NGS)-based method, no retroelement events were identified. To conclude, we show that although hypomethylating agents induce the expression of LINE-1-encoded proteins in myeloid cell lines, de novo somatic retrotransposition events do not arise during the long-term exposure to these agents.","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2764-2775"},"PeriodicalIF":4.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12515712/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144993041","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}

引用次数: 0

Loss of primary cilia promotes EphA2-mediated endothelial-to-mesenchymal transition in the ovarian tumor microenvironment. 原发纤毛的缺失促进了卵巢肿瘤微环境中epha2介导的内皮细胞向间质细胞的转化。

IF 4.5 2区医学

Molecular Oncology Pub Date : 2025-10-01 Epub Date: 2025-05-21 DOI: 10.1002/1878-0261.70057

Jin Gu Cho, Yubin Hah, Eunsik Yun, Hye In Ka, Aram Lee, Sora Han, Dawn Lee, Sung Wook Kim, Jong Hoon Park, Byung Su Kwon, Young Yang, Jongmin Kim

{"title":"Loss of primary cilia promotes EphA2-mediated endothelial-to-mesenchymal transition in the ovarian tumor microenvironment.","authors":"Jin Gu Cho, Yubin Hah, Eunsik Yun, Hye In Ka, Aram Lee, Sora Han, Dawn Lee, Sung Wook Kim, Jong Hoon Park, Byung Su Kwon, Young Yang, Jongmin Kim","doi":"10.1002/1878-0261.70057","DOIUrl":"10.1002/1878-0261.70057","url":null,"abstract":"Endothelial-to-mesenchymal transition (EndMT) is closely associated with tumor progression. Endothelial cells (ECs) in the tumor microenvironment (TME) use EndMT programs to facilitate tumor progression; however, the underlying mechanisms in ovarian cancer are poorly understood. Here, we describe the involvement of primary cilia in EndMT of the ovarian TME. We showed that ECs from human ovarian tumors displayed robust EndMT and impaired cilia formation, as was also observed in ECs in response to ovarian cancer cell culture-conditioned media (OV-CM). Notably, ECs lacking primary cilia exhibited increased OV-CM-induced EndMT. Vascular abnormalities, such as enhanced cell migration and vessel permeability, were observed in vitro. Furthermore, in vivo experiments using endothelial-specific kinesin family member 3A (Kif3a)-knockout mice showed enhanced EndMT in the ovarian TME. Mechanistically, we identified ephrin type-A receptor 2 (EphA2) as a key regulator of EndMT. Upon OV-CM treatment, EphA2 expression increased, and depletion of EphA2 in ECs decreased OV-CM-induced EndMT and vascular abnormalities. These results highlight that the loss of primary cilia and the consequent EphA2 activation are key mechanisms by which EndMT programs induce the acquisition of cancer-associated fibroblast-like cells in the ovarian TME, thereby promoting ovarian cancer progression.","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2951-2966"},"PeriodicalIF":4.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12515696/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144120253","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}

引用次数: 0

Single-cell transcriptomics redefines focal neuroendocrine differentiation as a distinct prostate cancer pathology. 单细胞转录组学将局灶性神经内分泌分化重新定义为一种独特的前列腺癌病理。

IF 4.5 2区医学

Molecular Oncology Pub Date : 2025-10-01 Epub Date: 2025-07-24 DOI: 10.1002/1878-0261.70099

Rosalia Quezada Urban, Shivakumar Keerthikumar, Ashlee Clark, Hong Wang, Belinda Phipson, Andrew Bakshi, Andrew Ryan, Heather Thorne, Renea A Taylor, Mitchell G Lawrence, Gail P Risbridger, Roxanne Toivanen, David L Goode

{"title":"Single-cell transcriptomics redefines focal neuroendocrine differentiation as a distinct prostate cancer pathology.","authors":"Rosalia Quezada Urban, Shivakumar Keerthikumar, Ashlee Clark, Hong Wang, Belinda Phipson, Andrew Bakshi, Andrew Ryan, Heather Thorne, Renea A Taylor, Mitchell G Lawrence, Gail P Risbridger, Roxanne Toivanen, David L Goode","doi":"10.1002/1878-0261.70099","DOIUrl":"10.1002/1878-0261.70099","url":null,"abstract":"Neuroendocrine prostate cancer (NEPC) tumours are classified by pathology into several distinct subtypes. Gene expression profiling has revealed transcriptional heterogeneity across NEPC, but this is rarely considered in the context of variation between pathologies. Diagnosis typically relies on immunohistochemical markers (CHGA, SYP, NCAM1) and genomic alterations in RB1, PTEN and TP53. We hypothesized that NEPC pathologies have unique transcriptional features. Single-cell RNA sequencing of 18 632 tumour cells from nine patient-derived xenograft models representing five pathologies (small-cell and large-cell neuroendocrine carcinomas, focal neuroendocrine differentiation (Focal NED), low-grade neuroendocrine and amphicrine) demonstrated pathway-specific enrichment. Focal NED and amphicrine tumours exhibited cellular subpopulations enriched for KRAS, IL2-STAT5 and TNF signalling pathways, absent in small- and large-cell carcinomas, which were instead enriched for Myc and E2F pathways. Furthermore, focal NED cells exhibited minimal clonal divergence from adjacent adenocarcinoma cells, while small cell carcinoma cells were clonally distinct. These data underscore significant transcriptional variation among NEPC pathologies, highlighting focal NED's unique biological context and its clinical implications.","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2776-2796"},"PeriodicalIF":4.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12515717/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144708181","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}

引用次数: 0

Not just a by-product: circular DNA molecules derived from V(D)J recombination are linked to worse prognosis in B-cell leukemia. 不仅仅是一种副产品：V(D)J重组产生的环状DNA分子与b细胞白血病的预后不良有关。

IF 4.5 2区医学

Molecular Oncology Pub Date : 2025-09-25 DOI: 10.1002/1878-0261.70134

Davide Pradella, Andrea Ventura

引用次数: 0