Molecular Oncology最新文献

{"title":"IDH mutation, glioma immunogenicity, and therapeutic challenge of primary mismatch repair deficient IDH-mutant astrocytoma PMMRDIA: a systematic review.","authors":"Olfat Ahmad, Tahani Ahmad, Stefan M Pfister","doi":"10.1002/1878-0261.13598","DOIUrl":"10.1002/1878-0261.13598","url":null,"abstract":"<p><p>In 2021, Suwala et al. described Primary Mismatch Repair Deficient IDH-mutant Astrocytoma (PMMRDIA) as a distinct group of gliomas. In unsupervised clustering, PMMRDIA forms distinct cluster, separate from other IDH-mutant gliomas, including IDH-mutant gliomas with secondary mismatch repair (MMR) deficiency. In the published cohort, three patients received treatment with an immune checkpoint blocker (ICB), yet none exhibited a response, which aligns with existing knowledge about the decreased immunogenicity of IDH-mutant gliomas in comparison to IDH-wildtype. In the case of PMMRDIA, the inherent resistance to the standard-of-care temozolomide caused by MMR deficiency is an additional challenge. It is known that a gain-of-function mutation of IDH1/2 genes produces the oncometabolite R-2-hydroxyglutarate (R-2-HG), which increases DNA and histone methylation contributing to the characteristic glioma-associated CpG island methylator phenotype (G-CIMP). While other factors could be involved in remodeling the tumor microenvironment (TME) of IDH-mutant gliomas, this systematic review emphasizes the role of R-2-HG and the subsequent G-CIMP in immune suppression. This highlights a potential actionable pathway to enhance the response of ICB, which might be relevant for addressing the unmet therapeutic challenge of PMMRDIA.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2822-2841"},"PeriodicalIF":6.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619801/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139712628","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":"Loss of SETD2 in wild-type VHL clear cell renal cell carcinoma sensitizes cells to STF-62247 and leads to DNA damage, cell cycle arrest, and cell death characteristic of pyroptosis.","authors":"Mathieu Johnson, Sandra Turcotte","doi":"10.1002/1878-0261.13770","DOIUrl":"https://doi.org/10.1002/1878-0261.13770","url":null,"abstract":"<p><p>Loss of chromosome 3p and loss of heterogeneity of the von Hippel-Lindau (VHL) gene are common characteristics of clear cell renal cell carcinoma (ccRCC). Despite frequent mutations on VHL, a fraction of tumors still grows with the expression of wild-type (WT) VHL and evolve into an aggressive subtype. Additionally, mutations on chromatin-modifying genes, such as the gene coding for the histone methyltransferase SET containing domain 2 (SETD2), are essential to ccRCC evolution. We previously identified STF-62247, a small molecule first discovered as a synthetically lethal molecule for VHL-deficient cells by blocking late stages of autophagy. This study investigated how other commonly mutated genes in ccRCC could impact the response to STF-62247. We showed that SETD2 inactivation in ccRCC cells expressing WT-VHL became vulnerable to STF-62247, as indicated by decreases in cell proliferation and survival. Furthermore, activation of the DNA damage response pathway leads to the loss of M-phase inducer phosphatase 1 (CDC25A) and cell cycle arrest in S phase. Cleavage of both caspase-3 and gasdermin E suggests that STF-62247 eliminates WT-VHL ccRCC cells through pyroptosis specifically when SETD2 is inactivated.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142730727","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":"Crosstalk between gut microbiota and tumor: tumors could cause gut dysbiosis and metabolic imbalance.","authors":"Siyuan Zhang, Haimei Wen, Ying Chen, Jingya Ning, Di Hu, Yujiao Dong, Chenyu Yao, Bo Yuan, Shuanying Yang","doi":"10.1002/1878-0261.13763","DOIUrl":"https://doi.org/10.1002/1878-0261.13763","url":null,"abstract":"<p><p>Gut microbiota has a proven link with the development and treatment of cancer. However, the causality between gut microbiota and cancer development is still unknown and deserves exploration. In this study, we aimed to explore the alterations in gut microbiota in murine tumor models and the crosstalk between the tumor and the gut microbiota. The subcutaneous and intravenous murine tumor models using both the colorectal cancer cell line MC38 and lung cancer cell line LLC were constructed. Then fecal samples before and after tumor inoculation were collected for whole metagenomics sequencing. Both subcutaneous and metastatic tumors markedly elevated the α-diversity of the gut microbiota. Relative abundance of Ligilactobacillus and Lactobacillus was reduced after subcutaneously inoculating tumor cells, whereas Bacteroides and Duncaniella were reduced in metastatic tumors, regardless of tumor type. At the species level, Lachnospiraceae bacterium was enriched after both subcutaneous and intravenous tumors inoculation, whereas levels of Muribaculaceae bacterium Isolate-110 (HZI), Ligilactobacillus murinus and Bacteroides acidifaciens reduced. Metabolic function analysis showed that the reductive pentose phosphate cycle, urea cycle, ketone body biosynthesis, ectoine biosynthesis, C4-dicarboxylic acid cycle, isoleucine biosynthesis, inosine 5'-monophosphate (IMP), and uridine 5'-monophosphate (UMP) biosynthesis were elevated after tumor inoculation, whereas the cofactor and vitamin biosynthesis were deficient. Principal coordinates analysis (PCoA) showed that subcutaneous and metastatic tumors partially shared the same effect patterns on gut microbiota. Furthermore, fecal microbiota transplantation revealed that this altered microbiota could influence tumor growth. Taken together, this study demonstrated that both colorectal cancer (MC38) and non-colorectal cancer (LLC) can cause gut dysbiosis and metabolic imbalance, regardless of tumor type and process of tumor inoculation, and this dysbiosis influenced the tumor growth. This research gives novel insights into the crosstalk between tumors and the gut microbiota.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142730721","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":"Integrative analysis of circulating tumor cells (CTCs) and exosomes from small-cell lung cancer (SCLC) patients: a comprehensive approach.","authors":"Dimitrios Papakonstantinou, Argyro Roumeliotou, Evangelia Pantazaka, Athanasios-Nasir Shaukat, Athina Christopoulou, Angelos Koutras, Foteinos-Ioannis Dimitrakopoulos, Vassilis Georgoulias, Anastasia Xagara, Evangelia Chantzara, Fillipos Koinis, Athanasios Kotsakis, Constantinos Stathopoulos, Galatea Kallergi","doi":"10.1002/1878-0261.13765","DOIUrl":"https://doi.org/10.1002/1878-0261.13765","url":null,"abstract":"<p><p>The increased metastatic ability of small-cell lung cancer (SCLC) necessitates the identification of new prognostic biomarkers for clinical evaluation during the disease course. Our previous research highlighted the clinical relevance of transcription factor JunB (JUNB), C-X-C chemokine receptor type 4 (CXCR4), and programmed cell death 1 ligand 1 (PD-L1) in breast and non-small cell lung cancer (NSCLC) patients. In the current study, we examined these biomarkers in circulating tumor cells (CTCs) and plasma-derived exosomes from 100 treatment-naïve SCLC patients. CTCs were analyzed using the VyCAP system, whereas exosomes were characterized molecularly and transcriptomically. JUNB, CXCR4, and PD-L1 were highly prevalent in CTCs. Patients exhibited significantly increased protein exosomal expression of JUNB and CXCR4 compared to healthy individuals. Overexpression of JUNB and CXCR4 in exosomes can distinguish patients from normal donors, offering an interesting tool for early diagnosis. The presence of JUNB and/or CXCR4 in CTCs correlated with significantly poorer overall survival. CXCR4 exosomal overexpression was associated with CTC presence and their phenotypes. Conclusively, a comprehensive analysis of CTCs and exosomes provides useful prognostic and potential diagnostic tools for SCLC patients.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142687725","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":"Gut microbiota diversity is prognostic and associated with benefit from chemo-immunotherapy in metastatic triple-negative breast cancer.","authors":"Andreas Ullern, Kristian Holm, Andreas Hagen Røssevold, Nikolai Kragøe Andresen, Corinna Bang, Ole Christian Lingjærde, Bjørn Naume, Johannes R Hov, Jon Amund Kyte","doi":"10.1002/1878-0261.13760","DOIUrl":"https://doi.org/10.1002/1878-0261.13760","url":null,"abstract":"<p><p>The gut microbiota influences multiple aspects of human health and disease. Several studies have indicated an association between the gut microbiota and response to immune checkpoint inhibitors in various cancers, but there is scarce data from breast cancer. The randomized ALICE trial demonstrated improved progression-free survival (PFS) from adding the programmed cell death 1 ligand 1 (PD-L1) inhibitor atezolizumab (atezo) to immunomodulating chemotherapy (chemo) in metastatic triple-negative breast cancer (mTNBC), even for PD-L1^negative disease. Herein, we investigated the microbiota composition and dynamics in the ALICE patients and their association with clinical outcome, by analyzing fecal samples collected at baseline and after 8 weeks. We applied 16S (V3-V4) rRNA sequencing to characterize the diversity and taxonomic composition. Kaplan-Meier and Cox proportional hazard models were used for time-to-event analyses. We found that high alpha diversity by Faith's phylogenetic diversity (PD) at baseline was associated with prolonged PFS in the total study population and in the atezo-chemo arm, but not in the placebo-chemo arm. Moreover, Faith's PD appeared to be predictive of benefit from atezolizumab. Patients with high Faith's PD exhibited a PFS hazard ratio of 0.34 (P = 0.018) in favor of the atezo-chemo arm, compared to 0.83 (P = 0.62) in the low Faith's PD group. Faith's PD was significantly reduced during treatment. At baseline, Bifidobacterium was significantly overrepresented in patients without clinical benefit in the atezo-chemo arm, but not in the placebo-chemo arm. These findings suggest that alpha diversity by Faith's PD should be further investigated as a prognostic and predictive biomarker in patients with mTNBC receiving chemo-immunotherapy.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639322","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":"Vertical inhibition of p110α/AKT and N-cadherin enhances treatment efficacy in PIK3CA-aberrated ovarian cancer cells.","authors":"Shibo Zhang, Hei Ip Hong, Victor C Y Mak, Yuan Zhou, Yiling Lu, Guanglei Zhuang, Lydia W T Cheung","doi":"10.1002/1878-0261.13761","DOIUrl":"10.1002/1878-0261.13761","url":null,"abstract":"<p><p>Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [PIK3CA, encoding PI3Kalpha (also known as p110α)] is one of the most commonly aberrated genes in human cancers. In serous ovarian cancer, PIK3CA amplification is highly frequent but PIK3CA point mutation is rare. However, whether PIK3CA amplification and PIK3CA driver mutations have the same functional impact in the disease is unclear. Here, we report that both PIK3CA amplification and E545K mutation are tumorigenic. While the protein kinase B (AKT) signaling axis was activated in both E545K knock-in cells and PIK3CA-overexpressing cells, the mitogen-activated protein kinase 3/1 (ERK1/2) pathway was induced selectively by E545K mutation but not PIK3CA amplification. Intriguingly, AKT signaling in these PIK3CA-aberrated cells increased transcriptional coactivator YAP1 (YAP) Ser127 phosphorylation and thereby cytoplasmic YAP levels, which in turn increased cell migration through Ras-related C3 botulinum toxin substrate 1 (RAC1) activation. In addition to the altered YAP signaling, AKT upregulated N-cadherin expression, which also contributed to cell migration. Pharmacological inhibition of N-cadherin reduced cell migratory potential. Importantly, co-targeting N-cadherin and p110α/AKT caused additive reduction in cell migration in vitro and metastases formation in vivo. Together, this study reveals the molecular pathways driven by the PIK3CA aberrations and the exploitable vulnerabilities in PIK3CA-aberrated serous ovarian cancer cells.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624078","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":"Integrative transcriptomic analysis identifies emetine as a promising candidate for overcoming acquired resistance to ALK inhibitors in lung cancer.","authors":"Sang-Min Park, Keeok Haam, Haejeong Heo, Doyeong Kim, Min-Ju Kim, Hyo-Jung Jung, Seongwon Cha, Mirang Kim, Haeseung Lee","doi":"10.1002/1878-0261.13738","DOIUrl":"https://doi.org/10.1002/1878-0261.13738","url":null,"abstract":"<p><p>Anaplastic lymphoma kinase (ALK; also known as ALK tyrosine kinase receptor) inhibitors (ALKi) are effective in treating lung cancer patients with chromosomal rearrangement of ALK. However, continuous treatment with ALKis invariably leads to acquired resistance in cancer cells. In this study, we propose an efficient strategy to suppress ALKi resistance through a meta-analysis of transcriptome data from various cell models of acquired resistance to ALKis. We systematically identified gene signatures that consistently showed altered expression during the development of resistance and conducted computational drug screening using these signatures. We identified emetine as a promising candidate compound to inhibit the growth of ALKi-resistant cells. We demonstrated that emetine exhibited effectiveness in inhibiting the growth of ALKi-resistant cells, and further interpreted its impact on the resistant signatures through drug-induced RNA-sequencing data. Our transcriptome-guided systematic approach paves the way for efficient drug discovery to overcome acquired resistance to cancer therapy.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623929","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":"Adenoviral delivery of the CIITA transgene induces T-cell-mediated killing in glioblastoma organoids.","authors":"Ilaria Salvato, Eliane Klein, Aurélie Poli, Mahsa Rezaeipour, Luca Ermini, Bakhtiyor Nosirov, Anuja Lipsa, Anaïs Oudin, Virginie Baus, Gian Mario Dore, Antonio Cosma, Anna Golebiewska, Antonio Marchini, Simone P Niclou","doi":"10.1002/1878-0261.13750","DOIUrl":"https://doi.org/10.1002/1878-0261.13750","url":null,"abstract":"<p><p>The immunosuppressive nature of the tumor microenvironment poses a significant challenge to effective immunotherapies against glioblastoma (GB). Boosting the immune response is critical for successful therapy. Here, we adopted a cancer gene therapy approach to induce T-cell-mediated killing of the tumor through increased activation of the immune system. Patient-based three-dimensional (3D) GB models were infected with a replication-deficient adenovirus (AdV) armed with the class II major histocompatibility complex (MHC-II) transactivator (CIITA) gene (Ad-CIITA). Successful induction of surface MHC-II was achieved in infected GB cell lines and primary human GB organoids. Infection with an AdV carrying a mutant form of CIITA with a single amino acid substitution resulted in cytoplasmic accumulation of CIITA without subsequent MHC-II expression. Co-culture of infected tumor cells with either peripheral blood mononuclear cells (PBMCs) or isolated T-cells led to dramatic breakdown of GB organoids. Intriguingly, both wild-type and mutant Ad-CIITA, but not unarmed AdV, triggered immune-mediated tumor cell death in the co-culture system, suggesting an at least partially MHC-II-independent process. We further show that the observed cancer cell killing requires the presence of either CD8⁺ or CD4⁺ T-cells and direct contact between GB and immune cells. We did not, however, detect evidence of activation of canonical T-cell-mediated cell death pathways. Although the precise mechanism remains to be determined, these findings highlight the potential of AdV-mediated CIITA delivery to enhance T-cell-mediated immunity against GB.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623928","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":"Replenishing co-downregulated miR-100-5p and miR-125b-5p in malignant germ cell tumors causes growth inhibition through cell cycle disruption.","authors":"Marta Ferraresso, Shivani Bailey, Luz Alonso-Crisostomo, Dawn Ward, Christos Panayi, Zachary G L Scurlock, Harpreet K Saini, Stephen P Smith, James C Nicholson, Anton J Enright, Cinzia G Scarpini, Nicholas Coleman, Matthew J Murray","doi":"10.1002/1878-0261.13757","DOIUrl":"https://doi.org/10.1002/1878-0261.13757","url":null,"abstract":"<p><p>MicroRNAs (miRNAs) are short, nonprotein-coding RNAs, and their expression is dysregulated in malignant germ cell tumors (GCTs). Here, we investigated the causes and consequences of downregulated miR-99a-5p/miR-100-5p (functionally identical) and miR-125b-5p levels in malignant GCTs regardless of age, site, or subtype. Quantitative RT-PCR was used to assess miR-99a-5p/miR-100-5p, miR-125b-5p, and associated gene expression in malignant GCT tissues/cell lines [seminoma (Sem), yolk sac tumor (YST), embryonal carcinoma (EC)]. Cells were treated with demethylating 5-azacytidine and pyrosequencing was performed. Combination miR-100-5p/miR-125b-5p mimic replenishment was used to treat malignant GCT cells. Global messenger RNA (mRNA) targets of the replenished miRNAs were identified and Metascape used to study pathway effects. We found that expression levels of miR-99a-5p/miR-100-5p and miR-125b-5p, their respective pri-miRNAs, and associated genes from chromosomes 11 and 21 (chr11/chr21) were downregulated and highly correlated in malignant GCT cells. Treatment with 5-azacytidine caused upregulation of these miRNAs, with pyrosequencing revealing hypermethylation of their chr11/chr21 loci, likely contributing to miR-100-5p/miR-125b-5p downregulation. Combination miR-100-5p/miR-125b-5p mimic replenishment resulted in growth inhibition in Sem/YST cells, with miR-100-5p/miR-125b-5p mRNA targets enriched in downregulated genes, which were involved in cell cycle (confirmed by flow cytometry) and signaling pathways. Knockdown of the miR-100-5p/miR-125b-5p target tripartite motif containing 71 (TRIM71kd) recapitulated miR-100-5p/miR-125b-5p replenishment, with growth inhibition and cell cycle disruption of Sem/YST/EC cells. Further, replenishment led to reduced lin-28 homolog A (LIN28A) levels and concomitant increases in let-7 (MIRLET7B) tumor suppressor miRNAs, creating a sustained reversion of cell phenotype. In summary, combination miR-100-5p/miR-125b-5p mimic replenishment or TRIM71kd caused growth inhibition in malignant GCT cells via cell cycle disruption. Further studies are now warranted, including mimic treatment alongside conventional platinum-based chemotherapy.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623841","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":"E-selectin affinity glycoproteomics reveals neuroendocrine proteins and the secretin receptor as a poor-prognosis signature in colorectal cancer.","authors":"Sofia Cotton, Dylan Ferreira, Marta Relvas-Santos, Andreia Brandão, Luís Pedro Afonso, Andreia Miranda, Eduardo Ferreira, Beatriz Santos, Martina Gonçalves, Paula Lopes, Lúcio Lara Santos, André M N Silva, José Alexandre Ferreira","doi":"10.1002/1878-0261.13733","DOIUrl":"https://doi.org/10.1002/1878-0261.13733","url":null,"abstract":"<p><p>Colorectal cancer (CRC) cells express sialylated Lewis antigens (sLe), crucial for metastasis via E-selectin binding. However, these glycoepitopes lack cancer specificity, and E-selectin-targeted glycoproteins remain largely unknown. Here, we established a framework for identifying metastasis-linked glycoproteoforms. More than 70% of CRC tumors exhibited overexpression of sLeA/X, yet without discernible associations with metastasis or survival. However, The Cancer Genome Atlas (TCGA) analysis unveiled differing expression patterns of sLeA/X-related glycogenes correlating with disease severity, indicating context-dependent regulation by distinct glycosyltransferases. Deeper exploration of metastatic tumor sialoglycoproteome identified nearly 600 glycoproteins, greatly expanding our understanding of the metastasis-related glycoproteome. These glycoproteins were linked to cell adhesion, oncogenic pathways, and neuroendocrine functions. Using an in-house algorithm, the secretin receptor (SCTR) emerged as a top-ranked targetable glycoprotein. Tumor screening confirmed SCTR's association with poor prognosis and metastasis, with N-glycosylation adding cancer specificity to this glycoprotein. Prognostic links were reinforced by TCGA-based investigations. In summary, SCTR, a relatively unknown CRC glycoprotein, holds potential as a biomarker of poor prognosis and as an E-selectin ligand, suggesting an unforeseen role in disease dissemination. Future investigations should focus on this glycoprotein's biological implications for clinical applications.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142605516","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}