Cellular Oncology最新文献

{"title":"Microbial metabolite trimethylamine-N-oxide induces intestinal carcinogenesis through inhibiting farnesoid X receptor signaling.","authors":"Wanru Zhang, Xiali Qin, Kexin Zhang, Jiahui Ma, Mengfan Li, Ge Jin, Xiang Liu, Sinan Wang, Bangmao Wang, Jing Wu, Tianyu Liu, Weilong Zhong, Hailong Cao","doi":"10.1007/s13402-024-00920-2","DOIUrl":"10.1007/s13402-024-00920-2","url":null,"abstract":"<p><strong>Purpose: </strong>Microbial dysbiosis is considered as a hallmark of colorectal cancer (CRC). Trimethylamine-N-oxide (TMAO) as a gut microbiota-dependent metabolite has recently been implicated in CRC development. Nevertheless, evidence relating TMAO to intestinal carcinogenesis remains largely unexplored. Herein, we aimed to examine the crucial role of TMAO in CRC progression.</p><p><strong>Methods: </strong>Apc^min/+ mice were treated with TMAO or sterile PBS for 14 weeks. Intestinal tissues were isolated to evaluate the effects of TMAO on the malignant transformation of intestinal adenoma. The gut microbiota of mouse feces was detected by 16S rRNA sequencing analysis. HCT-116 cells were used to provide further evidence of TMAO on the progression of CRC.</p><p><strong>Results: </strong>TMAO administration increased tumor cell and stem cell proliferation, and decreased apoptosis, accompanied by DNA damage and gut barrier impairment. Gut microbiota analysis revealed that TMAO induced changes in the intestinal microbial community structure, manifested as reduced beneficial bacteria. Mechanistically, TMAO bound to farnesoid X receptor (FXR), thereby inhibiting the FXR-fibroblast growth factor 15 (FGF15) axis and activating the Wnt/β-catenin signaling pathway, whereas the FXR agonist GW4064 could blunt TMAO-induced Wnt/β-catenin pathway activation.</p><p><strong>Conclusion: </strong>The microbial metabolite TMAO can enhance intestinal carcinogenesis by inhibiting the FXR-FGF15 pathway.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"1183-1199"},"PeriodicalIF":4.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139693349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The predictive significance of chromobox family members in prostate cancer in humans.","authors":"Xiaoting Xu, Cong Lai, Jiawen Luo, Juanyi Shi, Kaixuan Guo, Jintao Hu, Yelisudan Mulati, Yunfei Xiao, Degeng Kong, Cheng Liu, Jingang Huang, Kewei Xu","doi":"10.1007/s13402-024-00929-7","DOIUrl":"10.1007/s13402-024-00929-7","url":null,"abstract":"<p><strong>Purpose: </strong>The Chromobox (CBX) family proteins are crucial elements of the epigenetic regulatory machinery and play a significant role in the development and advancement of cancer. Nevertheless, there is limited understanding regarding the role of CBXs in development or progression of prostate cancer (PCa). Our objective is to develop a unique prognostic model associated with CBXs to improve the accuracy of predicting outcomes of patients with PCa.</p><p><strong>Methods: </strong>Data from TCGA and GEO databases were analyzed to assess differential expression, prognostic value, gene pathway enrichment, and immune cell infiltration. COX regression analysis was utilized to identify the independent prognostic factors that impact disease-free survival (DFS). The expression of CBX2 and FOXP3⁺ cells infiltration was verified by immunohistochemical staining of clinical tissue sections. In vitro proliferation, migration and invasion assay were conducted to examine the function of CBX2. RNA-seq was employed to examine the CBX2 related pathway enrichment.</p><p><strong>Results: </strong>CBX2, CBX3, CBX4, and CBX8 were upregulated, while CBX6 and CBX7 were downregulated in PCa tissues. CBXs expression varied by stage and grade. Elevated expression of CBX1, CBX2, CBX3, CBX4 and CBX8 is correlated with poor outcome. CBX2 expression, T stage, and Gleason score were independent prognostic factors. The expression level of CBX2 in PCa tissues was significantly higher than that in adjacent normal tissues. More Treg infiltration was observed in the group with high CBX2 expression. CBX2 expression affected PCa cell growth, migration, and invasion.</p><p><strong>Conclusions: </strong>CBX2 is involved in the development and advancement of PCa, suggesting its potential as a reliable prognostic indicator for PCa patients.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"1315-1331"},"PeriodicalIF":4.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139998034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TIPRL1 and its ATM-dependent phosphorylation promote radiotherapy resistance in head and neck cancer.","authors":"Célie Cokelaere, Rüveyda Dok, Emanuela E Cortesi, Peihua Zhao, Anna Sablina, Sandra Nuyts, Rita Derua, Veerle Janssens","doi":"10.1007/s13402-023-00895-6","DOIUrl":"10.1007/s13402-023-00895-6","url":null,"abstract":"<p><strong>Purpose: </strong>TIPRL1 (target of rapamycin signaling pathway regulator-like 1) is a known interactor and inhibitor of protein phosphatases PP2A, PP4 and PP6 - all pleiotropic modulators of the DNA Damage Response (DDR). Here, we investigated the role of TIPRL1 in the radiotherapy (RT) response of Head and Neck Squamous Cell Carcinoma (HNSCC).</p><p><strong>Methods: </strong>TIPRL1 mRNA (cBioportal) and protein expression (immunohistochemistry) in HNSCC samples were linked with clinical patient data. TIPRL1-depleted HNSCC cells were generated by CRISPR/Cas9 editing, and effects on colony growth, micronuclei formation (microscopy), cell cycle (flow cytometry), DDR signaling (immunoblots) and proteome (mass spectrometry) following RT were assessed. Mass spectrometry was used for TIPRL1 phosphorylation and interactomics analysis in irradiated cells.</p><p><strong>Results: </strong>TIPRL1 expression was increased in tumor versus non-tumor tissue, with high tumoral TIPRL1 expression associating with lower locoregional control and decreased survival of RT-treated patients. TIPRL1 deletion in HNSCC cells resulted in increased RT sensitivity, a faster but prolonged cell cycle arrest, increased micronuclei formation and an altered proteome-wide DDR. Upon irradiation, ATM phosphorylates TIPRL1 at Ser265. A non-phospho Ser265Ala mutant could not rescue the increased radiosensitivity phenotype of TIPRL1-depleted cells. While binding to PP2A-like phosphatases was confirmed, DNA-dependent protein kinase (DNA-PKcs), RAD51 recombinase and nucleosomal histones were identified as novel TIPRL1 interactors. Histone binding, although stimulated by RT, was adversely affected by TIPRL1 Ser265 phosphorylation.</p><p><strong>Conclusions: </strong>Our findings underscore a clinically relevant role for TIPRL1 and its ATM-dependent phosphorylation in RT resistance through modulation of the DDR, highlighting its potential as a new HNSCC predictive marker and therapeutic target.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"793-818"},"PeriodicalIF":4.9,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136399945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRPV1 inhibition suppresses non-small cell lung cancer progression by inhibiting tumour growth and enhancing the immune response.","authors":"Yang Wang, Yu Zhang, Jing Ouyang, Hanying Yi, Shiyu Wang, Dongbo Liu, Yingying Dai, Kun Song, Wenwu Pei, Ziyang Hong, Ling Chen, Wei Zhang, Zhaoqian Liu, Howard L Mcleod, Yijing He","doi":"10.1007/s13402-023-00894-7","DOIUrl":"10.1007/s13402-023-00894-7","url":null,"abstract":"<p><strong>Purpose: </strong>TRPV1 is a nonselective Ca²⁺ channel protein that is widely expressed and plays an important role during the occurrence and development of many cancers. Activation of TRPV1 channels can affect tumour progression by regulating proliferation, apoptosis and migration. Some studies have also shown that activating TRPV1 can affect tumour progression by modulating tumour immunity. However, the effects of TRPV1 on the development of non-small cell lung cancer (NSCLC) have not been explored clearly.</p><p><strong>Method: </strong>The Cancer Genome Atlas (TCGA) database and spatial transcriptomics datasets from 10 × Genomics were used to analyze TRPV1 expression in various tumour tissues. Cell proliferation and apoptosis were examined by cell counting kit 8 (CCK8), colony formation, and flow cytometry. Immunohistochemistry, qPCR, and western blotting were used to determine the mRNA and protein expression levels of TRPV1 and other related molecules. Tumour xenografts in BALB/C and C57BL/6J mice were used to determine the effects of TRPV1 on NSCLC development in vivo. Neurotransmitter content was examined by LC-MS/MS, ELISA and Immunohistochemistry. Immune cell infiltration was assessed by flow cytometry.</p><p><strong>Results: </strong>In this study, we found that TRPV1 expression was significantly upregulated in NSCLC and that patients with high TRPV1 expression had a poor prognosis. TRPV1 knockdown can significantly inhibit NSCLC proliferation and induce cell apoptosis through Ca²⁺-IGF1R signaling. In addition, TRPV1 knockdown resulted in increased infiltration of CD4⁺ T cells, CD8⁺ T cells, GZMB⁺CD8⁺ T cells and DCs and decreased infiltration of immunosuppressive MDSCs in NSCLC. In addition, TRPV1 knockout effectively decreased the expression of M2 macrophage markers CD163 and increased the expression of M1-associated, costimulatory markers CD86. Knockdown or knockout of TRPV1 significantly inhibit tumour growth and promoted an antitumour immune response through supressing γ-aminobutyric acid (GABA) secretion in NSCLC.</p><p><strong>Conclusion: </strong>Our study suggests that TRPV1 acts as a tumour promoter in NSCLC, mediating pro-proliferative and anti-apoptotic effects on NSCLC through IGF1R signaling and regulating GABA release to affect the tumour immune response.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"779-791"},"PeriodicalIF":4.9,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71414929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pathological response and tumor stroma immunogenic features predict long-term survival in non-small cell lung cancer after neoadjuvant chemotherapy.","authors":"Shuaibo Wang, Xujie Sun, Jiyan Dong, Li Liu, Hao Zhao, Renda Li, Zhenlin Yang, Na Cheng, Yalong Wang, Li Fu, Hang Yi, Zhuoheng Lv, Huandong Huo, Donghui Jin, Yousheng Mao, Lin Yang","doi":"10.1007/s13402-023-00914-6","DOIUrl":"10.1007/s13402-023-00914-6","url":null,"abstract":"<p><strong>Purpose: </strong>Major pathological response (MPR) has become a surrogate endpoint for overall survival (OS) in non-small cell lung cancer (NSCLC) after neoadjuvant therapy, however, the prognostic histologic features and optimal N descriptor after neoadjuvant therapy are poorly defined.</p><p><strong>Methods: </strong>We retrospectively analyzed data from 368 NSCLC patients who underwent surgery after neoadjuvant chemotherapy (NAC) from January 2010 to December 2020. The percentage of residual viable tumors in the primary tumor, lymph nodes (LN), and inflammation components within the tumor stroma were comprehensively reviewed. The primary endpoint was OS.</p><p><strong>Results: </strong>Of the 368 enrolled patients, 12.0% (44/368) achieved MPR in the primary tumor, which was associated with significantly better OS (HR, 0.36 0.17-0.77, p = 0.008) and DFS (HR = 0.59, 0.36-0.92, p = 0.038). In patients who did not have an MPR, we identified an immune-activated phenotype in primary tumors, characterized by intense tumor-infiltrating lymphocyte or multinucleated giant cell infiltration, that was associated with similar OS and DFS as patients who had MPR. Neoadjuvant pathologic grade (NPG), consisting of MPR and immune-activated phenotype, identified 30.7% (113/368) patients that derived significant OS (HR 0.28, 0.17-0.46, p < 0.001) and DFS (HR 0.44, 0.31-0.61, p < 0.001) benefit from NAC. Moreover, the combination of NPG and the number of positive LN stations (nS) in the multivariate analysis had a higher C-index (0.711 vs. 0.663, p < 0.001) than the ypTNM Stage when examining OS.</p><p><strong>Conclusion: </strong>NPG integrated with nS can provide a simple, practical, and robust approach that may allow for better stratification of patients when evaluating neoadjuvant chemotherapy in clinical practice.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"1005-1024"},"PeriodicalIF":4.9,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139693351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Asymmetric post-translational modifications regulate the nuclear translocation of STAT3 homodimers in response to leukemia inhibitory factor.","authors":"Mickael Diallo, Constança Pimenta, Fernanda Murtinheira, Daniela Martins-Alves, Francisco R Pinto, André Abrantes da Costa, Ricardo Letra-Vilela, Vanesa Martin, Carmen Rodriguez, Mário S Rodrigues, Federico Herrera","doi":"10.1007/s13402-023-00911-9","DOIUrl":"10.1007/s13402-023-00911-9","url":null,"abstract":"<p><p>STAT3 is a pleiotropic transcription factor overactivated in 70% of solid tumours. We have recently reported that inactivating mutations on residues susceptible to post-translational modifications (PTMs) in only one of the monomers (i.e. asymmetric) caused changes in the cellular distribution of STAT3 homodimers. Here, we used more controlled experimental conditions, i.e. without the interference of endogenous STAT3 (STAT3-/- HeLa cells) and in the presence of a defined cytokine stimulus (Leukemia Inhibitory Factor, LIF), to provide further evidence that asymmetric PTMs affect the nuclear translocation of STAT3 homodimers. Time-lapse microscopy for 20 min after LIF stimulation showed that S727 dephosphorylation (S727A) and K685 inactivation (K685R) slightly enhanced the nuclear translocation of STAT3 homodimers, while K49 inactivation (K49R) delayed STAT3 nuclear translocation. Our findings suggest that asymmetrically modified STAT3 homodimers could be a new level of STAT3 regulation and, therefore, a potential target for cancer therapy.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"1065-1070"},"PeriodicalIF":4.9,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11219437/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139040779","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":"ITGB2-ICAM1 axis promotes liver metastasis in BAP1-mutated uveal melanoma with retained hypoxia and ECM signatures.","authors":"Jiaoduan Li, Dongyan Cao, Lixin Jiang, Yiwen Zheng, Siyuan Shao, Ai Zhuang, Dongxi Xiang","doi":"10.1007/s13402-023-00908-4","DOIUrl":"10.1007/s13402-023-00908-4","url":null,"abstract":"<p><strong>Purpose: </strong>Uveal melanoma (UM) with BAP1 inactivating mutations has a high risk of metastasis, but the mechanism behind BAP1 deficiency driving UM metastasis is unknown.</p><p><strong>Methods: </strong>We analyzed the single-cell RNA sequencing (scRNA-Seq) data comprised primary and metastatic UM with or without BAP1 mutations (MUTs) to reveal inter- and intra-tumor heterogeneity among different groups. Then, an immune-competent mouse liver metastatic model was used to explore the role of ITGB2-ICAM1 in BAP1-associated UM metastasis.</p><p><strong>Results: </strong>Cluster 1 tumor cells expressed high levels of genes linked to tumor metastasis, such as GDF15, ATF3, and CDKN1A, all of which are associated with poor prognosis. The strength of communication between terminally exhausted CD8⁺ T cells and GDF15^hiATF3^hiCDKN1A^hi tumor cells was enhanced in BAP1-mutated UM, with CellChat analysis predicting strong ITGB2-ICAM1 signaling between them. High expression of either ITGB2 or ICAM1 was a worse prognostic indicator. Using an immune-competent mouse liver metastatic model, we indicated that inhibiting either ICAM1 or ITGB2 prevented liver metastasis in the BAP1-mutated group in vivo. The inhibitors primarily inhibited hypoxia- and ECM-related pathways indicated by changes in the expression of genes such as ADAM8, CAV2, ENO1, PGK1, LOXL2, ITGA5, and VCAN. etc. CONCLUSION: This study suggested that the ITGB2-ICAM1 axis may play a crucial role for BAP1-associated UM metastasis by preserving hypoxia- and ECM- related signatures, which provide a potential strategy for preventing UM metastasis in patients with BAP1 mutation.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"951-965"},"PeriodicalIF":4.9,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139040780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"OTUB1 accelerates hepatocellular carcinoma by stabilizing RACK1 via its non-canonical ubiquitination.","authors":"Liqun Peng, Tiangen Wu, Yingyi Liu, Dongli Zhao, Wenzhi He, Yufeng Yuan","doi":"10.1007/s13402-023-00913-7","DOIUrl":"10.1007/s13402-023-00913-7","url":null,"abstract":"<p><strong>Background: </strong>Dysregulated ubiquitination modification occupies a pivotal role in hepatocellular carcinoma (HCC) tumorigenesis and progression. The ubiquitin aldehyde binding 1 (OTUB1) was aberrantly upregulated and exhibited the pro-tumorigenic function in HCC. However, the underlying mechanisms and responsible targets of OTUB1 remain unclear.</p><p><strong>Methods: </strong>First, bioinformatics analysis, western blot and immunohistochemistry staining were applied to analyze OTUB1 expression in HCC specimens. Then, immunoprecipitation assay-tandem mass spectrometry (MS) combined with the gene set enrichment analysis (GSEA) was used to explore the downstream target of OTUB1. Co-immunoprecipitation and ubiquitination assays were used to identify the mechanisms involved. Finally, we explored the regulatory effect of MAZ on OTUB1 through ChIP-qPCR and dual-luciferase reporter assay.</p><p><strong>Results: </strong>OTUB1 was broadly elevated in HCC tissues and promoted the proliferation and metastasis of HCC in vitro and in vivo. The receptor for activated C kinase 1 (RACK1) performed as a functional partner of OTUB1 and its hyperactivation was associated with aggressive development and other malignant features in HCC by activating oncogenes transcription. Mechanistically, OTUB1 directly bound to RACK1 at its C-terminal domain and decreased the K48-linked ubiquitination of RACK1 through its non-canonical suppression of ubiquitination activity, which stabilized RACK1 protein levels in HCC cells. Therefore, OTUB1 significantly increased multiple oncogenes expression and activated PI3K/AKT and FAK/ERK signaling in a RACK1-dependent manner in HCC. Moreover, the transcription factor MAZ upregulated OTUB1 expression through identifying a putative response element of OTUB1 promoter area.</p><p><strong>Conclusions: </strong>Our findings might provide a new therapeutic strategy for HCC by modifying the MAZ-OTUB1-RACK1 axis.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"987-1004"},"PeriodicalIF":4.9,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11219430/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139693350","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":"Stiffened tumor microenvironment enhances perineural invasion in breast cancer via integrin signaling.","authors":"Bing Han, Xin Guan, Mingyue Ma, Baoling Liang, Linglie Ren, Yutong Liu, Ye Du, Shu-Heng Jiang, Dong Song","doi":"10.1007/s13402-023-00901-x","DOIUrl":"10.1007/s13402-023-00901-x","url":null,"abstract":"<p><strong>Background: </strong>Accumulating studies have shown that tumors are regulated by nerves, and there is abundant nerve infiltration in the tumor microenvironment. Many solid tumors including breast cancer (BRCA) have different degrees of perineural invasion (PNI), which is closely related to the tumor occurrence and progression. However, the regulatory mechanism of PNI in BRCA remains largely unexplored.</p><p><strong>Methods: </strong>PNI-related molecular events are analyzed by the RNAseq data of BRCA samples deposited in The Cancer Genome Atlas (TCGA) database. Extracellular matrix (ECM) components within the tumor microenvironment are analyzed by immunohistochemical staining of α-SMA, Sirius red staining, and Masson trichrome staining. Soft and stiff matrix gels, living cell imaging, and dorsal root ganglion (DRG) coculture assay are used to monitor cancer cell invasiveness towards nerves. Western blotting, qRT-PCR, enzyme-linked immunosorbent assay combined with neutralizing antibody and small molecular inhibitors are employed to decode molecular mechanisms.</p><p><strong>Results: </strong>Comparative analysis that the ECM was significantly associated with PNI status in the TCGA cohort. BRCA samples with higher α-SMA activity, fibrillar collagen, and collagen content had higher frequency of PNI. Compared with soft matrix, BRCA cells cultured in stiff matrix not only displayed higher cell invasiveness to DRG neurons but also had significant neurotrophic effects. Mechanistically, integrin β1 was identified as a functional receptor to the influence of stiff matrix on BRCA cells. Moreover, stiffened matrix-induced activation of integrin β1 transduces FAK-YAP signal cascade, which enhances cancer invasiveness and the neurotrophic effects. In clinical setting, PNI-positive BRCA samples had higher expression of ITGB1, phosphorylated FAK, YAP, and NGF compared with PNI-negative BRCA samples.</p><p><strong>Conclusions: </strong>Our findings suggest that stiff matrix induces expression of pro-metastatic and neurotrophic genes through integrin β1-FAK-YAP signals, which finally facilitates PNI in BRCA. Thus, our study provides a new mechanism for PNI in BRCA and highlights nerve-based tumor treatment strategies.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"867-882"},"PeriodicalIF":4.9,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138446721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting MEK/COX-2 axis improve immunotherapy efficacy in dMMR colorectal cancer with PIK3CA overexpression.","authors":"Kunwei Peng, Yongxiang Liu, Shousheng Liu, Zining Wang, Huanling Zhang, Wenzhuo He, Yanan Jin, Lei Wang, Xiaojun Xia, Liangping Xia","doi":"10.1007/s13402-024-00916-y","DOIUrl":"10.1007/s13402-024-00916-y","url":null,"abstract":"<p><strong>Purpose: </strong>PIK3CA mutation or overexpression is associated with immunotherapy resistance in multiple cancer types, but is also paradoxically associated with benefit of COX-2 inhibition on patient survival of colorectal cancer (CRC) with mismatch repair deficiency (dMMR). This study examined whether and how PIK3CA status affected COX-2-mediated tumor inflammation and immunotherapy response of dMMR CRC.</p><p><strong>Methods: </strong>Murine colon cancer cells MC38, CT26, and CT26-Mlh1-KO were used to construct PIK3CA knockdown and overexpression models to mimic dMMR CRC with PIK3CA dysregulation, and xenograft models were used to evaluate how PIK3CA regulate COX-2 expression, CD8⁺ T cells infiltration, tumor growth, and therapy response to anti-PD-L1 treatment using immunocompetent mice. Western blot was carried out to delineate the signaling pathways in human and mouse cancer cells, and immunohistochemical analysis together with bioinformatics analysis using human patient samples.</p><p><strong>Results: </strong>PIK3CA upregulates COX-2 expression through MEK/ERK signaling pathway independent of AKT signaling to promote tumor inflammation and immunosuppression. PIK3CA knockdown profoundly reduced CT26 tumor growth in a CD8⁺ T cell-dependent manner, while PIK3CA overexpression significantly inhibited CD8⁺ T cells infiltration and promoted tumor growth. Furthermore, MEK or COX-2 inhibition augmented the anti-tumor activity of anti-PD-L1 immunotherapy on dMMR CRC mouse models, accompanied with increased CD8⁺ T cells infiltration and activated tumor microenvironment.</p><p><strong>Conclusion: </strong>Our results identified that the PIK3CA hyperactivation in dMMR CRC upregulated COX-2 through MEK signaling, which inhibited CD8⁺ T cells infiltration and promoted tumor growth, together led to immunotherapy resistance. COX-2 or MEK inhibition may relieve therapy resistance and promote therapy efficacy of anti-PD-1/PD-L1 immunotherapy for treating dMMR CRC with PIK3CA overexpression or activating mutation.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"1043-1058"},"PeriodicalIF":4.9,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139693352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}