Molecular Oncology最新文献

{"title":"Decoding multicellular interaction networks-a new horizon in tumor microenvironment research.","authors":"Roi Balaban, Merav Cohen","doi":"10.1002/1878-0261.13810","DOIUrl":"https://doi.org/10.1002/1878-0261.13810","url":null,"abstract":"<p><p>The tumor microenvironment (TME) milieu directs a plethora of tumor-modulating functions. Recent years have seen pivotal breakthroughs in our understanding of the TME's role in tumor initiation and progression, with tangible clinical applications. Individual components of the TME exert their function predominantly by cell-cell crosstalk, both in the form of physical interaction and secreted factors. Notably, different spatial niches represent exclusive signaling hubs in the TME, propagating pro- or antitumoral functions. The exploration of these interactions has been vastly facilitated by novel molecular technologies, each of which provides a different perspective on this intricate intercellular communication network. Together, these complementary methods paint a detailed, high-resolution map of the TME's interaction landscape. In this viewpoint, we explore how cellular interactions can unlock a new level of understanding of TME complexity, and discuss the promises and challenges of characterizing tumors based on their cellular interaction footprint.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189841","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":"Stroma gene signature predicts responsiveness to chemotherapy in pancreatic ductal adenocarcinoma patient-derived xenograft models.","authors":"Alessia Anastasia, Laura Formenti, Paola Ostano, Lucia Minoli, Andrea Resovi, Lavinia Morosi, Claudia Fioravanti, Edoardo Micotti, Cristina Matteo, Eugenio Scanziani, Giovanna Chiorino, Raffaella Giavazzi, Carmen Ghilardi, Dorina Belotti","doi":"10.1002/1878-0261.13816","DOIUrl":"https://doi.org/10.1002/1878-0261.13816","url":null,"abstract":"<p><p>Despite many efforts to understand the molecular mechanisms of pancreatic ductal adenocarcinoma (PDAC) treatment resistance, there is still no reliable method for selecting patients who could benefit from standard pharmacological treatment. Here, four PDAC patient-derived xenografts (PDAC-PDXs) with different responses to gemcitabine plus nab-paclitaxel (nanoparticle albumin-bound paclitaxel) were studied to dissect the contribution of both tumor and host microenvironment to treatment response. PDAC-PDXs transplanted into the pancreas of immunodeficient mice retained the main genetic and histopathological characteristics of the original human tumors, including invasiveness and desmoplastic reaction. Response to chemotherapy was associated with a specific 294 stroma gene signature and was not due to the intrinsic responsiveness of tumor cells or differences in drug delivery. Human dataset analysis validated the expression of the 294 stroma gene signature in PDAC clinical samples, confirming PDAC-PDXs as a useful tool to study the biology of tumor-host interactions and to test drug efficacy. In summary, we identified a stroma gene signature that differentiates PDAC-PDXs that are responsive to gemcitabine plus Nab-paclitaxel treatment from those that are not, confirming the active role of the tumor microenvironment in the drug response.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143123384","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":"Detection of colorectal-cancer-associated bacterial taxa in fecal samples using next-generation sequencing and 19 newly established qPCR assays.","authors":"Thulasika Senthakumaran, Tone M Tannæs, Aina E F Moen, Stephan A Brackmann, David Jahanlu, Trine B Rounge, Vahid Bemanian, Hege S Tunsjø","doi":"10.1002/1878-0261.13700","DOIUrl":"10.1002/1878-0261.13700","url":null,"abstract":"<p><p>We have previously identified increased levels of distinct bacterial taxa within mucosal biopsies from colorectal cancer (CRC) patients. Following prior research, the aim of this study was to investigate the detection of the same CRC-associated bacteria in fecal samples and to evaluate the suitability of fecal samples as a non-invasive material for the detection of CRC-associated bacteria. Next-generation sequencing (NGS) of the 16S ribosomal RNA (rRNA) V4 region was performed to evaluate the detection of the CRC-associated bacteria in the fecal microbiota of cancer patients, patients with adenomatous polyp and healthy controls. Furthermore, 19 novel species-specific quantitative PCR (qPCR) assays were established to detect the CRC-associated bacteria. Approximately, 75% of the bacterial taxa identified in biopsies were reflected in fecal samples. NGS failed to detect low-abundance CRC-associated taxa in fecal samples, whereas qPCR exhibited high sensitivity and specificity in identifying all targeted taxa. Comparison of fecal microbial composition between the different patient groups showed enrichment of Fusobacterium nucleatum, Parvimonas micra, and Gemella morbillorum in cancer patients. Our findings suggest that low-abundance mucosa-associated bacteria can be detected in fecal samples using sensitive qPCR assays.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"412-429"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141545038","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":"Minimally invasive determination of pancreatic ductal adenocarcinoma (PDAC) subtype by means of circulating cell-free RNA.","authors":"Martin Metzenmacher, Gregor Zaun, Marija Trajkovic-Arsic, Phyllis Cheung, Timm M Reissig, Hendrik Schürmann, Nils von Neuhoff, Grainne O'Kane, Stephanie Ramotar, Anna Dodd, Steven Gallinger, Alexander Muckenhuber, Jennifer J Knox, Volker Kunzmann, Peter A Horn, Jörg D Hoheisel, Jens T Siveke, Smiths S Lueong","doi":"10.1002/1878-0261.13747","DOIUrl":"10.1002/1878-0261.13747","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) comprises two clinically relevant molecular subtypes that are currently determined using tissue biopsies, which are spatially biased and highly invasive. We used whole transcriptome sequencing of 10 plasma samples with tumor-informed subtypes, complemented by proteomic analysis for minimally invasive identification of PDAC subtype markers. Data were validated in independent large cohorts and correlated with treatment response and patient outcome. Differential transcript abundance analyses revealed 32 subtype-specific, protein-coding cell-free RNA (cfRNA) transcripts. The subtype specificity of these transcripts was validated in two independent tissue cohorts comprising 195 and 250 cases, respectively. Three disease-relevant cfRNA-defined subtype markers (DEGS1, KDELC1, and RPL23AP7) that consistently associated with basal-like tumors across all cohorts were identified. In both tumor and liquid biopsies, the overexpression of these markers correlated with poor survival. Moreover, elevated levels of the identified markers were linked to a poor response to systemic therapy and early relapse in resected patients. Our data indicate clinical applicability of cfRNA markers in determining tumor subtypes and monitoring disease recurrence.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"357-376"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142546427","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 ferroptosis for improved radiotherapy outcomes in HPV-negative head and neck squamous cell carcinoma.","authors":"Joo Kyung Noh, Min Kyeong Lee, Yeonseo Lee, Minji Bae, Soonki Min, Moonkyoo Kong, Jung Woo Lee, Su Il Kim, Young Chan Lee, Seong-Gyu Ko, Seon Rang Woo, Young-Gyu Eun","doi":"10.1002/1878-0261.13720","DOIUrl":"10.1002/1878-0261.13720","url":null,"abstract":"<p><p>To enhance the efficacy of radiotherapy (RT) in human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC), we explored targeting ferroptosis, a regulated cell death process. We developed a gene signature associated with ferroptosis using Cox proportional hazard modeling in HPV-negative HNSCC patients who underwent RT. This ferroptosis-related gene signature (FRGS) was a significant predictor of overall survival and recurrence-free survival in HPV-negative HNSCC patients who received RT. Subtype B of the FRGS, characterized by decreased expression of ferroptosis inducers [nuclear receptor coactivator 4 (NCOA4) and natural resistance-associated macrophage protein 2 homolog/divalent metal transporter 1 (NRAMP2/DMT1)] and increased expression of suppressors [phospholipid hydroperoxide glutathione peroxidase (GPX4) and ferritin heavy chain (FTH1)], was associated with poorer prognosis, potentially indicating the inhibition of ferroptosis. Furthermore, our in vitro and in vivo studies demonstrated that treatment with statins, such as atorvastatin and simvastatin, induced ferroptosis and sensitized radioresistant HNSCC cells to irradiation, improving radiosensitivity and potentially enhancing the response to RT. Additionally, in xenograft models, the combination of statins and RT led to a significant reduction in tumor initiation. These findings provide valuable insights for enhancing treatment and improving prognosis in HPV-negative HNSCC by targeting ferroptosis and utilizing statins to sensitize tumors to RT-induced cell death.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"540-557"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142291398","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":"CT45A1-mediated MLC2 (MYL9) phosphorylation promotes natural killer cell resistance and outer cell fate in a cell-in-cell structure, potentiating the progression of microsatellite instability-high colorectal cancer.","authors":"Hao-Wei Teng, Hsiang-Yueh Huang, Chun-Chi Lin, Yuh-Ching Twu, Wen-Hao Yang, Wen-Chun Lin, Hsin-Yi Lan, Yen-Yu Lin, Wei-Lun Hwang","doi":"10.1002/1878-0261.13736","DOIUrl":"10.1002/1878-0261.13736","url":null,"abstract":"<p><p>Patients with microsatellite instability-high (MSI-H) colorectal cancer (CRC) have high tumor mutation burden and tumor immunogenicity, exhibiting a higher response rate to immunotherapy and better survival. However, a portion of MSI-H CRC patients still experience adverse disease outcomes. We aimed to identify the tumor-autonomous regulators determining these heterogeneous clinical outcomes. The Cancer Genome Atlas (TCGA) dataset was used to identify regulators in MSI-H CRC patients with unfavorable outcomes. Stable CRC tumor clones expressing targeted regulators were established to evaluate migratory and stemness properties, immune cell vulnerability, and cell-in-cell (CIC) structure formation. RNA-sequencing (RNA-seq) was used to identify enriched biological pathways in stable CRC tumor clones. Clinicopathological characterization of formalin-fixed paraffin-embedded (FFPE) MSI-H CRC specimens was performed to explore the underlying mechanisms involved. We showed that cancer/testis antigen family 45 member A1 (CT45A1) expression was upregulated in MSI-H CRC patients with poor survival outcomes. CT45A1-expressing microsatellite stable (MSS) CRC cells showed enhanced migratory ability. However, CT45A1-expressing MSI-H CRC cells, but not MSS CRC cells, showed higher resistance to natural killer (NK) cell cytotoxicity and served as outer cells in homotypic CIC structures, preventing exogenous or therapeutic antibody access to inner CRC cells. Inactivating RHO-ROCK/MLCK-MLC2 signaling with small-molecule inhibitors or short-hairpin RNAs (shRNAs) targeting myosin light chain kinase (MYLK) abolished NK cell resistance and reduced the outer cell fate of CT45A1-expressing MSI-H CRC cells. In MSI-H CRC patients, CT45A1-positive tumors exhibited increased MLC2 phosphorylation, increased outer cell fate, and decreased survival. We demonstrated that CT45A1 potentiates the advanced progression of MSI-H CRC, and targeting MLC2 phosphorylation may enhance immunotherapy efficacy in CT45A1-positive MSI-H CRC patients.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"430-451"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350333","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":"Viral mimicry evasion: a new role for oncogenic KRAS mutations.","authors":"Raymond Chen, Aobo He, Daniel D De Carvalho","doi":"10.1002/1878-0261.13771","DOIUrl":"10.1002/1878-0261.13771","url":null,"abstract":"<p><p>\"Viral mimicry\" refers to the induction of an innate immune response and interferon signaling by endogenous stimuli such as double-stranded RNA (dsRNA). This response has been shown to have strong cancer therapeutic potential, including by enhancing the effectiveness of immune checkpoint inhibition (ICI) therapies, and may represent a tumor suppression mechanism that needs to be overcome for malignant transformation to proceed. In a recent study, Zhou and colleagues identify KRAS, a frequently mutated oncogene, as a negative regulator of dsRNA and viral mimicry in an ICI-resistant colorectal cancer model. Oncogenic KRAS^G12D mutations downregulate the RNA-binding protein DDX60 by activating the AKT signaling pathway, which inhibits STAT3, a critical transcription factor regulating DDX60 and other interferon-stimulated genes. Overexpression of DDX60, which competitively binds to dsRNA to prevent RISC-mediated degradation, or targeting of KRAS^G12D elevated dsRNA levels, resulting in viral mimicry activation and potentiation of ICI treatment. These results establish KRAS as a promising target to sensitize immune \"cold\" tumors to ICI therapy and demonstrate the potential role of oncogenic mutations in viral mimicry evasion during tumorigenesis.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"271-274"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142730734","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":"Oncogenic mutant KRAS inhibition through oxidation at cysteine 118.","authors":"Maximilian Kramer-Drauberg, Ettore Petrini, Alessia Mira, Enrico Patrucco, Rossella Scardaci, Ilenia Savinelli, Haiyun Wang, Keying Qiao, Giovanna Carrà, Marie-Julie Nokin, Zhiwei Zhou, Kenneth D Westover, David Santamaria, Paolo E Porporato, Chiara Ambrogio","doi":"10.1002/1878-0261.13798","DOIUrl":"10.1002/1878-0261.13798","url":null,"abstract":"<p><p>Specific reactive oxygen species activate the GTPase Kirsten rat sarcoma virus (KRAS) by reacting with cysteine 118 (C118), leading to an electron transfer between C118 and nucleoside guanosine diphosphate (GDP), which causes the release of GDP. Here, we have mimicked permanent oxidation of human KRAS at C118 by replacing C118 with aspartic acid (C118D) in KRAS to show that oncogenic mutant KRAS is selectively inhibited via oxidation at C118, both in vitro and in vivo. Moreover, the combined treatment of hydrogen-peroxide-producing pro-oxidant paraquat and nitric-oxide-producing inhibitor N(ω)-nitro-l-arginine methyl ester selectively inhibits human mutant KRAS activity by inducing oxidization at C118. Our study shows for the first time the vulnerability of human mutant KRAS to oxidation, thereby paving the way to explore oxidation-based anti-KRAS treatments in humans.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"311-328"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007649","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":"When molecular biology transforms clinical oncology: the EGFR journey in colorectal cancer.","authors":"Pietro Paolo Vitiello, Nadia Saoudi González, Alberto Bardelli","doi":"10.1002/1878-0261.13754","DOIUrl":"10.1002/1878-0261.13754","url":null,"abstract":"<p><p>The discovery of growth factors and their involvement in cancer represents the foundation of precision oncology. The preclinical and clinical development of agents targeting epidermal growth factor receptor (EGFR) in colorectal cancer (CRC) were accompanied by big hype and hopes, though the clinical testing of such agents clashed with intrinsic and acquired resistance, greatly limiting their therapeutic value. However, a better understanding of the biology of the EGFR signaling pathway in CRC, coupled with the development of liquid biopsy methodologies to study cancer evolution in real time, fostered the clinical refinement of anti-EGFR treatment in CRC. Such a workflow, based on the co-evolution of biology knowledge and clinical development, allowed to couple the discovery of relevant therapy resistance mechanisms to the development of strategies to bypass this resistance. A broader application of this paradigm could prove successful and create an effective shortcut between the bench and the bedside for treatment strategies other than targeted therapy.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"267-270"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142522465","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":"Functional interaction between receptor tyrosine kinase MET and ETS transcription factors promotes prostate cancer progression.","authors":"Elisa Carouge, Clémence Burnichon, Martin Figeac, Shéhérazade Sebda, Nathalie Vanpouille, Audrey Vinchent, Marie-José Truong, Martine Duterque-Coquillaud, David Tulasne, Anne Chotteau-Lelièvre","doi":"10.1002/1878-0261.13739","DOIUrl":"10.1002/1878-0261.13739","url":null,"abstract":"<p><p>Prostate cancer, the most common malignancy in men, has a relatively favourable prognosis. However, when it spreads to the bone, the survival rate drops dramatically. The development of bone metastases leaves patients with aggressive prostate cancer, the leading cause of death in men. Moreover, bone metastases are incurable and very painful. Hepatocyte growth factor receptor (MET) and fusion of genes encoding E26 transformation-specific (ETS) transcription factors are both involved in the progression of the disease. ETS gene fusions, in particular, have the ability to induce the migratory and invasive properties of prostate cancer cells, whereas MET receptor, through its signalling cascades, is able to activate transcription factor expression. MET signalling and ETS gene fusions are intimately linked to high-grade prostate cancer. However, the collaboration of these factors in prostate cancer progression has not yet been investigated. Here, we show, using cell models of advanced prostate cancer, that ETS translocation variant 1 (ETV1) and transcriptional regulator ERG (ERG) transcription factors (members of the ETS family) promote tumour properties, and that activation of MET signalling enhances these effects. By using a specific MET tyrosine kinase inhibitor in a humanised hepatocyte growth factor (HGF) mouse model, we also establish that MET activity is required for ETV1/ERG-mediated tumour growth. Finally, by performing a comparative transcriptomic analysis, we identify target genes that could play a relevant role in these cellular processes. Thus, our results demonstrate for the first time in prostate cancer models a functional interaction between ETS transcription factors (ETV1 and ERG) and MET signalling that confers more aggressive properties and highlight a molecular signature characteristic of this combined action.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"474-495"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391849","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}