Yang Chen, Hengyang Shen, Zhenling Wang, Changzhi Huang, Hongqiang Zhang, Yu Shao, Ying Tong, Lei Xu, Yunfei Lu, Zan Fu
{"title":"Recruitment of USP10 by GCS1 to deubiquitinate GRP78 promotes the progression of colorectal cancer via alleviating endoplasmic reticulum stress","authors":"Yang Chen, Hengyang Shen, Zhenling Wang, Changzhi Huang, Hongqiang Zhang, Yu Shao, Ying Tong, Lei Xu, Yunfei Lu, Zan Fu","doi":"10.1186/s13046-024-03176-8","DOIUrl":"https://doi.org/10.1186/s13046-024-03176-8","url":null,"abstract":"Long-term accumulation of misfolded proteins leads to endoplasmic reticulum (ER) stress in colorectal cancer (CRC). However, the precise pathways controlling the decision between survival and apoptosis in CRC are unclear. Therefore, in this study, we investigated the function and molecular mechanism of glucosidase I (GCS1) in regulating ER stress in CRC. A public database was used to confirm the expression level of GCS1 in CRC and normal tissues. Clinical samples from our center were used to confirm the mRNA and protein expression levels of GCS1. Cell proliferation, migration, invasion, and apoptosis assays revealed the biological role of GCS1. Immunohistochemical techniques were used to evaluate the expression of key proteins in subcutaneous implanted tumors in nude mice, which provided further evidence for the biological function of GCS1 in promoting cancer in vivo. The results of coimmunoprecipitation-mass spectrometry analysis and immunofluorescence colocalization analysis the interaction between GCS1 and GRP78. In addition, the mechanism of action of USP10, GRP78, and GCS1 at the post- translational level was investigated. Finally, a tissue microarray was used to examine the connection between GCS1 and GRP78 expression and intracellular localization of these proteins using immunohistochemistry and immunofluorescence. The experimental results revealed that GCS1 was substantially expressed in CRC, with higher expression indicating a worse prognosis. Thus, GCS1 can enhance the proliferation and metastasis while inhibiting the apoptosis of CRC cells both in vivo and in vitro. Mechanistically, GCS1 binds to GRP78, recruits USP10 for deubiquitination of GRP78 to promote its degradation, and decreases ER stress-mediated apoptosis, increasing CRC cell proliferation and metastasis. In summary, GCS1 stimulates CRC growth and migration and reduces ER stress-mediated apoptosis via USP10-mediated deubiquitination of GRP78. Our findings identify a possible therapeutic target for CRC.","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.3,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142208600","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":"STUB1-mediated K63-linked ubiquitination of UHRF1 promotes the progression of cholangiocarcinoma by maintaining DNA hypermethylation of PLA2G2A","authors":"Junsheng Chen, Da Wang, Guanhua Wu, Fei Xiong, Wenzheng Liu, Qi Wang, Yiyang Kuai, Wenhua Huang, Yongqiang Qi, Bing Wang, Yongjun Chen","doi":"10.1186/s13046-024-03186-6","DOIUrl":"https://doi.org/10.1186/s13046-024-03186-6","url":null,"abstract":"Cholangiocarcinoma (CCA) is a highly malignant tumor characterized by a lack of effective targeted therapeutic strategies. The protein UHRF1 plays a pivotal role in the preservation of DNA methylation and works synergistically with DNMT1. Posttranscriptional modifications (PTMs), such as ubiquitination, play indispensable roles in facilitating this process. Nevertheless, the specific PTMs that regulate UHRF1 in CCA remain unidentified. We confirmed the interaction between STUB1 and UHRF1 through mass spectrometry analysis. Furthermore, we investigated the underlying mechanisms of the STUB1-UHRF1/DNMT1 axis via co-IP experiments, denaturing IP ubiquitination experiments, nuclear‒cytoplasmic separation and immunofluorescence experiments. The downstream PLA2G2A gene, regulated by the STUB1-UHRF1/DNMT1 axis, was identified via RNA-seq. The negative regulatory mechanism of PLA2G2A was explored via bisulfite sequencing PCR (BSP) experiments to assess changes in promoter methylation. The roles of PLA2G2A and STUB1 in the proliferation, invasion, and migration of CCA cells were assessed using the CCK-8 assay, colony formation assay, Transwell assay, wound healing assay and xenograft mouse model. We evaluated the effects of STUB1/UHRF1 on cholangiocarcinoma by utilizing a primary CCA mouse model. This study revealed that STUB1 interacts with UHRF1, resulting in an increase in the K63-linked ubiquitination of UHRF1. Consequently, this facilitates the nuclear translocation of UHRF1 and enhances its binding affinity with DNMT1. The STUB1-UHRF1/DNMT1 axis led to increased DNA methylation of the PLA2G2A promoter, subsequently repressing its expression. Increased STUB1 expression in CCA was inversely correlated with tumor progression and overall survival. Conversely, PLA2G2A functions as a tumor suppressor in CCA by inhibiting cell proliferation, invasion and migration. These findings suggest that the STUB1-mediated ubiquitination of UHRF1 plays a pivotal role in tumor progression by epigenetically silencing PLA2G2A, underscoring the potential of STUB1 as both a prognostic biomarker and therapeutic target for CCA. ","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.3,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142208603","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":"Tumor-associated neutrophils upregulate Nectin2 expression, creating the immunosuppressive microenvironment in pancreatic ductal adenocarcinoma","authors":"Haizhen Luo, Naoki Ikenaga, Kohei Nakata, Nobuhiro Higashijima, Pingshan Zhong, Akihiro Kubo, Chenyi Wu, Chikanori Tsutsumi, Yuki Shimada, Masataka Hayashi, Koki Oyama, Satomi Date, Toshiya Abe, Noboru Ideno, Chika Iwamoto, Koji Shindo, Kenoki Ohuchida, Yoshinao Oda, Masafumi Nakamura","doi":"10.1186/s13046-024-03178-6","DOIUrl":"https://doi.org/10.1186/s13046-024-03178-6","url":null,"abstract":"Tumor-associated neutrophils (TANs) constitute an abundant component among tumor-infiltrating immune cells and have recently emerged as a critical player in pancreatic ductal adenocarcinoma (PDAC) progression. This study aimed to elucidate the pro-tumor mechanisms of TAN and identify a novel target for effective immunotherapy against PDAC. Microarray and cytokine array analyses were performed to identify the mechanisms underlying the function of TANs. Human and mouse TANs were obtained from differentiated HL-60 cells and orthotopically transplanted PDAC tumors, respectively. The interactions of TANs with cancer and cytotoxic T-cells were evaluated through in vitro co-culture and in vivo orthotopic or subcutaneous models. Single-cell transcriptomes from patients with PDAC were analyzed to validate the cellular findings. Increased neutrophil infiltration in the tumor microenvironment was associated with poor survival in patients with PDAC. TANs secreted abundant amounts of chemokine ligand 5 (CCL5), subsequently enhancing cancer cell migration and invasion. TANs subpopulations negatively correlated with cytotoxic CD8+ T-cell infiltration in PDAC and promoted T-cell dysfunction. TANs upregulated the membranous expression of Nectin2, which contributed to CD8+ T-cell exhaustion. Blocking Nectin2 improved CD8+ T-cell function and suppressed tumor progression in the mouse model. Single-cell analysis of human PDAC revealed two immunosuppressive TANs phenotypes: Nectin2+ TANs and OLR1+ TANs. Endoplasmic reticulum stress regulated the protumor activities in TANs. TANs enhance PDAC progression by secreting CCL5 and upregulating Nectin2. Targeting the immune checkpoint Nectin2 could represent a novel strategy to enhance immunotherapy efficacy in PDAC.","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.3,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142208601","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}
Jessica Wagner, C. Leah Kline, Lanlan Zhou, Vladimir Khazak, Wafik S. El-Deiry
{"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":null,"pages":null},"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}
Valentin Benboubker, George M. Ramzy, Sacha Jacobs, Patrycja Nowak-Sliwinska
{"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":null,"pages":null},"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}
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
{"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":null,"pages":null},"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}
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
{"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":null,"pages":null},"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}
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
{"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":null,"pages":null},"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}
Anna Røssberg Lauridsen, Aikaterini Skorda, Nuggi Ingholt Winther, Marie Lund Bay, Tuula Kallunki
{"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":null,"pages":null},"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<sup>+</sup> 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":null,"pages":null},"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}