Neoplasia最新文献

{"title":"The chemokine CX3CL1 promotes intraperitoneal tumour growth despite enhanced T-cell recruitment in ovarian cancer","authors":"Stefanie Seitz ,&nbsp;Tobias F. Dreyer ,&nbsp;Christoph Stange ,&nbsp;Katja Steiger ,&nbsp;Dirk Wohlleber ,&nbsp;Martina Anton ,&nbsp;Thuý An Pham ,&nbsp;Dominique Sauter-Peschke ,&nbsp;Ute Reuning ,&nbsp;Gabriele Multhoff ,&nbsp;Wilko Weichert ,&nbsp;Marion Kiechle ,&nbsp;Viktor Magdolen ,&nbsp;Holger Bronger","doi":"10.1016/j.neo.2025.101130","DOIUrl":"10.1016/j.neo.2025.101130","url":null,"abstract":"<div><div>T-cell recruiting chemokines are required for a successful immune intervention in ovarian cancer, and also for the efficacy of modern anticancer agents such as PARP inhibitors. The chemokine CX3CL1 recruits tumour-suppressive T-cells into solid tumours, but also mediates cell–cell adhesions, e.g. of tumour cells, through its membrane-bound form. So far, its role in ovarian cancer has only been rudimentarily addressed. We show that high CX3CL1 expression significantly correlates with worsened survival in human high-grade serous ovarian cancer (n=219). In preclinical ovarian cancer, CX3CL1 plays a dual role, as it enhances the adaptive anti-tumour response, but overall still promotes tumour growth, the latter as a feature of the intraperitoneal environment. Moreover, PARP inhibitors are able to increase CX3CL1 release from human ovarian cancer cells. Collectively, our study shows that CX3CL1 is a driver of intraperitoneal tumour growth in ovarian cancer, a feature that may compromise the anticancer effect of CX3CL1-inducing PARP inhibitors.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101130"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143042481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of TUBB3 as an immunotherapy target in lung cancer by genome wide in vivo CRISPR screening","authors":"Dan Zhao ,&nbsp;Ravindra Deshpande ,&nbsp;Kerui Wu ,&nbsp;Abhishek Tyagi ,&nbsp;Sambad Sharma ,&nbsp;Shih-Ying Wu ,&nbsp;Fei Xing ,&nbsp;Stacey O'Neill ,&nbsp;Jimmy Ruiz ,&nbsp;Feng Lyu ,&nbsp;Kounosuke Watabe","doi":"10.1016/j.neo.2024.101100","DOIUrl":"10.1016/j.neo.2024.101100","url":null,"abstract":"<div><div>Recent development of immune checkpoint inhibitors has revolutionized cancer immunotherapy. Although these drugs show dramatic effects on a subset of cancer patients, many other tumors are non-responsive and the pathological mechanism of the resistance is largely unknown. To identify genes underlying anti-PD-1 immunotherapy resistance using a systematic approach, we performed an <em>in vivo</em> genome wide CRISPR screening in lung cancer cells. We integrated our results with multi-omics clinical data and performed both <em>in vitro</em> and <em>in vivo</em> assays to evaluate the role of the top candidate in regulating cytotoxic T cell killing. We identified TUBB3 as a potential target to overcome the resistance and enhance the efficacy of anti-PD-1 immunotherapy. TUBB3 expression is upregulated in lung cancer patients, and its higher expression correlates with poorer patients’ survival. We found that TUBB3 expression was significantly elevated in the non-responders compared to responders in our patient cohort that received immunotherapies. Importantly, the results of our preclinical experiments showed that inhibition of TUBB3 with a small molecule inhibitor synergized with anti-PD-1 treatment and enhanced tumor cell killing by cytotoxic T cells. Consistently, anti-PD-1 resistant cells showed significantly higher expression of TUBB3; however, TUBB3 inhibition rendered the resistant cells more susceptible to T cell killing. Mechanistic studies revealed that blocking TUBB3 suppressed the expression of PD-L1 through the EMT-related SNAI1 gene. Our results provide a rationale for a novel combination therapy consisting of the TUBB3 inhibition and anti-PD-1 immunotherapy for lung cancer.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101100"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11699798/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142822733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “Tumorigenicity of IL-1α- and IL-1β-Deficient Fibrosarcoma Cells” [Neoplasia, Volume 10, Issue 6, June 2008, Pages 549–562]","authors":"Irina Nazarenko ,&nbsp;Rachid Marhaba ,&nbsp;Eli Reich ,&nbsp;Elena Voronov ,&nbsp;Mario Vitacolonna ,&nbsp;Dagmar Hildebrand ,&nbsp;Elena Elter ,&nbsp;Mohini Rajasagi ,&nbsp;Ron N. Apte ,&nbsp;Margot Zöller","doi":"10.1016/j.neo.2024.101087","DOIUrl":"10.1016/j.neo.2024.101087","url":null,"abstract":"","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101087"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11743877/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142904038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RUNX2 enhances bladder cancer progression by promoting glutamine metabolism","authors":"Zhigang Huang ,&nbsp;Bin Liu ,&nbsp;Xiaoju Li ,&nbsp;Chenghua Jin ,&nbsp;Quansen Hu ,&nbsp;Zhiwei Zhao ,&nbsp;Yimin Sun ,&nbsp;Qian Wang","doi":"10.1016/j.neo.2024.101120","DOIUrl":"10.1016/j.neo.2024.101120","url":null,"abstract":"<div><div>Bladder cancer is a prevalent malignancy within the urinary system. Prior research has suggested that glutamine metabolism plays a crucial role in driving bladder cancer progression. However, the precise molecular mechanism governing glutamine metabolism in bladder cancer is still inadequately understood. The research revealed a significant correlation between high levels of RUNX2 and SLC7A6 and advanced clinical stage, as well as poor prognosis, in bladder cancer patients. Furthermore, manipulating the levels of RUNX2 through overexpression or silencing demonstrated a significant impact on glutamine and bladder cancer progression. Mechanically, RUNX2 regulates the transcription of SLC7A6, resulting in enhanced glutamine metabolism and promoting the progression of bladder cancer. Overall, this research affirms the crucial function of RUNX2 as a key transcription factor to promoting glutamine and cancer development through modulation of SLC7A6. Targeting RUNX2 could represent a promising therapeutic approach for addressing aberrant glutamine metabolism in bladder cancer.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101120"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11743350/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142904041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical utility and predictive value of cerebrospinal fluid cell-free DNA profiling in non-small cell lung cancer patients with leptomeningeal metastasis","authors":"Sheng-Kai Liang ,&nbsp;Wei-Yu Liao ,&nbsp;Jin-Yuan Shih ,&nbsp;Chia-Lin Hsu ,&nbsp;Ching-Yao Yang ,&nbsp;Shang-Gin Wu ,&nbsp;Yen-Ting Lin ,&nbsp;Yueh-Feng Wen ,&nbsp;Lun-Che Chen ,&nbsp;Yen-Fu Chen ,&nbsp;Ya-Fang Chen ,&nbsp;Yen-Heng Lin ,&nbsp;Chong-Jen Yu","doi":"10.1016/j.neo.2024.101113","DOIUrl":"10.1016/j.neo.2024.101113","url":null,"abstract":"<div><div>Leptomeningeal metastasis (LM) is a challenging complication of non-small cell lung cancer (NSCLC). Cerebrospinal fluid (CSF) cell-free DNA (cfDNA) analysis using next-generation sequencing (NGS) offers insights into resistance mechanisms and potential treatment strategies. We conducted a study from February 2022 to April 2023 involving patients from five hospitals in Taiwan who had recurrent or advanced NSCLC with LM. These patients underwent CSF cfDNA analysis using a 118-gene targeted panel for NGS, with comprehensive clinical data collected. Among 25 enrolled patients, 22 (88.0 %) had <em>EGFR</em> mutations, while three (12.0 %) had <em>EML4-ALK</em> fusion, <em>KIF5B-RET</em> fusion, and <em>ERBB2</em> A775_G776insSVMA. CSF cfDNA sequencing of 27 samples (from 25 patients) all confirmed their original driver mutations. Of total cohort, 18 patients (72.0 %) underwent intrathecal pemetrexed (ITP), with a median survival time of 7.4 months (95.0 % confidence interval, 3.3–11.6) from the initiation of ITP to death. Among them, ten individuals (55.6 %) survived beyond 6 months. Notably, <em>MET</em> copy number gain (CNG) correlated significantly with survival time exceeding 6 months after ITP (<em>p</em> = 0.007). The coexistence of <em>EGFR</em> T790M and EGFR-independent resistance alterations was associated with shorter survival times after ITP, with a median survival time of 1.9 months compared to 9.9 months for those without <em>EGFR</em> T790M (<em>p</em> = 0.010). Our results highlight CSF cfDNA NGS's potential in LM resistance understanding and ITP efficacy prediction. <em>MET</em> CNG positively impacts survival for ITP recipients, whereas the coexistence <em>of EGFR</em> T790M and EGFR-independent resistance mechanisms leads to poor outcomes.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101113"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142878352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor-associated macrophages promote bladder cancer metastasis through the CCL20-CCR6 axis","authors":"Ryunosuke Nakagawa ,&nbsp;Kouji Izumi ,&nbsp;Kaoru Hiratsuka ,&nbsp;Takahiro Inaba ,&nbsp;Yoshiki Koketsu ,&nbsp;Ren Toriumi ,&nbsp;Shuhei Aoyama ,&nbsp;Taiki Kamijima ,&nbsp;Hiroshi Kano ,&nbsp;Tomoyuki Makino ,&nbsp;Renato Naito ,&nbsp;Suguru Kadomoto ,&nbsp;Hiroaki Iwamoto ,&nbsp;Hiroshi Yaegashi ,&nbsp;Shohei Kawaguchi ,&nbsp;Takahiro Nohara ,&nbsp;Kazuyoshi Shigehara ,&nbsp;Hiroki Nakata ,&nbsp;Wen-Jye Lin ,&nbsp;Atsushi Mizokami","doi":"10.1016/j.neo.2024.101103","DOIUrl":"10.1016/j.neo.2024.101103","url":null,"abstract":"<div><div>We investigated the mechanisms of interaction between bladder cancer (BC) cells and tumor-associated macrophages (TAMs). Coculturing BC cell lines (UMUC3 and T24) with macrophage-like cells differentiated from THP-1 into M2-like TAMs revealed a decrease in Cluster of Differentiation (CD) 68 expression and an increase in CD206 expression. This differentiation enhanced BC cell migration and invasion. Additionally, M2-like TAMs significantly increased the secretion of C–C motif chemokine ligand (CCL) 20, which promotes BC cell migration and invasion via the MEK/ERK signaling pathway through its paracrine effects. Coculturing with TAMs also elevated the expression of CC chemokine receptor (CCR) 6 in BC cells, indicating increased sensitivity to CCL20. Immunohistochemistry analysis of human BC tissues showed a significant correlation between CCR6 expression levels and BC prognosis. Inhibition of CCR6 reduced BC cell metastasis both in vitro and in vivo. Additionally, CXCL1 secretion from BC cells was found to contribute to the M2-like polarization of macrophages and to enhance BC cell migration and invasion through autocrine and indirect effects. In summary, CCL20 and CXCL1 play crucial roles in the interaction between BC cells and TAMs.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101103"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11729035/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142865675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"USP20 mediates malignant phenotypic changes in bladder cancer through direct interactions with YAP1","authors":"Wensun Chen ,&nbsp;Siqi Wu ,&nbsp;Yifan Chen ,&nbsp;Weijian Li ,&nbsp;Yiqing Cao ,&nbsp;Yingchun Liang ,&nbsp;Xiyu Dai ,&nbsp;Xinan Chen ,&nbsp;Yilin Chen ,&nbsp;Tian Chen ,&nbsp;Shenghua Liu ,&nbsp;Chen Yang ,&nbsp;Haowen Jiang","doi":"10.1016/j.neo.2024.101102","DOIUrl":"10.1016/j.neo.2024.101102","url":null,"abstract":"<div><div>Yes-associated protein 1 (YAP1) has attracted attention for its potential in the treatment of various types of malignancies. The Hippo-YAP1 axis is inhibited in bladder cancer (BC), which is a major driver of BC progression and oncogenesis. Hippo pathway activity is controlled by the phosphorylation cascade in the MST1/2-LATS1/2-YAP1 axis, in addition to other modifications such as ubiquitination of the Hippo pathway proteins through the co-regulation of E3 ligases and deubiquitinases. In this study, we identified USP20 as a Hippo/YAP1 pathway-related deubiquitinase using combined siRNA screening and a deubiquitinase overexpression assay. Further analysis revealed that USP20 directly regulated the expression of YAP1 and its downstream target genes connective tissue growth factor and cysteine-rich angiogenic inducer 61. A tissue microarray assay confirmed that USP20 expression was elevated in tumor tissues and correlated with YAP1 expression. Analysis of the underlying mechanisms revealed that USP20 directly interacted with the YAP1 protein and promoted its stability through inhibition of K48-linked poly-ubiquitination. Our findings revealed that USP20 serves as a deubiquitinase and regulates the Hippo-YAP1 pathway in BC.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101102"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11699748/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Kinomic profiling to predict sunitinib response of patients with metastasized clear cell Renal Cell Carcinoma","authors":"Jeannette C. Oosterwijk-Wakka ,&nbsp;Liesbeth Houkes ,&nbsp;Loes F.M. van der Zanden ,&nbsp;Lambertus A.L.M. Kiemeney ,&nbsp;Kerstin Junker ,&nbsp;Anne Y Warren ,&nbsp;Tim Eisen ,&nbsp;Ulrich Jaehde ,&nbsp;Marius T Radu ,&nbsp;Rob Ruijtenbeek ,&nbsp;Egbert Oosterwijk","doi":"10.1016/j.neo.2024.101108","DOIUrl":"10.1016/j.neo.2024.101108","url":null,"abstract":"<div><h3>Introduction</h3><div>Treatment with Sunitinib, a potent multitargeted receptor tyrosine kinase inhibitor (TKI) has increased the progression-free survival (PFS) and overall-survival (OS) of patients with metastasized renal cell carcinoma (mRCC). With modest OS improvement and variable response and toxicity predictive and/or prognostic biomarkers are needed to personalize patient management: Prediction of individual TKI therapy response and resistance will increase successful treatment outcome while reducing unnecessary drug use and expense. The aim of this study was to investigate whether kinase activity analysis can predict sunitinib response and/or toxicity using tissue samples obtained from primary clear cell RCC (ccRCC) from a cohort of clinically annotated patients with mRCC receiving sunitinib as first-line treatment.</div></div><div><h3>Materials and Methods</h3><div>EuroTARGET partners collected ccRCC and matched normal kidney tissue samples immediately after surgery, snap-frozen and stored at -80°C until use. Phosphotyrosine-activity profiling was performed using PamChip® peptide microarrays (144 peptides derived from known phosphorylation sites in Protein Tyrosine Kinase substrates) of lysed tissue samples (5 µg protein input) of 163 mRCC patients. Evolve software Was used to analyze kinome profiles and Bionavigator was used for unsupervised and supervised clustering. The kinexus kinase predictor (<span><span>www.phosphonet.ca</span><svg><path></path></svg></span>) was used to analyze the peptide lists within the clusters.</div></div><div><h3>Results</h3><div>Kinome data was available from 94 patients who received sunitinib as 1st-line treatment and had complete follow-up of their clinical data (PFS, OS and toxicity) for at least 6 months. Matched normal tissue was available from 14 mRCC patients. Supervised clustering of basal kinome activity could correctly classify mRCC patients with PFS &gt;9 months <em>versus</em> PFS&lt;9 months with an accuracy of 61 %. Unsupervised hierarchical clustering revealed 3 major clusters related to immune signaling, VEGF pathway, and immune signaling/cell adhesion. Basal kinase activity levels of patients with short PFS were substantially higher compared to patients who experienced extended PFS.</div></div><div><h3>Discussion/Conclusion</h3><div>Based on kinase levels ccRCC tumors can be subdivided into 3 clusters which may reflect the aggressiveness of these tumors. The accuracy of response prediction of 61 % based on basal kinase levels is too low to justify implementation. STK assays may help to predict sunitinib toxicity and guide clinical management. Additionally, it is possible that mRCC patients with an immune kinase signature are better checkpoint inhibitor candidates, but this needs to be studied.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101108"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11732189/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142899599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent advances of photodiagnosis and treatment for head and neck squamous cell carcinoma","authors":"Yining Zhang ,&nbsp;Zhenfang Li ,&nbsp;Chengchi Zhang ,&nbsp;Chengying Shao ,&nbsp;Yanting Duan ,&nbsp;Guowan Zheng ,&nbsp;Yu Cai ,&nbsp;Minghua Ge ,&nbsp;Jiajie Xu","doi":"10.1016/j.neo.2024.101118","DOIUrl":"10.1016/j.neo.2024.101118","url":null,"abstract":"<div><div>Head and neck squamous cell carcinoma (HNSCC) are the most common type of head and neck tumor that severely threatens human health due to its highly aggressive nature and susceptibility to distant metastasis. The diagnosis of HNSCC currently relies on biopsy and histopathological examination of suspicious lesions. However, the early mucosal changes are subtle and difficult to detect by conventional oral examination. As for treatment, surgery is still the primary treatment modality. Due to the complex anatomy and the lack of intraoperative modalities to accurately determine the incision margins, surgeons are in a dilemma between extensive tumor removal and improving the quality of patient survival. As more knowledge is gained about HNSCC, the increasing recognition of the value of optical imaging has been emphasized. Optical technology offers distinctive possibilities for early preoperative diagnosis, intraoperative real-time visualization of tumor margins, sentinel lymph node biopsies, phototherapy. Fluorescence imaging, narrow-band imaging, Raman spectroscopy, optical coherence tomography, hyperspectral imaging, and photoacoustic imaging have been reported for imaging HNSCC. This article provides a comprehensive overview of the fundamental principles and clinical applications of optical imaging in the diagnosis and treatment of HNSCC, focusing on identifying its strengths and limitations to facilitate advancements in this field.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101118"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11732236/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142899671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"β-Catenin mediated TAM phenotype promotes pancreatic cancer metastasis via the OSM/STAT3/LOXL2 axis","authors":"Yijia Zhang ,&nbsp;Xinya Zhu ,&nbsp;Liyuan Chen ,&nbsp;Tianyu Gao ,&nbsp;Guang Chen ,&nbsp;Jin Zhu ,&nbsp;Guoyu Wang ,&nbsp;Daiying Zuo","doi":"10.1016/j.neo.2024.101096","DOIUrl":"10.1016/j.neo.2024.101096","url":null,"abstract":"<div><div>Pancreatic ductal adenocarcinoma (PDAC) is characterized by its aggressive nature and dismal prognosis, largely attributed to its unique tumor microenvironment. However, the molecular mechanisms by which tumor-associated macrophages (TAMs) promote PDAC progression, particularly the role of β-catenin signaling in regulating TAM phenotype and function, remain incompletely understood.</div><div>Initially, we performed comprehensive analyses of RNA-seq and single-cell RNA-seq (scRNA-seq) datasets to investigate OSM and LOXL2 expression patterns in PDAC. Subsequently, the regulatory relationship between β-catenin and OSM in TAMs was examined using THP-1-derived macrophages. Furthermore, the functional impact of TAM-derived OSM on PDAC progression was evaluated through <em>in vitro</em> co-culture systems and an <em>in vivo</em> Panc02 lung metastasis model. Additionally, mechanistic studies employed pharmacological inhibitors and genetic approaches targeting β-catenin, OSM, and STAT3 signaling.</div><div>Notably, elevated expression of OSM and LOXL2 in PDAC specimens significantly correlated with poor patient survival. Intriguingly, scRNA-seq analysis revealed that β-catenin signaling was uniquely activated in TAMs among immune cells, which consequently regulated both TAM polarization and OSM expression. These OSM-expressing TAMs exhibited a distinct hybrid M1/M2 phenotype. Besides, our transcriptional profiling of TAMs revealed concurrent activation of both pro- and anti-inflammatory programs, with enrichment in Wnt signaling pathways. RNA-seq analysis of PDAC cells exposed to TAM-derived factors demonstrated enhanced mesenchymal transition and stemness properties, with direct enrichment of OSM signaling and extracellular matrix remodeling pathways. Mechanistically, β-catenin activation directly regulated both TAM phenotype and OSM expression, while TAM-conditioned medium enhanced PDAC cell migration, invasion, and lung metastasis. Importantly, inhibition of β-catenin signaling simultaneously altered TAM polarization and reduced OSM expression, which substantially attenuated epithelial-mesenchymal transition (EMT) in co-cultured PDAC cells. Moreover, STAT3 inhibition abolished OSM-induced LOXL2 expression and subsequent EMT programming.</div><div>Collectively, we identified a novel β-catenin/OSM-STAT3/LOXL2 signaling axis mediating TAM-induced PDAC progression. This pathway not only elucidates a previously unrecognized mechanism of β-catenin-mediated regulation of TAM function and phenotype but also presents potential therapeutic targets for intervention.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101096"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11745814/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142911030","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}