Journal of Experimental & Clinical Cancer Research最新文献

{"title":"Correction: Anti-tumor effects of ONC201 in combination with VEGF-inhibitors significantly impacts colorectal cancer growth and survival in vivo through complementary non-overlapping mechanisms","authors":"Jessica Wagner, C. Leah Kline, Lanlan Zhou, Vladimir Khazak, Wafik S. El-Deiry","doi":"10.1186/s13046-024-03185-7","DOIUrl":"https://doi.org/10.1186/s13046-024-03185-7","url":null,"abstract":"<p><b>Correction: J Exp Clin Cancer Res 37, 11 (2018)</b></p><p><b>https://doi.org/10.1186/s13046-018-0671-0</b></p><br/><p>Following publication of the original article [1], the authors have been alerted to an error in Fig. 3A that shows a duplication of a histological image in two panels in the figure. This image duplication error in Fig. 3A was missed by all the authors and reviewers of the paper.\u0000</p><p><b>Incorrect Fig. 3</b></p><figure><figcaption><b data-test=\"figure-caption-text\">Fig. 3</b></figcaption><picture><source srcset=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs13046-024-03185-7/MediaObjects/13046_2024_3185_Fig1_HTML.png?as=webp\" type=\"image/webp\"/><img alt=\"figure 1\" aria-describedby=\"Fig1\" height=\"1000\" loading=\"lazy\" src=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs13046-024-03185-7/MediaObjects/13046_2024_3185_Fig1_HTML.png\" width=\"685\"/></picture><p>ONC201 does not impact VEGF expression in xenografts or HUVEC sprouting. <b>a</b> VEGF-A expression as detected by immunohistochemistry in HT29 and HCT116 CRC xenografts. <b>b</b> HUVEC representative images of sprouting from HUVECs grown on Matrigel. <b>c</b> Quantitation of HUVEC sprouting and branching after 12 h of drug treatment. In vivo: <i>n</i> = 5 ONC201 treatment dose was 50 mg/kg weekly. HUVECS <i>N</i> = 4, ONC201 treatment dose 5 μM, bevacizumab dose 5 mg/ml</p><span>Full size image</span><svg aria-hidden=\"true\" focusable=\"false\" height=\"16\" role=\"img\" width=\"16\"><use xlink:href=\"#icon-eds-i-chevron-right-small\" xmlns:xlink=\"http://www.w3.org/1999/xlink\"></use></svg></figure><p><b>Correct Fig. 3</b></p><figure><figcaption><b data-test=\"figure-caption-text\">Fig. 3</b></figcaption><picture><source srcset=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs13046-024-03185-7/MediaObjects/13046_2024_3185_Fig2_HTML.png?as=webp\" type=\"image/webp\"/><img alt=\"figure 2\" aria-describedby=\"Fig2\" height=\"994\" loading=\"lazy\" src=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs13046-024-03185-7/MediaObjects/13046_2024_3185_Fig2_HTML.png\" width=\"685\"/></picture><p>ONC201 does not impact VEGF expression in xenografts or HUVEC sprouting. <b>a</b> VEGF-A expression as detected by immunohistochemistry in HT29 and HCT116 CRC xenografts. <b>b</b> HUVEC representative images of sprouting from HUVECs grown on Matrigel. <b>c</b> Quantitation of HUVEC sprouting and branching after 12 h of drug treatment. In vivo: <i>n</i> = 5 ONC201 treatment dose was 50 mg/kg weekly. HUVECS <i>N</i> = 4, ONC201 treatment dose 5 μM, bevacizumab dose 5 mg/ml</p><span>Full size image</span><svg aria-hidden=\"true\" focusable=\"false\" height=\"16\" role=\"img\" width=\"16\"><use xlink:href=\"#icon-eds-i-chevron-right-small\" xmlns:xlink=\"http://www.w3.org/1999/xlink\"></use></svg></figure><ol data-track-component=\"outbound reference\" data-track-context=\"references section\"><li data-counter=\"1.\"><p>Wagner J, Kline C, Zhou L,","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"31 1","pages":""},"PeriodicalIF":11.3,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142208656","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Challenges in validation of combination treatment strategies for CRC using patient-derived organoids","authors":"Valentin Benboubker, George M. Ramzy, Sacha Jacobs, Patrycja Nowak-Sliwinska","doi":"10.1186/s13046-024-03173-x","DOIUrl":"https://doi.org/10.1186/s13046-024-03173-x","url":null,"abstract":"Patient-derived organoids (PDOs) established from tissues from various tumor types gave the foundation of ex vivo models to screen and/or validate the activity of many cancer drug candidates. Due to their phenotypic and genotypic similarity to the tumor of which they were derived, PDOs offer results that effectively complement those obtained from more complex models. Yet, their potential for predicting sensitivity to combination therapy remains underexplored. In this review, we discuss the use of PDOs in both validation and optimization of multi-drug combinations for personalized treatment strategies in CRC. Moreover, we present recent advancements in enriching PDOs with diverse cell types, enhancing their ability to mimic the complexity of in vivo environments. Finally, we debate how such sophisticated models are narrowing the gap in personalized medicine, particularly through immunotherapy strategies and discuss the challenges and future direction in this promising field.","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"52 1","pages":""},"PeriodicalIF":11.3,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142208602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Novel engineered IL-2 Nemvaleukin alfa combined with PD1 checkpoint blockade enhances the systemic anti-tumor responses of radiation therapy","authors":"Kewen He, Nahum Puebla-Osorio, Hampartsoum B. Barsoumian, Duygu Sezen, Zahid Rafq, Thomas S. Riad, Yun Hu, Ailing Huang, Tifany A. Voss, Claudia S. Kettlun Leyton, Lily Jae Schuda, Ethan Hsu, Joshua Heiber, Maria-Angelica Cortez, James W. Welsh","doi":"10.1186/s13046-024-03183-9","DOIUrl":"https://doi.org/10.1186/s13046-024-03183-9","url":null,"abstract":"<p><b>Correction: J Exp Clin Cancer Res 43, 251 (2024)</b></p><p><b>https://doi.org/10.1186/s13046-024-03165-x</b></p><p>Following publication of the original article [1], the authors found an error in the affiliation of the 5th author, Zahid Rafiq. He was mistakenly assign to Affiliation 1. The details are given below:</p><p>\u0000<b>Incorrect affiliation</b>:</p><p>\u0000<sup>1</sup> Department of Radiation Oncology, Shandong First Medical University and Shandong Academy of Medical Sciences, Shandong Cancer Hospital and Institute, Jinan, Shandong, China.</p><p>\u0000<b>Correct affiliation</b>:</p><p>\u0000<sup>2</sup> Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.</p><p>This correction does not affect the overall result or conclusion of the article. The original article [1] has been corrected.</p><ol data-track-component=\"outbound reference\" data-track-context=\"references section\"><li data-counter=\"1.\"><p>He K, Puebla-Osorio N, Barsoumian HB, et al. Novel engineered IL-2 Nemvaleukin alfa combined with PD1 checkpoint blockade enhances the systemic anti-tumor responses of radiation therapy. J Exp Clin Cancer Res. 2024;43:251. https://doi.org/10.1186/s13046-024-03165-x.</p><p>Article CAS PubMed PubMed Central Google Scholar </p></li></ol><p>Download references<svg aria-hidden=\"true\" focusable=\"false\" height=\"16\" role=\"img\" width=\"16\"><use xlink:href=\"#icon-eds-i-download-medium\" xmlns:xlink=\"http://www.w3.org/1999/xlink\"></use></svg></p><h3>Authors and Affiliations</h3><ol><li><p>Department of Radiation Oncology, Shandong First Medical University and Shandong Academy of Medical Sciences, Shandong Cancer Hospital and Institute, Jinan, Shandong, China</p><p>Kewen He</p></li><li><p>Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA</p><p>Kewen He, Nahum Puebla-Osorio, Hampartsoum B. Barsoumian, Duygu Sezen, Zahid Rafq, Thomas S. Riad, Yun Hu, Ailing Huang, Tifany A. Voss, Claudia S. Kettlun Leyton, Lily Jae Schuda, Ethan Hsu, Maria-Angelica Cortez & James W. Welsh</p></li><li><p>Department of Radiation Oncology, Koç University School of Medicine, Istanbul, Turkey</p><p>Duygu Sezen</p></li><li><p>Mural Oncology PLC, Waltham, MA, USA</p><p>Joshua Heiber</p></li></ol><span>Authors</span><ol><li><span>Kewen He</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Nahum Puebla-Osorio</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Hampartsoum B. Barsoumian</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Duygu Sezen</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"62 1","pages":""},"PeriodicalIF":11.3,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142208604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Membrane RRM2-positive cells represent a malignant population with cancer stem cell features in intrahepatic cholangiocarcinoma.","authors":"Yongzhi Zhao, Shuting Xue, Danduo Wei, Jianjuan Zhang, Nachuan Zhang, Liping Mao, Niya Liu, Lei Zhao, Jianing Yan, Yifan Wang, Xiujun Cai, Saiyong Zhu, Stephanie Roessler, Junfang Ji","doi":"10.1186/s13046-024-03174-w","DOIUrl":"10.1186/s13046-024-03174-w","url":null,"abstract":"<p><strong>Background: </strong>Intrahepatic cholangiocarcinoma (iCCA) is one of the most lethal malignancies and highly heterogeneous. We thus aimed to identify and characterize iCCA cell subpopulations with severe malignant features.</p><p><strong>Methods: </strong>Transcriptomic datasets from three independent iCCA cohorts (iCCA cohorts 1-3, n = 382) and formalin-fixed and paraffin-embedded tissues from iCCA cohort 4 (n = 31) were used. An unbiased global screening strategy was established, including the transcriptome analysis with the activated malignancy/stemness (MS) signature in iCCA cohorts 1-3 and the mass spectrometry analysis of the sorted stemness reporter-positive iCCA cells. A group of cellular assays and subcutaneous tumor xenograft assay were performed to investigate functional roles of the candidate. Immunohistochemistry was performed in iCCA cohort 4 to examine the expression and localization of the candidate. Molecular and biochemical assays were used to evaluate the membrane localization and functional protein domains of the candidate. Cell sorting was performed and the corresponding cellular molecular assays were utilized to examine cancer stem cell features of the sorted cells.</p><p><strong>Results: </strong>The unbiased global screening identified RRM2 as the top candidate, with a significantly higher level in iCCA patients with the MS signature activation and in iCCA cells positive for the stemness reporter. Consistently, silencing RRM2 significantly suppressed iCCA malignancy phenotypes both in vitro and in vivo. Moreover, immunohistochemistry in tumor tissues of iCCA patients revealed an unreported cell membrane localization of RRM2, in contrast to its usual cytoplasmic localization. RRM2 cell membrane localization was then confirmed in iCCA cells via immunofluorescence with or without cell membrane permeabilization, cell fractionation assay and cell surface biotinylation assay. Meanwhile, an unclassical signal peptide and a transmembrane domain of RRM2 were revealed experimentally. They were essential for RRM2 trafficking to cell membrane via the conventional endoplasmic reticulum (ER)-Golgi secretory pathway. Furthermore, the membrane RRM2-positive iCCA cells were successfully sorted. These cells possessed significant cancer stem cell malignant features including cell differentiation ability, self-renewal ability, tumor initiation ability, and stemness/malignancy gene signatures. Patients with membrane RRM2-positive iCCA cells had poor prognosis.</p><p><strong>Conclusions: </strong>RRM2 had an alternative cell membrane localization. The membrane RRM2-positive iCCA cells represented a malignant subpopulation with cancer stem cell features.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"43 1","pages":"255"},"PeriodicalIF":11.4,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11378576/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142146733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HSF1 is a prognostic determinant and therapeutic target in intrahepatic cholangiocarcinoma.","authors":"Antonio Cigliano, Isabella Gigante, Marina Serra, Gianpaolo Vidili, Maria M Simile, Sara Steinmann, Francesco Urigo, Eleonora Cossu, Giovanni M Pes, Maria P Dore, Silvia Ribback, Egle P Milia, Elena Pizzuto, Serena Mancarella, Li Che, Rosa M Pascale, Gianluigi Giannelli, Matthias Evert, Xin Chen, Diego F Calvisi","doi":"10.1186/s13046-024-03177-7","DOIUrl":"10.1186/s13046-024-03177-7","url":null,"abstract":"<p><strong>Background: </strong>Intrahepatic cholangiocarcinoma (iCCA) is a lethal primary liver tumor characterized by clinical aggressiveness, poor prognosis, and scarce therapeutic possibilities. Therefore, new treatments are urgently needed to render this disease curable. Since cumulating evidence supports the oncogenic properties of the Heat Shock Factor 1 (HSF1) transcription factor in various cancer types, we investigated its pathogenetic and therapeutic relevance in iCCA.</p><p><strong>Methods: </strong>Levels of HSF1 were evaluated in a vast collection of iCCA specimens. The effects of HSF1 inactivation on iCCA development in vivo were investigated using three established oncogene-driven iCCA mouse models. In addition, the impact of HSF1 suppression on tumor cells and tumor stroma was assessed in iCCA cell lines, human iCCA cancer-associated fibroblasts (hCAFs), and patient-derived organoids.</p><p><strong>Results: </strong>Human preinvasive, invasive, and metastatic iCCAs displayed widespread HSF1 upregulation, which was associated with a dismal prognosis of the patients. In addition, hydrodynamic injection of a dominant-negative form of HSF1 (HSF1dn), which suppresses HSF1 activity, significantly delayed cholangiocarcinogenesis in AKT/NICD, AKT/YAP, and AKT/TAZ mice. In iCCA cell lines, iCCA hCAFs, and patient-derived organoids, administration of the HSF1 inhibitor KRIBB-11 significantly reduced proliferation and induced apoptosis. Cell death was profoundly augmented by concomitant administration of the Bcl-xL/Bcl2/Bcl-w inhibitor ABT-263. Furthermore, KRIBB-11 reduced mitochondrial bioenergetics and glycolysis of iCCA cells.</p><p><strong>Conclusions: </strong>The present data underscore the critical pathogenetic, prognostic, and therapeutic role of HSF1 in cholangiocarcinogenesis.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"43 1","pages":"253"},"PeriodicalIF":11.4,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11378393/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142146732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Why make it if you can take it: review on extracellular cholesterol uptake and its importance in breast and ovarian cancers.","authors":"Anna Røssberg Lauridsen, Aikaterini Skorda, Nuggi Ingholt Winther, Marie Lund Bay, Tuula Kallunki","doi":"10.1186/s13046-024-03172-y","DOIUrl":"10.1186/s13046-024-03172-y","url":null,"abstract":"<p><p>Cholesterol homeostasis is essential for healthy mammalian cells and dysregulation of cholesterol metabolism contributes to the pathogenesis of various diseases including cancer. Cancer cells are dependent on cholesterol. Malignant progression is associated with high cellular demand for cholesterol, and extracellular cholesterol uptake is often elevated in cancer cell to meet its metabolic needs. Tumors take up cholesterol from the blood stream through their vasculature. Breast cancer grows in, and ovarian cancer metastasizes into fatty tissue that provides them with an additional source of cholesterol. High levels of extracellular cholesterol are beneficial for tumors whose cancer cells master the uptake of extracellular cholesterol. In this review we concentrate on cholesterol uptake mechanisms, receptor-mediated endocytosis and macropinocytosis, and how these are utilized and manipulated by cancer cells to overcome their possible intrinsic or pharmacological limitations in cholesterol synthesis. We focus especially on the involvement of lysosomes in cholesterol uptake. Identifying the vulnerabilities of cholesterol metabolism and manipulating them could provide novel efficient therapeutic strategies for treatment of cancers that manifest dependency for extracellular cholesterol.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"43 1","pages":"254"},"PeriodicalIF":11.4,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11378638/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142146734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The dual role of POSTN in maintaining glioblastoma stem cells and the immunosuppressive phenotype of microglia in glioblastoma.","authors":"Hao Wang, Lin Yao, Jinming Chen, Yanyan Li, Zuopeng Su, Yongsheng Liu, Wen Li, Yun Xiong, Heyang Gao, Xiao Zhang, Youxin Zhou","doi":"10.1186/s13046-024-03175-9","DOIUrl":"10.1186/s13046-024-03175-9","url":null,"abstract":"<p><strong>Background: </strong>Glioblastoma (GBM) is an immunosuppressive, universally lethal cancer driven by glioblastoma stem cells (GSCs). The interplay between GSCs and immunosuppressive microglia plays crucial roles in promoting the malignant growth of GBM; however, the molecular mechanisms underlying this crosstalk are unclear. This study aimed to investigate the role of POSTN in maintaining GSCs and the immunosuppressive phenotype of microglia.</p><p><strong>Methods: </strong>The expression of POSTN in GBM was identified via immunohistochemistry, quantitative real-time PCR, and immunoblotting. Tumorsphere formation assay, Cell Counting Kit-8 assay and immunofluorescence were used to determine the key role of POSTN in GSC maintenance. ChIP-seq and ChIP-PCR were conducted to confirm the binding sequences of β-catenin in the promoter region of FOSL1. Transwell migration assays, developmental and functional analyses of CD4⁺ T cells, CFSE staining and analysis, enzyme-linked immunosorbent assays and apoptosis detection tests were used to determine the key role of POSTN in maintaining the immunosuppressive phenotype of microglia and thereby promoting the immunosuppressive tumor microenvironment. Furthermore, the effects of POSTN on GSC maintenance and the immunosuppressive phenotype of microglia were investigated in a patient-derived xenograft model and orthotopic glioma mouse model, respectively.</p><p><strong>Results: </strong>Our findings revealed that POSTN secreted from GSCs promotes GSC self-renewal and tumor growth via activation of the αVβ3/PI3K/AKT/β-catenin/FOSL1 pathway. In addition to its intrinsic effects on GSCs, POSTN can recruit microglia and upregulate CD70 expression in microglia through the αVβ3/PI3K/AKT/NFκB pathway, which in turn promotes Treg development and functionality and supports the formation of an immunosuppressive tumor microenvironment. In both in vitro models and orthotopic mouse models of GBM, POSTN depletion disrupted GSC maintenance, decreased the recruitment of immunosuppressive microglia and suppressed GBM growth.</p><p><strong>Conclusion: </strong>Our findings reveal that POSTN plays critical roles in maintaining GSCs and the immunosuppressive phenotype of microglia and provide a new therapeutic target for treating GBM.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"43 1","pages":"252"},"PeriodicalIF":11.4,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11373117/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142127216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multibiomarker panels in liquid biopsy for early detection of pancreatic cancer - a comprehensive review.","authors":"Kim-Lea Reese, Klaus Pantel, Daniel J Smit","doi":"10.1186/s13046-024-03166-w","DOIUrl":"10.1186/s13046-024-03166-w","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) is frequently detected in late stages, which leads to limited therapeutic options and a dismal overall survival rate. To date, no robust method for the detection of early-stage PDAC that can be used for targeted screening approaches is available. Liquid biopsy allows the minimally invasive collection of body fluids (typically peripheral blood) and the subsequent analysis of circulating tumor cells or tumor-associated molecules such as nucleic acids, proteins, or metabolites that may be useful for the early diagnosis of PDAC. Single biomarkers may lack sensitivity and/or specificity to reliably detect PDAC, while combinations of these circulating biomarkers in multimarker panels may improve the sensitivity and specificity of blood test-based diagnosis. In this narrative review, we present an overview of different liquid biopsy biomarkers for the early diagnosis of PDAC and discuss the validity of multimarker panels.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"43 1","pages":"250"},"PeriodicalIF":11.4,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11367781/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142114325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel engineered IL-2 Nemvaleukin alfa combined with PD1 checkpoint blockade enhances the systemic anti-tumor responses of radiation therapy.","authors":"Kewen He, Nahum Puebla-Osorio, Hampartsoum B Barsoumian, Duygu Sezen, Zahid Rafiq, Thomas S Riad, Yun Hu, Ailing Huang, Tiffany A Voss, Claudia S Kettlun Leyton, Lily Jae Schuda, Ethan Hsu, Joshua Heiber, Maria-Angelica Cortez, James W Welsh","doi":"10.1186/s13046-024-03165-x","DOIUrl":"10.1186/s13046-024-03165-x","url":null,"abstract":"<p><strong>Background: </strong>Combining interleukin-2 (IL-2) with radiotherapy (RT) and immune checkpoint blockade (ICB) has emerged as a promising approach to address ICB resistance. However, conventional IL-2 cytokine therapy faces constraints owing to its brief half-life and adverse effects. RDB 1462, the mouse ortholog of Nemvaleukin alfa, is an engineered IL-2 with an intermediate affinity that selectively stimulates antitumor CD8 T and NK cells while limiting regulatory T cell expansion. This study aimed to evaluate the antitumor activity and mechanism of action of the combination of RDB 1462, RT, and anti-PD1 in mouse tumor models.</p><p><strong>Methods: </strong>Two bilateral lung adenocarcinoma murine models were established using 344SQ-Parental and 344SQ anti-PD1-resistant cell lines. Primary tumors were treated with RT, and secondary tumors were observed for evidence of abscopal effects. We performed immune phenotyping by flow cytometry, analyzed 770 immune-related genes using NanoString, and performed T cell receptor (TCR) repertoire analysis. Serum pro-inflammatory cytokine markers were analyzed by 23-plex kit.</p><p><strong>Results: </strong>Compared to native IL-2 (RDB 1475), RDB 1462 demonstrated superior systemic antitumoral responses, attributable, at least in part, to augmented levels of CD4 and CD8 T cells with the latter. Our findings reveal substantial reductions in primary and secondary tumor volumes compared to monotherapy controls, with some variability observed among different dosing schedules of RDB 1462 combined with RT. Blood and tumor tissue-based flow cytometric phenotyping reveals an increase in effector memory CD8 and CD4 T cells and a decrease in immunosuppressive cells accompanied by a significant increase in IL-2, IFN-γ, and GM-CSF levels in the combination group. Transcriptomic profiling and TCR sequencing reveal favorable gene expression and T cell repertoire patterns with the dual combination. Furthermore, integrating anti-PD1 therapy with RT and RDB 1462 further reduced primary and secondary tumor volumes, prolonged survival, and decreased lung metastasis. Observations of immune cell profiles indicated that RT with escalating doses of RDB 1462 significantly reduced tumor growth and increased tumor-specific immune cell populations.</p><p><strong>Conclusion: </strong>The addition of Nemvaleukin therapy may enhance responses to RT alone and in combination with anti-PD1.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"43 1","pages":"251"},"PeriodicalIF":11.4,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11367833/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142114326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"USP36 promotes tumorigenesis and tamoxifen resistance in breast cancer by deubiquitinating and stabilizing ERα.","authors":"Ting Zhuang, Shuqing Zhang, Dongyi Liu, Zhongbo Li, Xin Li, Jiaoyan Li, Penghe Yang, Chenmiao Zhang, Jiayao Cui, Mingxi Fu, Fangyu Shen, Lei Yuan, Zhao Zhang, Peng Su, Jian Zhu, Huijie Yang","doi":"10.1186/s13046-024-03160-2","DOIUrl":"10.1186/s13046-024-03160-2","url":null,"abstract":"<p><strong>Background: </strong>Breast cancer is the most prevalent cancer in women globally. Over-activated estrogen receptor (ER) α signaling is considered the main factor in luminal breast cancers, which can be effectively managed with selective estrogen receptor modulators (SERMs) like tamoxifen. However, approximately 30-40% of ER + breast cancer cases are recurrent after tamoxifen therapy. This implies that the treatment of breast cancer is still hindered by resistance to tamoxifen. Recent studies have suggested that post-translational modifications of ERα play a significant role in endocrine resistance. The stability of both ERα protein and its transcriptome is regulated by a balance between E3 ubiquitin ligases and deubiquitinases. According to the current knowledge, approximately 100 deubiquitinases are encoded in the human genome, but it remains unclear which deubiquitinases play a critical role in estrogen signaling and endocrine resistance. Thus, decoding the key deubiquitinases that significantly impact estrogen signaling, including the control of ERα expression and stability, is critical for the improvement of breast cancer therapeutics.</p><p><strong>Methods: </strong>We used several ER positive breast cancer cell lines, DUB siRNA library screening, xenograft models, endocrine-resistant (ERα-Y537S) model and performed immunoblotting, real time PCR, RNA sequencing, immunofluorescence, and luciferase activity assay to investigate the function of USP36 in breast cancer progression and tamoxifen resistance.</p><p><strong>Results: </strong>In this study, we identify Ubiquitin-specific peptidase 36 (USP36) as a key deubiquitinase involved in ERα signaling and the advancement of breast cancer by deubiquitinases siRNA library screening. In vitro and in vivo studies showed that USP36, but not its catalytically inactive mutant (C131A), could promote breast cancer progression through ERα signaling. Conversely, silencing USP36 inhibited tumorigenesis. In models resistant to endocrine therapy, silencing USP36 destabilized the resistant form of ERα (Y537S) and restored sensitivity to tamoxifen. Molecular studies indicated that USP36 inhibited K48-linked polyubiquitination of ERα and enhanced the ERα transcriptome. It is interesting to note that our results suggest USP36 as a novel biomarker for treatment of breast cancer.</p><p><strong>Conclusion: </strong>Our study revealed the possibility that inhibiting USP36 combined with tamoxifen could provide a potential therapy for breast cancer.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"43 1","pages":"249"},"PeriodicalIF":11.4,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11365244/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142114329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}