Journal of Experimental & Clinical Cancer Research最新文献

{"title":"Cancer-associated fibroblasts, tumor and radiotherapy: interactions in the tumor micro-environment.","authors":"Kris T P M Raaijmakers, Gosse J Adema, Johan Bussink, Marleen Ansems","doi":"10.1186/s13046-024-03251-0","DOIUrl":"https://doi.org/10.1186/s13046-024-03251-0","url":null,"abstract":"<p><p>Cancer-associated fibroblasts (CAFs) represent a group of genotypically non-malignant stromal cells in the tumor micro-environment (TME) of solid tumors that encompasses up to 80% of the tumor volume. Even though the phenotypic diversity and plasticity of CAFs complicates research, it is well-established that CAFs can affect many aspects of tumor progression, including growth, invasion and therapy resistance. Although anti-tumorigenic properties of CAFs have been reported, the majority of research demonstrates a pro-tumorigenic role for CAFs via (in)direct signaling to cancer cells, immunomodulation and extracellular matrix (ECM) remodeling. Following harsh therapeutic approaches such as radio- and/or chemotherapy, CAFs do not die but rather become senescent. Upon conversion towards senescence, many pro-tumorigenic characteristics of CAFs are preserved or even amplified. Senescent CAFs continue to promote tumor cell therapy resistance, modulate the ECM, stimulate epithelial-to-mesenchymal transition (EMT) and induce immunosuppression. Consequently, CAFs play a significant role in tumor cell survival, relapse and potentially malignant transformation of surviving cancer cells following therapy. Modulating CAF functioning in the TME therefore is a critical area of research. Proposed strategies to enhance therapeutic efficacy include reverting senescent CAFs towards a quiescent phenotype or selectively targeting (non-)senescent CAFs. In this review, we discuss CAF functioning in the TME before and during therapy, with a strong focus on radiotherapy. In the future, CAF functioning in the therapeutic TME should be taken into account when designing treatment plans and new therapeutic approaches.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"43 1","pages":"323"},"PeriodicalIF":11.4,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142856582","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":"SNAI1 promotes epithelial-mesenchymal transition and maintains cancer stem cell-like properties in thymic epithelial tumors through the PIK3R2/p-EphA2 Axis.","authors":"Haoran E, Lei Zhang, Zhenhua Yang, Long Xu, Tao Wang, Junhong Guo, Lang Xia, Juemin Yu, Heyong Wang, Yunlang She, Junqi Wu, Yue Zhao, Chang Chen, Deping Zhao","doi":"10.1186/s13046-024-03243-0","DOIUrl":"https://doi.org/10.1186/s13046-024-03243-0","url":null,"abstract":"<p><strong>Background: </strong>Thymic epithelial tumors (TETs) are infrequent malignancies that arise from the anterior mediastinum. Therapeutic options for TETs, especially thymic carcinoma (TC), remain relatively constrained. This study aims to investigate the oncogenic hub gene and its underlying mechanisms in TETs, as well as to identify potential therapeutic targets.</p><p><strong>Methods: </strong>Weighted gene co-expression network analysis (WGCNA) and differential gene expression (DEG) analysis were utilized to identify significant oncogenes using The Cancer Genome Atlas (TCGA) database. LASSO logistic regression analysis was performed to assess the association between hub genes and clinical parameters. The influence of the hub gene on promoting epithelial-mesenchymal transition (EMT), tumor progression, and regulating cancer stem cell-like properties was assessed both in vitro and in vivo. Single-cell RNA sequencing (scRNA-seq) was utilized to analyze the alterations in the tumor and its microenvironment following the administration of the hub gene's inhibitor. Multiplex immunohistochemistry (mIHC) was employed to validate the results. The potential mechanism was further elucidated through the utilization of Cleavage Under Targets and Tagmentation (CUT&Tag), RNA-sequencing, chromatin immunoprecipitation (ChIP), CUT&RUN, luciferase reporter assay, co-immunoprecipitation (Co-IP), mass spectrometry (MS) and phosphoproteomic assays.</p><p><strong>Results: </strong>SNAI1 was identified as a hub transcription factor for TETs, and its positive correlation with the invasiveness of the disease was confirmed. Subsequent experiments revealed that the upregulation of SNAI1 augmented the migration, invasion, and EMT of TET cell lines. Furthermore, we observed that the overexpression of SNAI1 sustained cancer stem cell-like properties. ScRNA-seq demonstrated that the use of a SNAI1 inhibitor inhibited the transition of macrophages from M1 to M2 phenotype, a finding further validated by multiplex immunohistochemistry (mIHC). Phosphoinositide-3-kinase regulatory subunit 2 (PIK3R2) was identified as one of the downstream targets of SNAI1 through CUT&Tag and RNA-sequencing, a finding validated by ChIP-qPCR, CUT&RUN-qPCR, luciferase reporter and immunofluorescence assays. Co-IP, MS and phosphoproteomic assays further confirmed that PIK3R2 directly interacted with phosphorylated EphA2 (p-EphA2), facilitating downstream GSK3β/β-catenin signaling pathway.</p><p><strong>Conclusion: </strong>The tumorigenic role of SNAI1 through the PIK3R2/p-EphA2 axis was preliminarily validated in TETs. A potential therapeutic strategy for TETs may involve the inhibition of SNAI1.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"43 1","pages":"324"},"PeriodicalIF":11.4,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142866103","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":"FOLR2⁺ macrophage depletion from intestinal metaplasia to early gastric cancer: single-cell sequencing insight into gastric cancer progression.","authors":"Yuxin He, Jiayu Wang, Zilin Deng, Huang Feng, Mingzhan Du, Deqing Zhang, Guangbo Zhang, Tongguo Shi, Weichang Chen","doi":"10.1186/s13046-024-03245-y","DOIUrl":"https://doi.org/10.1186/s13046-024-03245-y","url":null,"abstract":"<p><strong>Background: </strong>The immune landscape associated with different subtypes of intestinal metaplasia (IM) and early gastric cancer (EGC) remains unclear. This study aimed to investigate the immune landscape of complete intestinal metaplasia (CIM), incomplete intestinal metaplasia (IIM), and EGC, as well as the underlying mechanisms of EGC progression.</p><p><strong>Methods: </strong>Gastric biopsy samples were collected from five patients with CIM, six patients with IIM, and four patients with EGC, followed by single-cell RNA sequencing. Multiplex immunohistochemical staining was employed to validate the samples from the aforementioned patients. To elucidate the potential mechanisms involved, in vitro coculture experiments were conducted using FOLR2⁺/FOLR2^- macrophages and CD8⁺ T cells. Flow cytometry was utilized to investigate the biological functions of FOLR2⁺ macrophages in the progression of EGC.</p><p><strong>Results: </strong>Five subpopulations of macrophages were identified in CIM, IIM and EGC samples. FOLR2⁺ macrophages possess antitumor immune potential, and the proportion of FOLR2⁺ macrophage gradually decreased from the CIM stage to the IIM and EGC stages. FOLR2⁺ macrophages were significantly positively correlated with CD8⁺ T cells and activated the cytotoxicity of CD8⁺ T cells via antigen cross-presentation. Additionally, during the progression of EGC, epithelial cells progressively upregulated APP expression, thus inducing necroptosis of FOLR2⁺ macrophages via the APP‒TNFRSF21 axis.</p><p><strong>Conclusions: </strong>Our work provides an understanding of the potential mechanisms underlying the malignant transformation of IM mediated by FOLR2⁺ macrophages.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"43 1","pages":"326"},"PeriodicalIF":11.4,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142866097","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":"Pathogenic mitochondrial DNA variants are associated with response to anti-VEGF therapy in ovarian cancer PDX models.","authors":"Daniele Boso, Ilaria Piga, Chiara Trento, Sonia Minuzzo, Eleonora Angi, Luisa Iommarini, Elisabetta Lazzarini, Leonardo Caporali, Claudio Fiorini, Luigi D'Angelo, Monica De Luise, Ivana Kurelac, Matteo Fassan, Anna Maria Porcelli, Filippo Navaglia, Ilaria Billato, Giovanni Esposito, Giuseppe Gasparre, Chiara Romualdi, Stefano Indraccolo","doi":"10.1186/s13046-024-03239-w","DOIUrl":"https://doi.org/10.1186/s13046-024-03239-w","url":null,"abstract":"<p><strong>Background: </strong>Mitochondrial DNA (mtDNA) pathogenic variants have been reported in several solid tumors including ovarian cancer (OC), the most lethal gynecologic malignancy, and raised interest as they potentially induce mitochondrial dysfunction and rewiring of cellular metabolism. Despite advances in recent years, functional characterization of mtDNA variants in cancer and their possible modulation of drug response remain largely uncharted.</p><p><strong>Methods: </strong>Here, we characterized mtDNA variants in OC patient derived xenografts (PDX) and investigated their impact on cancer cells at multiple levels.</p><p><strong>Results: </strong>Genetic analysis revealed that mtDNA variants predicted as pathogenic, mainly involving complex I and IV genes, were present in all but one PDX (n = 20) at different levels of heteroplasmy, including 7 PDXs with homoplasmic variants. Functional analyses demonstrated that pathogenic mtDNA variants impacted on respiratory complexes activity and subunits abundance as well as on mitochondrial morphology. Moreover, PDX cells bearing homoplasmic mtDNA variants behaved as glucose-addicted and could barely survive glucose starvation in vitro. RNA-seq analysis indicated that mtDNA mutated (heteroplasmy > 50%) PDXs were endowed with upregulated glycolysis and other pathways connected with cancer metabolism. These findings led us to investigate whether pathogenic mtDNA variants correlated with response to anti-VEGF therapy, since the latter was shown to reduce glucose availability in tumors. Strikingly, PDXs bearing homoplasmic pathogenic mtDNA variants associated with improved survival upon anti-VEGF treatment in mice, compared with mtDNA wild type or low heteroplasmy PDXs.</p><p><strong>Conclusions: </strong>These results hint at mtDNA variants as potential biomarkers of response to antiangiogenic drugs.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"43 1","pages":"325"},"PeriodicalIF":11.4,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142866100","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":"Molecular insights unlocking therapeutic potential for multiple myeloma and bone disease management.","authors":"Tiziana Bruno, Valeria Catena, Giovanni Blandino, Maurizio Fanciulli, Silvia Di Agostino","doi":"10.1186/s13046-024-03248-9","DOIUrl":"https://doi.org/10.1186/s13046-024-03248-9","url":null,"abstract":"<p><p>Multiple myeloma (MM), a hematologic malignancy characterized by the clonal expansion of plasma cells within the bone marrow, is associated with severe health complications, including osteolytic bone lesions that significantly increase the risk of fractures, leading to higher morbidity and mortality rates. One intriguing protein in this context is the RNA polymerase binding factor Che-1/AATF (Che-1), which has emerged as a potential player in the survival and proliferation of myeloma cells. Hippo pathway has been shown to be an important mediator of oncogenesis in solid tumors, especially for its role in shaping a tumor microenvironment favorable to cancer maintenance and spread. The Hippo pathway is also implicated in the pathogenesis of the osteolytic lesions that occurs in MM, since it deregulates the activities of mesenchymal populations of the bone matrix. In this commentary we wish to highlight some new molecular aspects elucidated in the paper by Bruno et al. regarding the proliferation of MM and the onset of bone lesions [Leukemia 38:877-882, 1]. A series of recent findings has revealed a crosstalk between the RNA polymerase binding factor Che-1 and the HIPPO downstream co-transcriptional factor TAZ, bringing to light new emerging molecular targets in MM to limit the development of bone lesions.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"43 1","pages":"322"},"PeriodicalIF":11.4,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142856526","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":"The oncogenic lncRNA MIR503HG suppresses cellular senescence counteracting supraphysiological androgen treatment in prostate cancer.","authors":"Julia Kallenbach, Mahdi Rasa, Mehdi Heidari Horestani, Golnaz Atri Roozbahani, Katrin Schindler, Aria Baniahmad","doi":"10.1186/s13046-024-03233-2","DOIUrl":"https://doi.org/10.1186/s13046-024-03233-2","url":null,"abstract":"<p><strong>Background: </strong>The androgen receptor (AR), a ligand-dependent transcription factor, plays a key role in regulating prostate cancer (PCa) growth. The novel bipolar androgen therapy (BAT) uses supraphysiological androgen levels (SAL) that suppresses growth of PCa cells and induces cellular senescence functioning as a tumor suppressive mechanism. The role of long non-coding RNAs (lncRNAs) in the regulation of SAL-mediated senescence remains unclear. This study focuses on the SAL-repressed lncRNA MIR503HG, examining its involvement in androgen-controlled cellular senescence in PCa.</p><p><strong>Methods: </strong>Transcriptome and ChIP-Seq analyses of PCa cells treated with SAL were conducted to identify SAL-downregulated lncRNAs. Expression levels of MIR503HG were analyzed in 691 PCa patient tumor samples, mouse xenograft tumors and treated patient-derived xenografts. Knockdown and overexpression experiments were performed to assess the role of MIR503HG in cellular senescence and proliferation using senescence-associated β-Gal assays, qRT-PCRs, and Western blotting. The activity of MIR503HG was confirmed in PCa tumor spheroids.</p><p><strong>Results: </strong>A large patient cohort analysis shows that MIR503HG is overexpressed in metastatic PCa and is associated with reduced patient survival, indicating its potential oncogenic role. Notably, SAL treatment suppresses MIR503HG expression across four different PCa cell lines and patient-derived xenografts but interestingly not in the senescence-resistant LNCaP Abl EnzaR cells. Functional assays reveal that MIR503HG promotes PCa cell proliferation and inhibits SAL-mediated cellular senescence, partly through miR-424-5p. Mechanistic analyses and rescue experiments indicate that MIR503HG regulates the AKT-p70S6K and the p15^INK4b-pRb pathway. Reduced expression of MIR503HG by SAL or knockdown resulted in decreased BRCA2 levels suggesting a role in DNA repair mechanisms and potential implications for PARP inhibitor sensitivity by SAL used in BAT clinical trial.</p><p><strong>Conclusions: </strong>The lncRNA MIR503HG acts as an oncogenic regulator in PCa by repressing cellular senescence. SAL-induced suppression of MIR503HG enhances the tumor-suppressive effects of AR signaling, suggesting that MIR503HG could serve as a biomarker for BAT responsiveness and as a target for combination therapies with PARP inhibitors.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"43 1","pages":"321"},"PeriodicalIF":11.4,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142830752","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: CD147 promotes collective invasion through cathepsin B in hepatocellular carcinoma.","authors":"Shi-Jie Wang, Dong Chao, Wei Wei, Gang Nan, Jia-Yue Li, Fen-Ling Liu, Ling Li, Jian-Li Jiang, Hong-Yong Cui, Zhi-Nan Chen","doi":"10.1186/s13046-024-03246-x","DOIUrl":"https://doi.org/10.1186/s13046-024-03246-x","url":null,"abstract":"","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"43 1","pages":"320"},"PeriodicalIF":11.4,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142830751","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":"Cryoablation-induced neutrophil Ca²⁺ elevation and NET formation exacerbate immune escape in colorectal cancer liver metastasis.","authors":"Hongtong Tan, Yiquan Jiang, Lujun Shen, Gulijiayina Nuerhashi, Chunyong Wen, Ling Gu, Yujia Wang, Han Qi, Fei Cao, Tao Huang, Ying Liu, Weining Xie, Wuguo Deng, Weijun Fan","doi":"10.1186/s13046-024-03244-z","DOIUrl":"10.1186/s13046-024-03244-z","url":null,"abstract":"<p><strong>Background: </strong>Liver metastasis poses a significant barrier to effective immunotherapy in patients with colorectal cancer. Cryoablation has emerged as a vital supplementary therapeutic approach for these patients. However, its impact on the tumor microenvironment following the ablation of liver metastases remains unclear.</p><p><strong>Methods: </strong>We acquired multi-omics time-series data at 1 day, 5 days, and 14 days post-cryoablation, based on tumor and peripheral blood samples from clinical patients, cell co-culture models, and a liver metastases mouse model built on the MC38 cell line in C57BL/6 J mice. This dataset included single-cell transcriptomic sequencing, bulk tissue transcriptomic sequencing, 4D-Label-Free proteomics, flow cytometry data, western blot data, and histological immunofluorescence staining of pathological specimens.</p><p><strong>Results: </strong>We found that a neutrophil-related inflammatory state persisted for at least 14 days post-cryoablation. During this period, neutrophils underwent phenotypic changes, shifting from the N1 to the N2 type. Cryoablation also caused a significant increase in intracellular Ca²⁺ concentration in neutrophils, which triggered the formation of PAD4-dependent neutrophil extracellular traps (NETs), further promoting immune evasion. Moreover, animal studies demonstrated that depleting or inhibiting the CXCL2-CXCR2 signaling axis within neutrophils, or degrading NETs, could effectively restore the host's anti-tumor immune response.</p><p><strong>Conclusions: </strong>These findings underscore the critical role of neutrophils and their NETs in immune escape following cryoablation. Targeting the CXCL2-CXCR2-Ca²⁺-PAD4 axis could enhance the therapeutic response to PD-1 antibodies, providing a potential strategy to improve treatment outcomes for colorectal cancer with liver metastases.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"43 1","pages":"319"},"PeriodicalIF":11.4,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11626751/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142796376","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":"Inhibition of the chemokine receptors CXCR1 and CXCR2 synergizes with docetaxel for effective tumor control and remodeling of the immune microenvironment of HPV-negative head and neck cancer models.","authors":"Lucas A Horn, Hanne Lind, Kristen Fousek, Haiyan Qin, Nika Rajabian, Shantel Angstadt, Nicole Hsiao-Sanchez, Miriam M Medina-Enriquez, Marcus D Kelly, Clint T Allen, Sarah M Hammoudeh, Roberto Weigert, Dean Y Maeda, John A Zebala, Claudia Palena","doi":"10.1186/s13046-024-03240-3","DOIUrl":"10.1186/s13046-024-03240-3","url":null,"abstract":"<p><strong>Background: </strong>Relapsed head and neck squamous cell carcinoma (HNSCC) unrelated to HPV infection carries a poor prognosis. Novel approaches are needed to improve the clinical outcome and prolong survival in this patient population which has poor long-term responses to immune checkpoint blockade. This study evaluated the chemokine receptors CXCR1 and CXCR2 as potential novel targets for the treatment of HPV-negative HNSCC.</p><p><strong>Methods: </strong>Expression of IL-8, CXCR1, and CXCR2 was investigated in HNSCC tissues and human cell line models. Inhibition of CXCR1/2 with the clinical stage, small molecule inhibitor, SX-682, was evaluated in vitro and in vivo using human xenografts and murine models of HNSCC, both as a monotherapy and in combination with the taxane chemotherapy, docetaxel.</p><p><strong>Results: </strong>High levels of IL-8, CXCR1, and CXCR2 expression were observed in HPV-negative compared to HPV-positive HNSCC tumors or cell lines. Treatment of HPV-negative HNSCC cell lines in vitro with SX-682 sensitized the tumor cells to the cytotoxic activity of docetaxel. In vivo, treatment of HNSCC xenograft models with the combination of SX-682 plus docetaxel led to strong anti-tumor control resulting in tumor cures. This phenomenon was associated with an increase of microRNA-200c and a decreased expression of its target, tubulin beta-3, a protein involved in resistance to microtubule-targeting chemotherapies. In vivo treatment of a murine syngeneic model of HNSCC with SX-682 plus docetaxel led to potent anti-tumor efficacy through a simultaneous decrease in suppressive CXCR2⁺ polymorphonuclear, myeloid-derived suppressor cells and an increase in cytotoxic CD8⁺ T cells in the combination therapy treated tumors compared to controls.</p><p><strong>Conclusions: </strong>This study reports, for the first time, mechanistic findings through which the combination of CXCR1/2 inhibition and docetaxel chemotherapy exhibits synergy in models of HPV-negative HNSCC. These findings provide rationale for the use of this novel combination approach to treat HPV-negative HNSCC patients and for future combination studies of CXCR1/2 inhibition, docetaxel, and immune-based therapies.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"43 1","pages":"318"},"PeriodicalIF":11.4,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619435/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142787553","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":"Receptor tyrosine kinase inhibition leads to regression of acral melanoma by targeting the tumor microenvironment.","authors":"Eric A Smith, Rachel L Belote, Nelly M Cruz, Tarek E Moustafa, Carly A Becker, Amanda Jiang, Shukran Alizada, Anastasia Prokofyeva, Tsz Yin Chan, Tori A Seasor, Michael Balatico, Emilio Cortes-Sanchez, David H Lum, John R Hyngstrom, Hanlin Zeng, Dekker C Deacon, Allie H Grossmann, Richard M White, Thomas A Zangle, Robert L Judson-Torres","doi":"10.1186/s13046-024-03234-1","DOIUrl":"10.1186/s13046-024-03234-1","url":null,"abstract":"<p><strong>Background: </strong>Acral melanoma (AM) is an aggressive melanoma variant that arises from palmar, plantar, and nail unit melanocytes. Compared to non-acral cutaneous melanoma (CM), AM is biologically distinct, has an equal incidence across genetic ancestries, typically presents in advanced stage disease, is less responsive to therapy, and has an overall worse prognosis.</p><p><strong>Methods: </strong>An independent analysis of published sequencing data was performed to evaluate the frequency of receptor tyrosine kinase (RTK) ligands and adapter protein gene variants and expression. To target these genetic variants, a zebrafish acral melanoma model and preclinical patient-derived xenograft (PDX) mouse models were treated with a panel of RTK inhibitors. Residual PDX tumors were evaluated for changes in proliferation, vasculature, necrosis, and ferroptosis by histology and immunohistochemistry.</p><p><strong>Results: </strong>RTK ligands and adapter proteins are frequently amplified, translocated, and/or overexpressed in AM. Dual FGFR/VEGFR inhibitors decrease acral-analogous melanocyte proliferation and migration in zebrafish, and the potent pan-FGFR/VEGFR inhibitor, Lenvatinib, uniformly induces tumor regression in AM PDX tumors but only slows tumor growth in CM models. Unlike other multi-RTK inhibitors, Lenvatinib is not directly cytotoxic to dissociated AM PDX tumor cells and instead disrupts tumor architecture and vascular networks.</p><p><strong>Conclusion: </strong>Considering the great difficulty in establishing AM cell culture lines, these findings suggest that AM may be more sensitive to microenvironment perturbations than CM. In conclusion, dual FGFR/VEGFR inhibition may be a viable therapeutic strategy that targets the unique biology of AM.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"43 1","pages":"317"},"PeriodicalIF":11.4,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11613472/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774365","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}