Cellular Oncology最新文献

{"title":"Deciphering the molecular landscape: evolutionary progression from gynecomastia to aggressive male breast cancer.","authors":"Chuang Yang, Zhonglin Wang, Lijun Qian, Jingyue Fu, Handong Sun","doi":"10.1007/s13402-024-00964-4","DOIUrl":"10.1007/s13402-024-00964-4","url":null,"abstract":"<p><strong>Background: </strong>Gynecomastia denotes the benign proliferation of glandular breast tissue and stands as a recognized risk factor for male breast cancer. Nonetheless, the underlying carcinogenic mechanisms orchestrating the progression from gynecomastia to cancer remain poorly understood.</p><p><strong>Methods: </strong>This study employed single-cell RNA sequencing (scRNA-seq) to meticulously dissect the cellular landscape of gynecomastia and unravel potential associations with male breast cancer at a single-cell resolution. Pseudotime and evolutionary analyses were executed to delineate the distinct features characterizing gynecomastia and male breast cancer. The TCGA database, along with cell-cell communication analysis and immunohistochemistry staining, was harnessed to validate differential gene expression, specifically focusing on CD13.</p><p><strong>Result: </strong>From the copy number variation profiles and evolutionary tree, we inferred shared mutation characteristics (18p⁺ and 18q⁺) underpinning both conditions. The developmental trajectory unveiled an intriguing overlap between gynecomastia and malignant epithelial cells. Moreover, the differential gene CD13 emerged as a common denominator in both gynecomastia and male breast cancer when compared with normal mammary tissue. Cell-cell interaction analysis and communication dynamics within the tumor microenvironment spotlighted distinctions between CD13⁺ and CD13^- subsets, with the former exhibiting elevated expression of FGFR1-FGF7.</p><p><strong>Conclusions: </strong>Our investigation provides novel insights into the evolutionary progression from gynecomastia to male breast cancer, shedding light on the pivotal role of CD13 in driving this transition. The identification of CD13 as a potential therapeutic target suggests the feasibility of CD13-targeted interventions, specifically tailored for male breast cancer treatment.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":"1831-1843"},"PeriodicalIF":6.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141418100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The PPP2R1A cancer hotspot mutant p.R183W increases clofarabine resistance in uterine serous carcinoma cells by a gain-of-function mechanism.","authors":"Michiel Remmerie, Rüveyda Dok, Zhigang Wang, Judit Domènech Omella, Sophie Alen, Célie Cokelaere, Lisa Lenaerts, Erwin Dreesen, Sandra Nuyts, Rita Derua, Veerle Janssens","doi":"10.1007/s13402-024-00963-5","DOIUrl":"10.1007/s13402-024-00963-5","url":null,"abstract":"<p><strong>Purpose: </strong>Uterine serous carcinoma (USC) is generally associated with poor prognosis due to a high recurrence rate and frequent treatment resistance; hence, there is a need for improved therapeutic strategies. Molecular analysis of USC identified several molecular markers, useful to improve current treatments or identify new druggable targets. PPP2R1A, encoding the Aα subunit of the tumor suppressive Ser/Thr phosphatase PP2A, is mutated in up to 40% of USCs. Here, we investigated the effect of the p.R183W PPP2R1A hotspot variant on treatment response to the nucleoside analogue clofarabine.</p><p><strong>Methods and results: </strong>USC cells stably expressing p.R183W Aα showed increased resistance to clofarabine treatment in vitro and, corroborated by decreased clofarabine-induced apoptosis, G1 phase arrest, DNA-damage (γH2AX) and activation of ATM and Chk1/2 kinases. Phenotypic rescue by pharmacologic PP2A inhibition or dicer-substrate siRNA (dsiRNA)-mediated B56δ subunit knockdown supported a gain-of-function mechanism of Aα p.R183W, promoting dephosphorylation and inactivation of deoxycytidine kinase (dCK), the cellular enzyme responsible for the conversion of clofarabine into its bioactive form. Therapeutic assessment of related nucleoside analogues (gemcitabine, cladribine) revealed similar effects, but in a cell line-dependent manner. Expression of two other PPP2R1A USC mutants (p.P179R or p.S256F) did not affect clofarabine response in our cell models, arguing for mutant-specific effects on treatment outcome as well.</p><p><strong>Conclusions: </strong>While our results call for PPP2R1A mutant and context-dependent effects upon clofarabine/nucleoside analogue monotherapy, combining clofarabine with a pharmacologic PP2A inhibitor proved synergistically in all tested conditions, highlighting a new generally applicable strategy to improve treatment outcome in USC.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":"1811-1829"},"PeriodicalIF":6.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141418102","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":"Clinical value of ¹⁸F-FDG PET/CT in patients with newly diagnosed acute leukemia.","authors":"Jiamin Fang, Jie Chen, Xinqi Li, Pengpeng Li, Xiaoyan Liu, Yong He, Fuling Zhou","doi":"10.1007/s13402-024-00993-z","DOIUrl":"https://doi.org/10.1007/s13402-024-00993-z","url":null,"abstract":"<p><strong>Purpose: </strong>To explore the correlation between semi-quantitative parameters of ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography/computed tomography (PET/CT) scans findings and the clinical features of patients with acute leukemia (AL), as well as to evaluate the clinical utility of ¹⁸F-FDG PET/CT in the management of AL.</p><p><strong>Methods: </strong>A retrospective study was conducted with 44 patients newly diagnosed with acute leukemia (AL) at Zhongnan Hospital of Wuhan University between January 2019 and August 2024.</p><p><strong>Results: </strong>Multivariate analysis revealed that age at diagnosis of AL (odds ratio [OR]: 0.888, P < 0.01) and percentage of blasts in the peripheral blood (PB) (OR: 1.061, P < 0.05) were independent predictors of the appearance of active extramedullary disease (EMD). Kaplan-Meier survival analysis for patients with EMD(+) indicated that those with organ infiltration beyond the lymph nodes experienced markedly reduced overall survival (OS) compared to those without such infiltration (157 days and 806 days, respectively). Furthermore, in the AL subgroup with EMD, the ratio of the maximum standardized uptake value (SUVmax) in the bone marrow (BM) to SUVmax of the liver emerged as an independent prognostic factor for OS (Hazard ratio [HR]: 2.372; 95% confidence interval [CI]: 1.079-5.214, P < 0.05).</p><p><strong>Conclusion: </strong>¹⁸F-FDG PET/CT offers the benefits of being non-invasive and highly sensitive for the thorough evaluation of disease status in patients newly diagnosed with AL. Furthermore, the SUVmax BM/liver ratio is of significant clinical importance for prognosticating outcomes in patients with AL presenting EMD.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307181","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":"Circadian system disorder induced by aberrantly activated EFNB2-EPHB2 axis leads to facilitated liver metastasis in gastric cancer","authors":"Qing Li, Yuxuan Lin, Bo Ni, Haigang Geng, Chaojie Wang, Enhao Zhao, Chunchao Zhu","doi":"10.1007/s13402-024-00991-1","DOIUrl":"https://doi.org/10.1007/s13402-024-00991-1","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Liver is one of the most preferred destinations for distant metastasis of gastric cancer (GC) and liver metastasis usually predicts poor prognosis. The achievement of liver metastasis requires continued cross-talk of complex members in tumor microenvironment (TME) including tumor associated macrophages (TAMs).</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Results from 35 cases of ex vivo cultured living tissues of GC liver metastasis have elucidated that circadian rhythm disorder (CRD) of key molecules involved in circadian timing system (CTS) facilitates niche outgrowth. We next analyzed 69 cases of liver metastasis from patients bearing GC and designed co-culture or 3D cell culture, discovering that TAMs expressing EFNB2 could interact with tumor cell expressing EPHB2 for forward downstream signaling and lead to CRD of tumor cells. Moreover, we performed intrasplenic injection models assessed by CT combined 3D organ reconstruction bioluminescence imaging to study liver metastasis and utilized the clodronate treatment, bone marrow transplantation or EPH inhibitor for in vivo study followed by exploring the clinical therapeutic value of which in patient derived xenograft (PDX) mouse model.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Ex vivo studies demonstrated that CRD of key CTS molecules facilitates niche outgrowth in liver metastases. In vitro studies revealed that TAMs expressing EFNB2 interact with tumor cells expressing EPHB2, leading to CRD and downstream signaling activation. The underlying mechanism is the enhancement of the Warburg effect in metastatic niches.</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>Overall, we aim to uncover the mechanism in TAMs induced CRD which promotes liver metastasis of GC and provide novel ideas for therapeutic strategies.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"39 1","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142259421","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":"Exosomes: from basic research to clinical diagnostic and therapeutic applications in cancer","authors":"Salomé Araujo-Abad, José Marcos Berna, Elena Lloret-Lopez, Andrés López-Cortés, Miguel Saceda, Camino de Juan Romero","doi":"10.1007/s13402-024-00990-2","DOIUrl":"https://doi.org/10.1007/s13402-024-00990-2","url":null,"abstract":"<p>Cancer continues to pose a global threat despite potent anticancer drugs, often accompanied by undesired side effects. To enhance patient outcomes, sophisticated multifunctional approaches are imperative. Small extracellular vesicles (EVs), a diverse family of naturally occurring vesicles derived from cells, offer advantages over synthetic carriers. Among the EVs, the exosomes are facilitating intercellular communication with minimal toxicity, high biocompatibility, and low immunogenicity. Their tissue-specific targeting ability, mediated by surface molecules, enables precise transport of biomolecules to cancer cells. Here, we explore the potential of exosomes as innovative therapeutic agents, including cancer vaccines, and their clinical relevance as biomarkers for clinical diagnosis. We highlight the cargo possibilities, including nucleic acids and drugs, which make them a good delivery system for targeted cancer treatment and contrast agents for disease monitoring. Other general aspects, sources, and the methodology associated with therapeutic cancer applications are also reviewed. Additionally, the challenges associated with translating exosome-based therapies into clinical practice are discussed, together with the future prospects for this innovative approach.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"14 1","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142259427","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":"Low-dose SAHA enhances CD8+ T cell-mediated antitumor immunity by boosting MHC I expression in non-small cell lung cancer","authors":"Wenqian Dong, Bing He, Yanhong Cao, Rui Yang, Shuang Zhang, Yujie Kong, Dapeng Lu, Xu Zheng, Yanjiao Hou, Maoxin Zhu, Chen Wang, Shihao Yu, Dechun Cui, Hao Wang, Baolong Wang","doi":"10.1007/s13402-024-00989-9","DOIUrl":"https://doi.org/10.1007/s13402-024-00989-9","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Non-small cell lung cancer (NSCLC) is a highly aggressive type of lung cancer with poor responses to traditional therapies such as surgery, radiotherapy, and chemotherapy. While immunotherapy has become an effective approach for treating multiple types of cancer, solid tumors frequently exhibit immune escape through various mechanisms, including downregulation of MHC I expression. However, whether the upregulation of MHC I expression can improve the immunotherapeutic effect on NSCLC remains unexplored. Suberoylanilide hydroxamic acid (SAHA) is a potent histone deacetylase (HDAC) inhibitor that has been applied clinically to treat lymphoma, but a high dose of SAHA kills tumor cells and normal cells without preference. Here, we report that low-dose SAHA enhances CD8⁺ T cell-mediated antitumor immunity by upregulating MHC I expression in NSCLC cells.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Flow cytometric analysis, quantitative real-time PCR and western blot were used to analyze the expression of MHC I, STAT1 and Smad2/3 in both human and mouse NSCLC cell lines after SAHA treatment. The nuclear translocation of phosphorylated STAT1 and Smad2/3 was investigated by western blot and immunofluorescence staining. The mechanisms underlying STAT1 and Smad2/3 upregulation were analyzed through database searches and chromatin immunoprecipitation-qPCR. Finally, we assessed the antitumor effect of specific CD8⁺ T cells with SAHA treatment in vivo and in vitro.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>We showed that low-dose SAHA upregulated the expression of MHC I in NSCLC cell lines without affecting cell viability. We also provided evidence that high levels of MHC I induced by SAHA promoted the activation, proliferation, and cytotoxicity of specific CD8⁺ T cells in mouse models. Mechanistically, low-dose SAHA increased the levels of H3K9ac and H3K27ac in the promoters of the STAT1, Smad2 and Smad3 genes in NSCLC cells by inhibiting HDAC activity, resulting in elevated expression levels of STAT1, Smad2 and Smad3. The nuclear translocation of phosphorylated STAT1 and Smad2/3 markedly upregulated the expression of MHC I in NSCLC cells.</p><h3 data-test=\"abstract-sub-heading\">Conclusions</h3><p>Low-dose SAHA enhances CD8⁺ T cell-mediated antitumor immunity by boosting MHC I expression in NSCLC cells. Thus, we revealed a key mechanism of SAHA-mediated enhanced antitumor immunity, providing insights into a novel immunotherapy strategy for NSCLC.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"28 1","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142259430","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":"A review on the functional characteristics of the c-Myeloproliferative Leukaemia (c-MPL) gene and its isoforms","authors":"Mohammad Amjad Hussain, Shankar Prasad Das, Mithila Kulkarni, Suparna Laha","doi":"10.1007/s13402-024-00988-w","DOIUrl":"https://doi.org/10.1007/s13402-024-00988-w","url":null,"abstract":"<p>The c-MPL-TPO axis regulates hematopoiesis by activating various signalling cascades, including JAK/STAT, MAPK/ERK, and PIK3/AKT. Here, we have summarized how TPO is regulated by c-MPL and, how mutations in the c-MPL regulate hematopoiesis. We also focus on its non-hematological regulatory role in diseases like Unstable Angina and pathways like DNA damage repair, skeletal homeostasis, &amp; apoptotic regulation of neurons/HSCs at the embryonic state. We discuss the therapeutic efficiency of c-MPL and, its potential to be developed as a bio-marker for detecting metastasis and development of chemo-resistance in various cancers, justifying the multifaceted nature of c-MPL. We have also highlighted the importance of c-MPL isoforms and their stoichiometry in controlling the HSC quiescent and proliferative state. The regulation of the ratio of different isoforms through gene-therapy can open future therapeutic avenues. A systematic understanding of c-MPL-isoforms would undoubtedly take one step closer to facilitating c-MPL from basic-research towards translational medicine.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"3 1","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142259429","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":"BHLHE41, a transcriptional repressor involved in physiological processes and tumor development","authors":"Caroline Bret, Fabienne Desmots-Loyer, Jérôme Moreaux, Thierry Fest","doi":"10.1007/s13402-024-00973-3","DOIUrl":"https://doi.org/10.1007/s13402-024-00973-3","url":null,"abstract":"<p>BHLHE41 is a nuclear transcriptional repressor that belongs to the basic helix-loop-helix protein superfamily. <i>BHLHE41</i> expression tends to be restricted to specific tissues and is regulated by environmental cues and biological events. BHLHE41 homodimerizes or heterodimerizes with various partners, influencing its transcription factor function. BHLHE41 is involved in the regulation of many physiological processes implicated in tissue/organ homeostasis, such as myogenesis, adipogenesis, circadian rhythms and DNA repair. At cellular level, BHLHE41 is involved in the regulation of mesenchymal stem cell properties, tissue-specific macrophage functions and lymphoid lineage physiology. In several cancer types, BHLHE41 modulates the expression of different transcriptional programs influencing cell cycle control, apoptosis, invasiveness, epithelial to mesenchymal transition and hypoxia response in the tumor environment. Depending on the cancer cell type, BHLHE41 can act as a tumor suppressor or an oncogene, and could be a target for innovative therapies. This review summarizes the available knowledge on BHLHE41 structure, biological functions, regulation and potential partners, as well as its role in physiological processes, and its implication in major cancer steps.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"12 1","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142197730","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":"Next-generation BCMA-targeted chimeric antigen receptor CARTemis-1: the impact of manufacturing procedure on CAR T-cell features.","authors":"Belén Sierro-Martínez, Virginia Escamilla-Gómez, Laura Pérez-Ortega, Beatriz Guijarro-Albaladejo, Paola Hernández-Díaz, María de la Rosa-Garrido, Maribel Lara-Chica, Alfonso Rodríguez-Gil, Juan Luis Reguera-Ortega, Luzalba Sanoja-Flores, Blanca Arribas-Arribas, Miguel Ángel Montiel-Aguilera, Gloria Carmona, Maria Jose Robles, Teresa Caballero-Velázquez, Javier Briones, Hermann Einsele, Michael Hudecek, Jose Antonio Pérez-Simón, Estefanía García-Guerrero","doi":"10.1007/s13402-024-00984-0","DOIUrl":"https://doi.org/10.1007/s13402-024-00984-0","url":null,"abstract":"<p><strong>Purpose: </strong>CAR therapy targeting BCMA is under investigation as treatment for multiple myeloma. However, given the lack of plateau in most studies, pursuing more effective alternatives is imperative. We present the preclinical and clinical validation of a new optimized anti-BCMA CAR (CARTemis-1). In addition, we explored how the manufacturing process could impact CAR-T cell product quality and fitness.</p><p><strong>Methods: </strong>CARTemis-1 optimizations were evaluated at the preclinical level both, in vitro and in vivo. CARTemis-1 generation was validated under GMP conditions, studying the dynamics of the immunophenotype from leukapheresis to final product. Here, we studied the impact of the manufacturing process on CAR-T cells to define optimal cell culture protocol and expansion time to increase product fitness.</p><p><strong>Results: </strong>Two different versions of CARTemis-1 with different spacers were compared. The longer version showed increased cytotoxicity. The incorporation of the safety-gene EGFRt into the CARTemis-1 structure can be used as a monitoring marker. CARTemis-1 showed no inhibition by soluble BCMA and presents potent antitumor effects both in vitro and in vivo. Expansion with IL-2 or IL-7/IL-15 was compared, revealing greater proliferation, less differentiation, and less exhaustion with IL-7/IL-15. Three consecutive batches of CARTemis-1 were produced under GMP guidelines meeting all the required specifications. CARTemis-1 cells manufactured under GMP conditions showed increased memory subpopulations, reduced exhaustion markers and selective antitumor efficacy against MM cell lines and primary myeloma cells. The optimal release time points for obtaining the best fit product were > 6 and < 10 days (days 8-10).</p><p><strong>Conclusions: </strong>CARTemis-1 has been rationally designed to increase antitumor efficacy, overcome sBCMA inhibition, and incorporate the expression of a safety-gene. The generation of CARTemis-1 was successfully validated under GMP standards. A phase I/II clinical trial for patients with multiple myeloma will be conducted (EuCT number 2022-503063-15-00).</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142079286","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":"Pre-existing cell subpopulations in primary prostate cancer tumors display surface fingerprints of docetaxel-resistant cells.","authors":"Stanislav Drápela, Barbora Kvokačková, Eva Slabáková, Anna Kotrbová, Kristína Gömöryová, Radek Fedr, Daniela Kurfürstová, Martin Eliáš, Vladimír Študent, Frederika Lenčéšová, Ganji Sri Ranjani, Vendula Pospíchalová, Vítězslav Bryja, Wytske M van Weerden, Martin Puhr, Zoran Culig, Jan Bouchal, Karel Souček","doi":"10.1007/s13402-024-00982-2","DOIUrl":"https://doi.org/10.1007/s13402-024-00982-2","url":null,"abstract":"<p><strong>Purpose: </strong>Docetaxel resistance is a significant obstacle in the treatment of prostate cancer (PCa), resulting in unfavorable patient prognoses. Intratumoral heterogeneity, often associated with epithelial-to-mesenchymal transition (EMT), has previously emerged as a phenomenon that facilitates adaptation to various stimuli, thus promoting cancer cell diversity and eventually resistance to chemotherapy, including docetaxel. Hence, understanding intratumoral heterogeneity is essential for better patient prognosis and the development of personalized treatment strategies.</p><p><strong>Methods: </strong>To address this, we employed a high-throughput single-cell flow cytometry approach to identify a specific surface fingerprint associated with docetaxel-resistance in PCa cells and complemented it with proteomic analysis of extracellular vesicles. We further validated selected antigens using docetaxel-resistant patient-derived xenografts in vivo and probed primary PCa specimens to interrogate of their surface fingerprint.</p><p><strong>Results: </strong>Our approaches revealed a 6-molecule surface fingerprint linked to docetaxel resistance in primary PCa specimens. We observed consistent overexpression of CD95 (FAS/APO-1), and SSEA-4 surface antigens in both in vitro and in vivo docetaxel-resistant models, which was also observed in a cell subpopulation of primary PCa tumors exhibiting EMT features. Furthermore, CD95, along with the essential enzymes involved in SSEA-4 synthesis, ST3GAL1, and ST3GAL2, displayed a significant increase in patients with PCa undergoing docetaxel-based therapy, correlating with poor survival outcomes.</p><p><strong>Conclusion: </strong>In summary, we demonstrate that the identified 6-molecule surface fingerprint associated with docetaxel resistance pre-exists in a subpopulation of primary PCa tumors before docetaxel treatment. Thus, this fingerprint warrants further validation as a promising predictive tool for docetaxel resistance in PCa patients prior to therapy initiation.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003719","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}