Molecular Oncology最新文献

EMT-associated bias in the Parsortix® system observed with pancreatic cancer cell lines. Parsortix®系统在胰腺癌细胞系中观察到emt相关偏倚

IF 6.6 2区医学

Molecular Oncology Pub Date : 2025-06-18 DOI: 10.1002/1878-0261.70066

Nele Vandenbussche, Renske Imschoot, Béatrice Lintermans, Lode Denolf, Joachim Taminau, Charlotte Fieuws, Geert Berx, Kris Gevaert, Kathleen B M Claes

{"title":"EMT-associated bias in the Parsortix® system observed with pancreatic cancer cell lines.","authors":"Nele Vandenbussche, Renske Imschoot, Béatrice Lintermans, Lode Denolf, Joachim Taminau, Charlotte Fieuws, Geert Berx, Kris Gevaert, Kathleen B M Claes","doi":"10.1002/1878-0261.70066","DOIUrl":"https://doi.org/10.1002/1878-0261.70066","url":null,"abstract":"Pancreatic cancer has a 5-year survival rate of 12%, highlighting the need for reliable biomarkers for early detection and disease monitoring. Circulating tumor cells (CTCs) have emerged as a promising biomarker, yet their detection remains challenging. This study evaluates the Parsortix® system, a microfluidic device that enriches CTCs based on size and deformability, using pancreatic cancer cell lines. As increasing evidence indicates that during epithelial-to-mesenchymal transition (EMT) a cell's deformability increases, we evaluated possible biases by the device. The EMT stage of three pancreatic cancer cell lines, CAPAN-1, MIA PaCa-2, and PANC-1, was assessed to classify them as epithelial, mesenchymal-like, and hybrid, respectively. Spike-in experiments showed that epithelial and hybrid phenotypes were more efficiently captured (62.6 ± 18.5% and 65.4 ± 11.1%) than mesenchymal-like cancer cells (32.8 ± 10.2%). These results were confirmed using an EMT-inducible breast cancer cell line. Lower recovery rates were found for the cells in a mesenchymal-like state (31.5 ± 6.4%) than those in an epithelial state (47.56 ± 7.2%). In conclusion, the Parsortix® device may underestimate the number of mesenchymal CTCs.","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144326225","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

Evaluation and modification of tumor cell isolation techniques from malignant effusions for rapid drug sensitivity testing. 用于快速药敏试验的恶性积液肿瘤细胞分离技术的评价与改进。

IF 6.6 2区医学

Molecular Oncology Pub Date : 2025-06-17 DOI: 10.1002/1878-0261.70072

Navit Mooshayef, Hana Barhom, Sumit Chatterji, Netta Hecht, Oran Warhaftig, Iris Kamer, Oranit Zadok, Jair Bar, Limor Broday, Amir Onn, Michael Peled

{"title":"Evaluation and modification of tumor cell isolation techniques from malignant effusions for rapid drug sensitivity testing.","authors":"Navit Mooshayef, Hana Barhom, Sumit Chatterji, Netta Hecht, Oran Warhaftig, Iris Kamer, Oranit Zadok, Jair Bar, Limor Broday, Amir Onn, Michael Peled","doi":"10.1002/1878-0261.70072","DOIUrl":"https://doi.org/10.1002/1878-0261.70072","url":null,"abstract":"Non-small cell lung cancer treatment decisions rely on several diagnostic steps. Tests that rely on DNA sequencing often fail to capture the full mutational landscape of tumor cells, and drug sensitivity testing (DST) has limitations hindering widespread use currently. One of the major challenges for DST is the rapid isolation of a sufficient number of live tumor cells that would allow testing of multiple drugs simultaneously. To address this challenge, we have developed a DST procedure specifically tailored for tumor cells originating from malignant pleural effusions. We first identified tumor cells by anti-epithelial cell adhesion molecule (EpCAM) flow cytometry and then compared several methods for tumor cell isolation: immunomagnetic enrichment of epithelial cells using EpCAM, negative selection via immunomagnetic CD45+ cell depletion, and size-based separation and capture of tumor cells utilizing cell strainers. Of these methods, repeated rounds of CD45+ cell depletion, in which the number of rounds is set by the initial percentage of tumor cells in the sample, were the most effective. By combining tumor cell enrichment with DST, we have developed a system which generates DST results that correlate with clinical outcomes.","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144310214","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

Beyond cytotoxic T cells: reprogrammed regulatory T cells help facilitate response to dual checkpoint blockade. 超越细胞毒性T细胞：重编程调节性T细胞有助于促进对双检查点封锁的反应。

IF 6.6 2区医学

Molecular Oncology Pub Date : 2025-06-15 DOI: 10.1002/1878-0261.70076

Tullia C Bruno, Anthony R Cillo

{"title":"Beyond cytotoxic T cells: reprogrammed regulatory T cells help facilitate response to dual checkpoint blockade.","authors":"Tullia C Bruno, Anthony R Cillo","doi":"10.1002/1878-0261.70076","DOIUrl":"https://doi.org/10.1002/1878-0261.70076","url":null,"abstract":"Combination immunotherapies have entered the treatment armamentarium of oncology, but important knowledge gaps remain in our understanding of how these therapeutics work. A recent study by Rolig, Peng, and colleagues has shed new light on how dual blockade of PD1 and LAG3 enhances antitumor immunity. The authors first interrogated LAG3 expression on T cells across murine tumor models, classifying the models as LAG3hi or LAG3lo. Next, they found that LAG3hi models were unresponsive to anti-PD1 alone but responsive to combination therapy with anti-PD1 + anti-LAG3. Surprisingly, the response to anti-PD1 + anti-LAG3 in LAG3hi models was associated with reprogramming of CD4+ regulatory T cells (Treg) from the canonically immunosuppressive state to an inflammatory state characterized by loss of expression of the transcription factor Foxp3 and upregulation of transcription factor Tbet. Importantly, an analogous reprogrammed Treg state was associated with response to anti-PD1 + anti-LAG3 and longer overall survival in patients with metastatic melanoma. This work highlights the importance of cells beyond cytotoxic CD8+ T cells as drivers of response to immunotherapy and sets the stage for subsequent mechanistic and translational studies.","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302516","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

A DIA-MS-based proteomics approach to find potential serum prognostic biomarkers in glioblastoma patients. 基于dia - ms的蛋白质组学方法寻找胶质母细胞瘤患者潜在的血清预后生物标志物。

IF 6.6 2区医学

Molecular Oncology Pub Date : 2025-06-15 DOI: 10.1002/1878-0261.70068

Anne Clavreul, François Guillonneau, Odile Blanchet, Hamza Lasla, Audrey Rousseau, Catherine Guette, Alice Boissard, Cécile Henry, Morgan Dhondt, Pascal Jézéquel, Philippe Menei, Jean-Michel Lemée

{"title":"A DIA-MS-based proteomics approach to find potential serum prognostic biomarkers in glioblastoma patients.","authors":"Anne Clavreul, François Guillonneau, Odile Blanchet, Hamza Lasla, Audrey Rousseau, Catherine Guette, Alice Boissard, Cécile Henry, Morgan Dhondt, Pascal Jézéquel, Philippe Menei, Jean-Michel Lemée","doi":"10.1002/1878-0261.70068","DOIUrl":"https://doi.org/10.1002/1878-0261.70068","url":null,"abstract":"No blood-based protein biomarkers are currently available for routine clinical use to determine the prognosis of patients with glioblastoma (GB). We performed data-independent acquisition mass spectrometry (DIA-MS)-based proteomics on 96 presurgical serum samples from patients with GB and 30 serum samples from healthy controls to identify such markers. Among the 622 serum proteins differentially expressed between the GB and control groups, 191 had a |log2(fold change)| ≥ 0.58 and an area under the curve ≥ 0.75. An analysis of their prognostic value revealed that high levels of IL1R2 and low levels of CRTAC1 and HRG were associated with poor survival. Multivariate Cox regression analysis identified IL1R2 as an independent prognostic factor for PFS and CRTAC1 as an independent prognostic factor for OS. The concentration of CRTAC1 in serum samples from an independent cohort of short- and long-term survivors of GB (STS and LTS, respectively) by ELISA was shown to be lower in the STS than in the LTS group. CRTAC1, HRG, and IL1R2 could potentially be used to better inform prognosis and predict treatment response in GB patients.","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302514","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

A nucleotide-independent, pan-RAS-targeted DARPin elicits anti-tumor activity in a multimodal manner. 一个核苷酸独立的泛ras靶向DARPin以多模式方式引发抗肿瘤活性。

IF 6.6 2区医学

Molecular Oncology Pub Date : 2025-06-15 DOI: 10.1002/1878-0261.70061

Jonas N Kapp, Wouter P R Verdurmen, Jonas V Schaefer, Kari Kopra, Gabriela Nagy-Davidescu, Elodie Richard, Marie-Julie Nokin, Patrick Ernst, Rastislav Tamaskovic, Martin Schwill, Ralph Degen, Claudia Scholl, David Santamaria, Andreas Plückthun

{"title":"A nucleotide-independent, pan-RAS-targeted DARPin elicits anti-tumor activity in a multimodal manner.","authors":"Jonas N Kapp, Wouter P R Verdurmen, Jonas V Schaefer, Kari Kopra, Gabriela Nagy-Davidescu, Elodie Richard, Marie-Julie Nokin, Patrick Ernst, Rastislav Tamaskovic, Martin Schwill, Ralph Degen, Claudia Scholl, David Santamaria, Andreas Plückthun","doi":"10.1002/1878-0261.70061","DOIUrl":"https://doi.org/10.1002/1878-0261.70061","url":null,"abstract":"The KRAS oncoprotein is a frequent tumor driver in lung, pancreatic, and colorectal cancers and has proven to be a challenging pharmaceutical target. The first KRAS-targeted therapeutics are now being tested in clinical trials but the consequences of preferentially targeting the GDP or GTP state of KRAS and the relevance of RAS nanoclustering have remained unclear. Here we report a Designed Ankyrin Repeat Protein (DARPin) that recognizes the RAS switch I/II region with low nm affinity, independently of the nucleotide bound (GDP- or GTP state). This DARPin, termed '784_F5', occupies the effector recognition lobe, resulting in interference with SOS-mediated activation, RAS downstream effector interactions, and KRAS nanoclustering. Consequently, this anti-RAS DARPin potently blocks downstream signaling, leading to a strong reduction in proliferation and anchorage-independent growth in RAS-dependent cell lines. We showed that the expression of '784_F5', the pan-RAS, nucleotide-independent DARPin can lead to tumor regression in a colorectal xenograft model which may hold promise for further investigation and development.","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302515","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

Tumor clusters with divergent inflammation and human retroelement expression determine the clinical outcome of patients with serous ovarian cancer. 具有不同炎症和人类逆转录因子表达的肿瘤簇决定了浆液性卵巢癌患者的临床预后。

IF 6.6 2区医学

Molecular Oncology Pub Date : 2025-06-10 DOI: 10.1002/1878-0261.70067

Laura Glossner, Markus Eckstein, Christoph Mark, Matthias W Beckmann, Arndt Hartmann, Pamela L Strissel, Reiner Strick

{"title":"Tumor clusters with divergent inflammation and human retroelement expression determine the clinical outcome of patients with serous ovarian cancer.","authors":"Laura Glossner, Markus Eckstein, Christoph Mark, Matthias W Beckmann, Arndt Hartmann, Pamela L Strissel, Reiner Strick","doi":"10.1002/1878-0261.70067","DOIUrl":"https://doi.org/10.1002/1878-0261.70067","url":null,"abstract":"High-grade serous ovarian carcinoma (HGSOC) associates with the worst patient outcome. Understanding the tumor environment in terms of quantifying endogenous retroviruses (ERVs) and LINE-1 expression and their correlations with inflammation genes, checkpoint inhibitors and patient survival is needed. Analysis of 102 treatment-naïve HGSOC and control tissues for ERVs, LINE-1, inflammation and immune checkpoints identified five clusters with diverse patient recurrence-free survivals. One cluster termed Triple-I with the best patient survival showed the highest number of tumor infiltrating lymphocytes along with 22 overexpressed genes, including CXCL9 and AIM2. However, Triple-I associated with the lowest ERV/LINE-1 expression. The tumor cluster with the second-best patient survival had both high ERV/LINE-1 expression and inflammation. Multiplex-immunohistochemistry revealed CD28 protein solely on immune cells, without co-expression of the inhibitory CTLA4 receptor. The largest tumor cluster with high ERV/LINE-1 expression but low inflammation showed a significant low gene expression of the dsRNA sensors MDA5 and RIG-I supporting an aberrant block in IFN signaling. Our study represents an intrinsic 'molecular and immunological snapshot' of the HGSOC tumor environment important for understanding retroelements and inflammation for clinical relevance.","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144258583","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

Cytomegalovirus infection is common in prostate cancer and antiviral therapies inhibit progression in disease models. 巨细胞病毒感染在前列腺癌中很常见，抗病毒治疗可抑制疾病模型的进展。

IF 6.6 2区医学

Molecular Oncology Pub Date : 2025-06-10 DOI: 10.1002/1878-0261.70073

Johanna Classon, Moa Stenudd, Margherita Zamboni, Kanar Alkass, Carl-Johan Eriksson, Lars Pedersen, Alrik Schörling, Anna Thoss, Anders Bergh, Pernilla Wikström, Hans-Olov Adami, Henrik Toft Sørensen, Henrik Druid, Jonas Frisén

{"title":"Cytomegalovirus infection is common in prostate cancer and antiviral therapies inhibit progression in disease models.","authors":"Johanna Classon, Moa Stenudd, Margherita Zamboni, Kanar Alkass, Carl-Johan Eriksson, Lars Pedersen, Alrik Schörling, Anna Thoss, Anders Bergh, Pernilla Wikström, Hans-Olov Adami, Henrik Toft Sørensen, Henrik Druid, Jonas Frisén","doi":"10.1002/1878-0261.70073","DOIUrl":"https://doi.org/10.1002/1878-0261.70073","url":null,"abstract":"Metastatic prostate cancer is incurable, and new therapeutic targets and drugs are urgently needed. Viral infections are associated with several cancer types, but a link between viruses and prostate oncogenesis has not been established. Only recently, an association between human cytomegalovirus (CMV) seropositivity and increased risk of prostate cancer mortality was demonstrated. Here, we show that CMV infection is common in the normal prostate epithelium and in prostate tumor tissue, with 70-92% of tumors being infected. Additionally, we report that commonly studied prostate cancer cell lines are CMV infected. Loss-of-function experiments demonstrate that CMV promotes cell survival, proliferation, and androgen receptor signaling, identifying it as a therapeutic target in castration-sensitive and castration-resistant prostate cancer. Several anti-CMV pharmaceutical compounds in clinical use inhibited cell expansion in prostate cancer models both in vitro and in vivo. We conclude that CMV is common in prostate cancer, promotes core prostate cancer cell programs, and can be inhibited by well-tolerated drugs. These findings motivate investigation into potential clinical benefits of CMV inhibition in the treatment of prostate cancer.","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144258582","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 anticancer effect of the HDAC inhibitor belinostat is enhanced by inhibitors of Bcl-x_L or Mcl-1 in ovarian cancer. Bcl-xL或Mcl-1抑制剂可增强HDAC抑制剂belinostat在卵巢癌中的抗癌作用。

IF 6.6 2区医学

Molecular Oncology Pub Date : 2025-06-08 DOI: 10.1002/1878-0261.70050

Cécilia Thomine, Sterenn Guillemot, Louis-Bastien Weiswald, Romane Florent, Edwige Abeilard, Florence Giffard, Emilie Brotin, Mélanie Briand, Enora Dolivet, Laurent Poulain, Marie Villedieu

{"title":"The anticancer effect of the HDAC inhibitor belinostat is enhanced by inhibitors of Bcl-xL or Mcl-1 in ovarian cancer.","authors":"Cécilia Thomine, Sterenn Guillemot, Louis-Bastien Weiswald, Romane Florent, Edwige Abeilard, Florence Giffard, Emilie Brotin, Mélanie Briand, Enora Dolivet, Laurent Poulain, Marie Villedieu","doi":"10.1002/1878-0261.70050","DOIUrl":"https://doi.org/10.1002/1878-0261.70050","url":null,"abstract":"Identifying innovative therapeutic strategies is crucial to improve clinical management of ovarian cancer. Previously, we showed that ovarian cancer cell apoptosis can be triggered by inhibiting the anti-apoptotic proteins Bcl-xL and Mcl-1 and/or by inducing their pro-apoptotic partners Bim, Puma, and Noxa. The expression of these pro-apoptotic proteins can be hindered by excessive histone deacetylation, resulting from HDAC overexpression. This study aimed to evaluate whether belinostat, an FDA-approved pan-HDAC inhibitor, could increase Bim, Puma, and/or Noxa expression and induce ovarian cancer cell death, either alone or in combination with strategies targeting Bcl-xL or Mcl-1. Belinostat exerted a cytostatic effect and, at higher concentrations, an apoptotic effect in SKOV3 and IGROV1-R10 ovarian cancer cells. It induced a concentration-dependent increase in Bim, Puma, and Noxa protein expression, while partially repressing that of Bcl-xL. Inhibition of Bcl-xL sensitized both cell lines to belinostat, as did inhibition of Mcl-1 in IGROV1-R10 cells. Interestingly, belinostat's anticancer activity was also enhanced by inhibitors of Bcl-xL or Mcl-1 in patient-derived tumor organoids. This study therefore positions belinostat-based strategies as promising therapies for ovarian cancer.","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248801","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

Unraveling LINE-1 retrotransposition in head and neck squamous cell carcinoma. 揭示头颈部鳞状细胞癌中LINE-1逆转录转位。

IF 6.6 2区医学

Molecular Oncology Pub Date : 2025-06-04 DOI: 10.1002/1878-0261.70063

Jenifer Brea-Iglesias, Ana Oitabén, Sonia Zumalave, Bernardo Rodriguez-Martin, María Gallardo-Gómez, Martín Santamarina, Ana Pequeño-Valtierra, Laura Juaneda-Magdalena, Ramón García-Escudero, José Luis López-Cedrún, Máximo Fraga, José M C Tubio, Mónica Martínez-Fernández

{"title":"Unraveling LINE-1 retrotransposition in head and neck squamous cell carcinoma.","authors":"Jenifer Brea-Iglesias, Ana Oitabén, Sonia Zumalave, Bernardo Rodriguez-Martin, María Gallardo-Gómez, Martín Santamarina, Ana Pequeño-Valtierra, Laura Juaneda-Magdalena, Ramón García-Escudero, José Luis López-Cedrún, Máximo Fraga, José M C Tubio, Mónica Martínez-Fernández","doi":"10.1002/1878-0261.70063","DOIUrl":"https://doi.org/10.1002/1878-0261.70063","url":null,"abstract":"The relevant role of LINE-1 (L1) retrotransposition in cancer has been recurrently demonstrated in recent years. However, the repetitive nature of retrotransposons makes their identification and detection inaccessible for clinical practice. Also, its clinical relevance for cancer patients is still limited. Here, we developed RetroTest, a new efficient method to quantify L1 activation based on targeted sequencing and a sophisticated bioinformatic pipeline, allowing its application in tumor biopsies. Firstly, we performed RetroTest benchmarking to confirm its high specificity and reliability. Then, we unraveled L1 activation in head-and-neck squamous cell carcinoma (HNSCC) according to an extensive patient cohort including all tumor stages. L1 retrotransposition estimation revealed a surprisingly early activation in HNSCC progression, contrary to its classical association with advanced stages. In addition, L1 activation together with genomic mutational profiling in normal adjacent tissues supported a field cancerization process, a phenomenon where a tissue develops multiple patches of cells with genetic and/or epigenetic alterations, increasing the risk of cancer development in that area. Overall, our results underline an early L1 activation in HNSCC and field characterization, raising L1 as a promising early diagnostic biomarker and supporting the importance of estimating L1 retrotransposition in clinical practice toward a more efficient diagnosis in HNSCC.","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144225976","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

Combined spatially resolved metabolomics and spatial transcriptomics reveal the mechanism of RACK1-mediated fatty acid synthesis. 结合空间解析代谢组学和空间转录组学揭示了 RACK1 介导脂肪酸合成的机制。

IF 6.6 2区医学

Molecular Oncology Pub Date : 2025-06-01 Epub Date: 2024-10-18 DOI: 10.1002/1878-0261.13752

Lixiu Xu, Jinqiu Li, Junqi Ma, Ayshamgul Hasim

{"title":"Combined spatially resolved metabolomics and spatial transcriptomics reveal the mechanism of RACK1-mediated fatty acid synthesis.","authors":"Lixiu Xu, Jinqiu Li, Junqi Ma, Ayshamgul Hasim","doi":"10.1002/1878-0261.13752","DOIUrl":"10.1002/1878-0261.13752","url":null,"abstract":"Lipid metabolism is altered in rapidly proliferating cancer cells, where fatty acids (FAs) are utilized in the synthesis of sphingolipids and glycerophospholipids to produce cell membranes and signaling molecules. Receptor for activated C-kinase 1 (RACK1; also known as small ribosomal subunit protein) is an intracellular scaffolding protein involved in signaling pathways. Whether such lipid metabolism is regulated by RACK1 is unknown. Here, integrated spatially resolved metabolomics and spatial transcriptomics revealed that accumulation of lipids in cervical cancer (CC) samples correlated with overexpression of RACK1, and RACK1 promoted lipid synthesis in CC cells. Chromatin immunoprecipitation verified binding of sterol regulatory element-binding protein 1 (SREBP1) to acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN) promoters. RACK1 enhanced de novo FA synthesis by upregulating expression of sterol regulatory element binding transcription factor 1 (SREBP1) and lipogenic genes FASN and ACC1. Co-immunoprecipitation and western blotting revealed that RACK1 interacted with protein kinase B (AKT) to activate the AKT/mammalian target of rapamycin (mTOR)/SREBP1 signaling pathway to promote FA synthesis. Cell proliferation and apoptosis experiments suggested that RACK1-regulated FA synthesis is key in the progression of CC. Thus, RACK1 enhanced lipid synthesis through the AKT/mTOR/SREBP1 signaling pathway to promote the growth of CC cells. RACK1 may become a therapeutic target for CC.","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"1668-1686"},"PeriodicalIF":6.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12161477/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470166","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