Neoplasia最新文献

{"title":"TPM4 overexpression drives colon epithelial cell tumorigenesis by suppressing differentiation and promoting proliferation","authors":"Rajsumeet S. Macwan ,&nbsp;Giulio Ferrero ,&nbsp;Barbara Pardini ,&nbsp;Alessio Naccarati ,&nbsp;Piotr B. Kozlowski ,&nbsp;Michael J. Papetti","doi":"10.1016/j.neo.2024.101093","DOIUrl":"10.1016/j.neo.2024.101093","url":null,"abstract":"<div><h3>Objective</h3><div>The high morbidity and mortality associated with colorectal cancer (CRC) and the recent increases in early-onset CRC obviate the need for novel methods to detect and treat this disease, particularly at early stages. We hypothesize that aberrant expression of genes involved in the crypt-luminal migration of colon epithelial cells, a process necessary for their growth arrest and maturation, may disrupt differentiation and transition cells from a normal to tumorigenic state.</div></div><div><h3>Methods</h3><div>We searched for contractility- and motility-related genes that are dysregulated in human CRC relative to normal colon. RNA expression of one such gene, tropomyosin 4 (<em>TPM4</em>), was measured by qRT-PCR and RNA-seq in human colorectal tissues at various stages of tumorigenesis: CRC, adenoma, and at-risk (grossly normal mucosa from a patient with Familial Adenomatous Polyposis, or FAP), relative to controls. Effects of aberrant <em>TPM4</em> expression on colon epithelial cell proliferation and maturation were determined by overexpression using stable transfection in spontaneously differentiating Caco2 cells or silencing using siRNA in proliferating cells.</div></div><div><h3>Results</h3><div><em>TPM4</em> is overexpressed at various stages of tumorigenesis, including CRC, adenoma, and grossly normal FAP colon tissue, as well as in proliferating versus differentiating Caco2 cells. <em>TPM4.2</em> overexpression in differentiating Caco2 cells markedly inhibits certain aspects of maturation, notably sucrase isomaltase and glutathione-S-transferase alpha1 expression, and causes morphological and cell junction abnormalities. Conversely, siRNA-mediated suppression of <em>TPM4.2</em> inhibits Caco2 proliferation.</div></div><div><h3>Conclusions</h3><div><em>TPM4</em> overexpression attenuates colon epithelial cell differentiation and promotes proliferation. Therefore, <em>TPM4</em> expression may be a biomarker to enhance strategies for CRC diagnosis and treatment.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101093"},"PeriodicalIF":4.8,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142743805","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":"5-Aza-2′-deoxycytidin (Decitabine) increases cancer-testis antigen expression in head and neck squamous cell carcinoma and modifies immune checkpoint expression, especially in CD39-positive CD8 and CD4 T cells","authors":"Adrian Fehn ,&nbsp;Adrian von Witzleben ,&nbsp;Ayla Grages ,&nbsp;Tsima Abou Kors ,&nbsp;Jasmin Ezić ,&nbsp;Annika C. Betzler ,&nbsp;Cornelia Brunner ,&nbsp;Patrick J. Schuler ,&nbsp;Marie-Nicole Theodoraki ,&nbsp;Thomas K. Hoffmann ,&nbsp;Simon Laban","doi":"10.1016/j.neo.2024.101086","DOIUrl":"10.1016/j.neo.2024.101086","url":null,"abstract":"<div><div>Failure of immunotherapy in head and neck squamous cell carcinoma (HNSCC) patients represents an unmet need to augment leverage of adaptive immunity. Immunogenic cancer-testis antigen (CTA) expression as well as lymphocyte differentiation and function are regulated by DNA methylation. Therefore, epigenetic therapy via inhibition of DNA-Methyltransferases by 5-Aza-2′-deoxycytidine (DAC) serves a promising adjuvant in immunotherapy.</div><div>We investigated the effects of DAC on CTA expression and proliferative capacity in HNSCC cell lines and on the expression of 12 immune checkpoint molecules (ICM) on lymphocytes of oropharyngeal squamous cell carcinoma (OPSCC) patients and healthy donors.</div><div>In all cell lines CTA were upregulated accompanied by decreased proliferation. In lymphocytes pronounced alterations of the ICM repertoire were observed, influenced by donor type and subpopulation. On CD39+ CD4 and CD8 T cells, the expression of co-stimulatory ICM GITR and OX40 increased dose dependently, whereas expression decreased on CD39- CD4 T cells. PD1 expression increased primarily on CD39+ CD8 T cells and decreased on CD39- CD4 T cells. CD27 expression decreased primarily in CD8 T cells, but increased in CD39- CD4 T cells, whereas ICOS expression was lowered in both CD39+ and CD39- subsets of CD4 as well as CD8 T cells.</div><div>DAC treatment increased immunogenicity and decreased proliferation in HNSCC cells while enhancing expression of co-stimulatory ICM GITR and OX40. We propose low dose DAC treatment as a adjuvant to immunotherapy.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101086"},"PeriodicalIF":4.8,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142721167","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":"Structure and function of the lysine methyltransferase SETD2 in cancer: From histones to cytoskeleton","authors":"Christina Michail,&nbsp;Fernando Rodrigues Lima,&nbsp;Mireille Viguier,&nbsp;Frédérique Deshayes","doi":"10.1016/j.neo.2024.101090","DOIUrl":"10.1016/j.neo.2024.101090","url":null,"abstract":"<div><div>SETD2 is known to be the unique histone methyltransferase responsible for the trimethylation of the lysine 36 of histone H3 thus generating H3K36me3. This epigenetic mark is critical for transcriptional activation and elongation, DNA repair, mRNA splicing, and DNA methylation. Recurrent SETD2-inactivating mutations and altered H3K36me3 levels are found in cancer at high frequency and numerous studies indicate that SETD2 acts as a tumor suppressor. Recently, SETD2 was further shown to methylate non-histone proteins particularly the cytoskeletal proteins tubulin and actin with subsequent impacts on cytoskeleton structure, mitosis and cell migration.</div><div>Herein, we provide a review of the role of SETD2 in different cancers with special emphasis on the structural basis of the functions of this key lysine methyltransferase. Moreover, beyond the role of this enzyme in epigenetics and H3K36me3-dependent processes, we highlight the putative role of \"non-epigenetic/H3K36me3\" functions of SETD2 in cancer, particularly those involving the cytoskeleton.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101090"},"PeriodicalIF":4.8,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142702719","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":"Early separation and parallel clonal selection of dedifferentiated and well-differentiated components in dedifferentiated liposarcoma","authors":"Tetsuya Sekita ,&nbsp;Naofumi Asano ,&nbsp;Takashi Kubo ,&nbsp;Hirohiko Totsuka ,&nbsp;Sachiyo Mitani ,&nbsp;Naoko Hattori ,&nbsp;Akihiko Yoshida ,&nbsp;Eisuke Kobayashi ,&nbsp;Motokiyo Komiyama ,&nbsp;Toshikazu Ushijima ,&nbsp;Robert Nakayama ,&nbsp;Masaya Nakamura ,&nbsp;Akira Kawai ,&nbsp;Hitoshi Ichikawa","doi":"10.1016/j.neo.2024.101074","DOIUrl":"10.1016/j.neo.2024.101074","url":null,"abstract":"<div><div>Dedifferentiated liposarcoma (DDLPS) comprises a high-grade dedifferentiated (DD) component and a juxtaposed well-differentiated (WD) component. The DD component is believed to originate from the WD component by acquiring additional genomic alterations. In this study, we performed multiregion genome, epigenome, and transcriptome analyses of three patients with DDLPS. In two patients, there were few common genomic alterations across all samples, but many common alterations within DD or WD component samples. Phylogenetic trees predicted from the genomic alterations were consistent with those predicted from DNA methylation patterns. The expression patterns of adipogenesis-related genes differed between DD and WD components and also among patients in connection with their CpG island methylation status. These results indicate that in some patients, WD and DD components are evolutionarily separated at very early stages of tumorigenesis, and are formed through relatively long clonal selection with acquisition of different driver genomic alterations and DNA methylation changes.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101074"},"PeriodicalIF":4.8,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142702720","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 “Inhibition of Pancreatic Intraepithelial Neoplasia Progression to Carcinoma by Nitric Oxide-Releasing Aspirin in p48Cre/+-LSL-KrasG12D/+ Mice” [Neoplasia, Volume 14, Issue 9 (2012) 778-787]","authors":"Chinthalapally V Rao ,&nbsp;Altaf Mohammed ,&nbsp;Naveena B Janakiram ,&nbsp;Qian Li ,&nbsp;Rebekah L Ritchie ,&nbsp;Stan Lightfoot ,&nbsp;Awasthi Vibhudutta ,&nbsp;Vernon E Steele","doi":"10.1016/j.neo.2024.101081","DOIUrl":"10.1016/j.neo.2024.101081","url":null,"abstract":"","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101081"},"PeriodicalIF":4.8,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693077","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":"Depletion of regulatory T cells enhances the T cell response induced by the neoantigen vaccine with weak immunogenicity","authors":"Ruichen Huang ,&nbsp;Qiao Zhou ,&nbsp;Jiajun Liu ,&nbsp;Yang Xia ,&nbsp;Yang Jiao ,&nbsp;Bi Zhao ,&nbsp;Tangtao Feng ,&nbsp;Haosu Zhou ,&nbsp;Xiuyan Song ,&nbsp;Hao Qin ,&nbsp;Jun Wang ,&nbsp;Lan Cheng ,&nbsp;Yunye Ning ,&nbsp;Qinying Sun ,&nbsp;Yanfang Liu ,&nbsp;Xiaoping Su ,&nbsp;Yuchao Dong ,&nbsp;Wei Zhang","doi":"10.1016/j.neo.2024.101088","DOIUrl":"10.1016/j.neo.2024.101088","url":null,"abstract":"<div><h3>Background</h3><div>The neoantigen vaccine has remarkable potential in treating advanced cancer due to its tumor specificity and ability to bypass central tolerance mechanisms. However, numerous neoantigens show poor immunogenicity, and the immune inhibitory factors of present in both tumors and tumor-draining lymph nodes impair the efficacy of cancer neoantigen vaccine. Eliminating immunosuppressive cells will improve the priming and expansion of anti-tumor immune cells induced by the vaccine.</div></div><div><h3>Methods</h3><div>In this study, a Treg-depleting regimen (consisting of CD25mAb and low-dose cyclophosphamide (LD-CTX)) was used in conjunction with a neoantigen vaccine for treating mice with solid tumors. We constructed two types of tumor models and investigated differences in therapy efficacy in the four groups (PBS, vaccine, CD25mAb+CTX and combination) at the genetic and protein levels. ELISPOT and TCR sequencing were applied to detect the expansion of neoantigen reactive T cells (NRT) and tumor antigen spreading.</div></div><div><h3>Results</h3><div>In the combinational group, the ELISPOT results showed an obvious expansion of NRT cells induced by weak immunogenic peptides. The combinational group exhibited significant improvement in inhibiting the tumor growth extended the survival time of tumor-bearing mice, and promoted T cells infiltration into tumors. Besides, compared to the Vac group, more neoantigen-targeted and TAA-targeted T cells were detected in the combinational group by TCR sequencing. The results of transcriptomic sequencing and flow cytometry showed that the number of Tregs in the combinational group was lower, while the proportions of memory effector T cells and effector T cells were higher than those in the vaccine group. An increase in mature DCs was also observed in vaccinated mice after receiving this Treg-depleting strategy.</div></div><div><h3>Conclusion</h3><div>Our research first revealed that inhibiting the normal function of Tregs transformed “weaker” neoantigens into “stronger” ones, while also contributing to the proliferation of NRT cells. This Treg-depleting strategy allowed neoantigens with poor immunogenicity to elicit a robust immune response, thereby augmenting the efficacy of the neoantigen vaccine in delaying tumor growth and prolonging the survival of the hosts.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101088"},"PeriodicalIF":4.8,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695963","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":"Engineering and characterization of Hu3A4: A novel humanized antibody with potential as a therapeutic agent against myeloid lineage leukemias","authors":"Sisi Li ,&nbsp;Zhujun Wang ,&nbsp;Xiaoping Guo ,&nbsp;Yongmin Tang","doi":"10.1016/j.neo.2024.101084","DOIUrl":"10.1016/j.neo.2024.101084","url":null,"abstract":"<div><div>Leukemia stem cells (LSCs) play a critical role in the initiation, recurrence, and resistance to treatment of leukemia. Eradicating LSCs is crucial for the complete elimination of the disease. CD45RA is identified as an important marker for LSC subsets in acute myeloid leukemia (AML), providing a strategic target for therapy. In this report, we introduce Hu3A4, an innovative humanized CD45RA antibody devised to target LSCs expressing this antigen. Hu3A4 retains the antigen-recognition ability of its parental antibody while removing sequences from the variable region that could elicit human anti-mouse immune reactions. The modified variable regions of the heavy and light chains were intricately fused with the constant regions of human IgG1 heavy and light chains, respectively, producing a humanized antibody that emulates the structure of natural IgG. Hu3A4 was produced through recombinant expression in Chinese Hamster Ovary (CHO) cells, which ensured stable gene integration. In vitro tests revealed that Hu3A4 could effectively target and lyse the cells. Further, in vivo studies highlighted Hu3A4′s substantial anti-leukemic activity, significantly prolonging survival times in treated animal models compared to controls (P &lt; 0.01). To summarize, Hu3A4 exhibits remarkable bioactivity and offers a promising therapeutic potential for the treatment of leukemia patients. Progressing Hu3A4 through additional preclinical and clinical studies is crucial to validate its efficacy as a therapeutic agent for leukemia.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101084"},"PeriodicalIF":4.8,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142689290","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":"Non-redundant roles of the CCR1 and CCR2 chemokine axes in monocyte recruitment during lung metastasis","authors":"Alessia G. Liner ,&nbsp;Merel van Gogh ,&nbsp;Marko Roblek ,&nbsp;Matthias Heikenwalder ,&nbsp;Lubor Borsig","doi":"10.1016/j.neo.2024.101089","DOIUrl":"10.1016/j.neo.2024.101089","url":null,"abstract":"<div><div>Monocytes and monocyte-derived macrophages facilitate cancer progression and metastasis. Inflammatory monocytes expressing CCR2 are actively recruited to metastatic lungs, where they promote tumor cell extravasation, metastatic outgrowth, and an immunosuppressive environment. The role of CCR1 in this process has remained unclear. We used Ccr1- and Ccr2-deficient mice and two different tumor cells lines, MC38 and LLC1 with and without Ccl2-deficiency <em>in vitro</em> and <em>in vivo</em>. The recruitment of both Ccr1- and Ccr2-deficient monocytes towards the Ccl2 chemokine was significantly impaired, while no substantial recruitment was observed towards Ccl5 <em>in vitro</em>. MC38 and LLC1 Ccl2-deficient tumor cells showed reduced lung metastasis in both Ccr1- and Ccr2-deficient mice when compared to wild-type mice. We detected reduced numbers of macrophages and myeloid cells in both chemokine receptor-deficient mice. Lung metastasis in both Ccr1- and Ccr2-deficient mice could be rescued to the same levels as in wild-type mice by an adoptive transfer of Ccr2-deficient but not Ccr1-deficient monocytic cells. Accumulation of Ccr1-deficient monocytes in the lungs was severely impaired upon intravenous monocyte injection, indicating the importance of this axis in cell recruitment. Moreover, the efficient recruitment of adoptive transferred Ccr2-deficient monocytes to the lungs and the restoration of lung metastasis suggests an involvement of an additional, Ccr2-independent chemokine pathway. This data defines the non-redundant functions of the Ccr1- and Ccr2-chemokine axes in monocyte recruitment and macrophage presence during lung metastasis. While Ccr2 is essential for the release of monocytes from the bone marrow, Ccr1 is primarily responsible for monocyte presence at metastatic sites.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101089"},"PeriodicalIF":4.8,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142683057","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":"Sequential treatment of anti-PD-L1 therapy prior to anti-VEGFR2 therapy contributes to more significant clinical benefits in non-small cell lung cancer","authors":"Qiao-xin Lin ,&nbsp;Wen-wen Song ,&nbsp;Wen-xia Xie ,&nbsp;Yi-ting Deng ,&nbsp;Yan-na Gong ,&nbsp;Yi-ru Liu ,&nbsp;Yi Tian ,&nbsp;Wen-ya Zhao ,&nbsp;Ling Tian ,&nbsp;Dian-na Gu","doi":"10.1016/j.neo.2024.101077","DOIUrl":"10.1016/j.neo.2024.101077","url":null,"abstract":"<div><h3>Objective</h3><div>Anti-angiogenic therapy and immune checkpoint blockade therapy are currently important treatments for non-small cell lung cancer. However, the combined use of the two therapies is controversial, and few studies have investigated the effects of different time sequences of the two therapies on treatment outcomes.</div></div><div><h3>Methods</h3><div>The tumor-bearing mouse model was established and the mice were divided into four groups, including AA-ICB sequence group, ICB-AA sequence group, synchronization group and the control group. Immunohistochemistry was used to assess tumor microvessels and PD-L1 expression. Selected immune cell populations were evaluated using flow cytometry. Meta-analysis and clinical information were used to elucidate the clinical effects of administration sequence.</div></div><div><h3>Results</h3><div>We found that anti-PD-L1 treatment followed by anti-VEGFR2 therapy exerts the best inhibitory effect on tumor growth. Different sequences of anti-angiogenic therapy and immune checkpoint blockade therapy resulted in different proportions of tumor microvessels and immune cell populations in the tumor microenvironment. We further revealed that the administration of anti-PD-L1 before anti-VEGFR brought more normalized tumor blood vessels and CD8⁺T cell infiltration and reduced immunosuppressive cells in the tumor microenvironment. Subsequent re-transplantation experiments confirmed the long-term benefits of this treatment strategy. The meta-analysis reinforced that immunotherapy prior to anti-angiogenic therapy or combination therapy have better therapeutic effects in advanced non-small cell lung cancer.</div></div><div><h3>Conclusion</h3><div>Our study demonstrated that the therapeutic effect of anti-angiogenic treatment after immune checkpoint therapy was superior to that of concurrent therapy, whereas anti-angiogenic therapy followed by immunotherapy did not bring more significant clinical benefits than independent monotherapy.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101077"},"PeriodicalIF":4.8,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142677488","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":"Depletion of β1,6-N-acetylglucosaminyltransferase reduces E-selectin binding capacity and migratory potential of human gastrointestinal adenocarcinoma cells","authors":"Lisa Staffeldt ,&nbsp;Hanna Maar ,&nbsp;Julia Beimdiek ,&nbsp;Samuel Chambers ,&nbsp;Kristoffer Riecken ,&nbsp;Mark von Itzstein ,&nbsp;Falk F.R. Buettner ,&nbsp;Arun Everest-Dass ,&nbsp;Tobias Lange","doi":"10.1016/j.neo.2024.101083","DOIUrl":"10.1016/j.neo.2024.101083","url":null,"abstract":"<div><div>The commonly altered glycosylation of tumor cells is a hallmark of tumor progression and metastasis formation. One prominent example is the interaction of sialylated glycans at the tumor cell surface with endothelial (E)-selectin as an early event of an adhesion cascade that enables extravasation of circulating tumor cells (CTCs) into distant tissues. In a previous study, we identified GCNT3 (mucin-type core2/ core4 β1,6-<em>N</em>-acetylglucosaminyltransferase) highly over-expressed in gastrointestinal adenocarcinoma cells that facilitate the canonical E-selectin ligands sialyl-Lewis A and X (sLeA/X) for E-selectin binding and endothelial adhesion. Here we show that shRNA-mediated, stable depletion of GCNT3 reduced sLeA (tumor marker CA19-9) presentation on two out of three tested human gastrointestinal adenocarcinoma cell lines, concurrently showing reduced static E-selectin binding. Significant effects of GCNT3 depletion on dynamic, shear-resistant tumor cell adhesion on immobilized E-selectin as well as endothelial cells were only partially and inconsistently observable as were effects on tumor cell proliferation (2D) or 3D colony formation. Nevertheless, tumor cell migration was consistently reduced upon GCNT3 depletion in all tested cell lines. Detailed glycome analyses revealed that GCNT3 depletion caused cell line-specific alterations in <em>N</em>- and <em>O</em>-glycans as well as glycosphingolipids, collectively mainly associating with decreased Core-2 structures resulting in varied abundance of sialylation and Lewis antigen with consistent phenotypic changes. Distinctive <em>N</em>- and <em>O</em>-glycosylation features were found to be inherent to specific cell types. These findings suggest GCNT3 products as possible carriers of sLeA and static E-selectin binding sites as well as common pro-migratory glycans in human gastrointestinal cancer.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101083"},"PeriodicalIF":4.8,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639943","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}