scholarly journals Carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) in Pancreatic Ductal Adenocarcinoma (PDA): An integrative analysis of a novel therapeutic target

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Ritu Pandey ◽  
Muhan Zhou ◽  
Shariful Islam ◽  
Baowei Chen ◽  
Natalie K Barker ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Therapeutic Target ◽  
Cell Activity ◽  
Gene Expression Omnibus ◽  
The Cancer Genome Atlas ◽  
Ductal Adenocarcinoma ◽  
Wild Type ◽  
Cancer Genome Atlas ◽  
Novel Therapeutic

AbstractWe investigated biomarker CEACAM6, a highly abundant cell surface adhesion receptor that modulates the extracellular matrix (ECM) in pancreatic ductal adenocarcinoma (PDA). The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) RNA-Seq data from PDA patients were analyzed for CEACAM6 expression and evaluated for overall survival, association, enrichment and correlations. A CRISPR/Cas9 Knockout (KO) of CEACAM6 in PDA cell line for quantitative proteomics, mitochondrial bioenergetics and tumor growth in mice were conducted. We found CEACAM6 is over-expressed in primary and metastatic basal and classical PDA subtypes. Highest levels are in classical activated stroma subtype. CEACAM6 over-expression is universally a poor prognostic marker in KRAS mutant and wild type PDA. High CEACAM6 expression is associated with low cytolytic T-cell activity in both basal and classical PDA subtypes and correlates with low levels of T-REG markers. In HPAF-II cells knockout of CEACAM6 alters ECM-cell adhesion, catabolism, immune environment, transmembrane transport and autophagy. CEACAM6 loss increases mitochondrial basal and maximal respiratory capacity. HPAF-II CEACAM6−/− cells are growth suppressed by >65% vs. wild type in mice bearing tumors. CEACAM6, a key regulator affects several hallmarks of PDA including the fibrotic reaction, immune regulation, energy metabolism and is a novel therapeutic target in PDA.

scholarly journals Role of tumor mutation burden-related signatures in the prognosis and immune microenvironment of pancreatic ductal adenocarcinoma

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Rong Tang ◽  
Xiaomeng Liu ◽  
Wei Wang ◽  
Jie Hua ◽  
Jin Xu ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Predictive Accuracy ◽  
The Cancer Genome Atlas ◽  
Ductal Adenocarcinoma ◽  
Immune Microenvironment ◽  
Tumor Mutation Burden ◽  
Oncogenic Pathways ◽  
Mutation Burden ◽  
Cancer Genome Atlas

Abstract Background High tumor mutation burden (TMB) has gradually become a sensitive biomarker for predicting the response to immunotherapy in many cancers, including lung, bladder and head and neck cancers. However, whether high TMB predicts the response to immunotherapy and prognosis in pancreatic ductal adenocarcinoma (PDAC) remained obscure. Hence, it is significant to investigate the role of genes related to TMB (TRGs) in PDAC. Methods The transcriptome and mutation data of PDAC was downloaded from The Cancer Genome Atlas-Pancreatic Adenocarcinoma (TCGA). Five independent external datasets of PDAC were chosen to validate parts of our results. qRT-PCR and immunohistochemical staining were also performed to promote the reliability of this study. Results The median overall survival (OS) was significantly increased in TMB_low group compared with the counterpart with higher TMB score after tumor purity adjusted (P = 0.03). 718 differentially expressed TRGs were identified and functionally enriched in some oncogenic pathways. 67 TRGs were associated with OS in PDAC. A prognostic model for the OS was constructed and showed a high predictive accuracy (AUC = 0.849). We also found TMB score was associated with multiple immune components and signatures in tumor microenvironment. In addition, we identified a PDAC subgroup featured with TMBlowMicrosatellite instabilityhigh (MSIhigh) was associated with prolonged OS and a key molecule, ANKRD55, potentially mediating the survival benefits. Conclusion This study analyzed the biological function, prognosis value, implications for mutation landscape and potential influence on immune microenvironment of TRGs in PDAC, which contributed to get aware of the role of TMB in PDAC. Future studies are expected to investigate how these TRGs regulate the initiation, development or repression of PDAC.

SF3B1 as a novel therapeutic target in pancreatic ductal adenocarcinoma: antitumoral effects of the splicing inhibitor Pladienolide B

Pancreatology ◽  
2019 ◽  
Vol 19 ◽  
pp. S78
Author(s):  
Emilia Alors-Pérez ◽  
Ricardo Blázquez-Encinas ◽  
Sergio Pedraza-Arévalo ◽  
Juan Manuel Jimenez-Vacas ◽  
Cristina Viyuela-Garcia ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Therapeutic Target ◽  
Ductal Adenocarcinoma ◽  
Pladienolide B ◽  
Novel Therapeutic

scholarly journals Schlafen 5 as a novel therapeutic target in pancreatic ductal adenocarcinoma

Oncogene ◽  
2021 ◽  
Author(s):  
Mariafausta Fischietti ◽  
Frank Eckerdt ◽  
Gavin T. Blyth ◽  
Ahmet D. Arslan ◽  
William M. Mati ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Therapeutic Target ◽  
Ductal Adenocarcinoma ◽  
Novel Therapeutic

scholarly journals Role of Tumor Mutation Burden-related Signatures in the Prognosis and Immune Microenvironment of Pancreatic Ductal Adenocarcinoma

2021 ◽  
Author(s):  
Rong Tang ◽  
Xiaomeng Liu ◽  
Wei Wang ◽  
Jie Hua ◽  
Jin Xu ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Predictive Accuracy ◽  
The Cancer Genome Atlas ◽  
Ductal Adenocarcinoma ◽  
Immune Microenvironment ◽  
Tumor Mutation Burden ◽  
Oncogenic Pathways ◽  
Mutation Burden ◽  
Cancer Genome Atlas

Abstract Background High tumor mutation burden (TMB) has gradually become a sensitive biomarker for predicting the response to immunotherapy in many cancers, including lung, bladder and head and neck cancers. Nonetheless, whether high TMB could predict the response to immunotherapy and prognosis in pancreatic ductal adenocarcinoma (PDAC), a classic “cold” tumor, remained obscure. Hence, it is significant to investigate the role of genes related to TMB (TRGs) in PDAC.Methods The transcriptome and mutation data of PDAC was downloaded from The Cancer Genome Atlas-Pancreatic Adenocarcinoma (TCGA). Five independent external datasets of PDAC were chosen to validate parts of our results. qRT-PCR and immunohistochemical staining were also performed to promote the reliability of this study. Results The median overall survival (OS) was significantly increased in TMB_low group compared with the counterpart with higher TMB score after tumor purity adjusted (P = 0.03). 718 differentially expressed TRGs were identified and functionally enriched in some oncogenic pathways. 67 TRGs were associated with OS in PDAC. A prognostic model for the OS was constructed and showed a high predictive accuracy (AUC = 0.849). We also found TMB score was associated with multiple immune components and signatures in tumor microenvironment. In addition, we identified a PDAC subgroup featured with TMBlowMSIhigh was associated with prolonged OS and a key molecule, ANKRD55, potentially mediating the survival benefits.Conclusion This study analyzed the biological function, prognosis value, implications for mutation landscape and potential influence on immune microenvironment of TRGs in PDAC, which contributed to get aware of the role of TMB in PDAC. Future studies are expected to investigate how these TRGs regulate the initiation, development or repression of PDAC.

scholarly journals RUNX1 and REXO2 are associated with the heterogeneity and prognosis of IDH wild type lower grade glioma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Haiwei Wang ◽  
Xinrui Wang ◽  
Liangpu Xu ◽  
Ji Zhang ◽  
Hua Cao
Keyword(s):  
Transcription Factor ◽  
Low Frequency ◽  
Tumor Grade ◽  
The Cancer Genome Atlas ◽  
Lower Grade ◽  
Wild Type ◽  
Lower Grade Glioma ◽  
Cancer Genome Atlas ◽  
Worse Prognosis ◽  
Genome Atlas

AbstractBased on isocitrate dehydrogenase (IDH) alterations, lower grade glioma (LGG) is divided into IDH mutant and wild type subgroups. However, the further classification of IDH wild type LGG was unclear. Here, IDH wild type LGG patients in The Cancer Genome Atlas and Chinese Glioma Genome Atlas were divided into two sub-clusters using non-negative matrix factorization. IDH wild type LGG patients in sub-cluster2 had prolonged overall survival and low frequency of CDKN2A alterations and low immune infiltrations. Differentially expressed genes in sub-cluster1 were positively correlated with RUNX1 transcription factor. Moreover, IDH wild type LGG patients with higher stromal score or immune score were positively correlated with RUNX1 transcription factor. RUNX1 and its target gene REXO2 were up-regulated in sub-cluster1 and associated with the worse prognosis of IDH wild type LGG. RUNX1 and REXO2 were associated with the higher immune infiltrations. Furthermore, RUNX1 and REXO2 were correlated with the worse prognosis of LGG or glioma. IDH wild type LGG in sub-cluster2 was hyper-methylated. REXO2 hyper-methylation was associated with the favorable prognosis of LGG or glioma. At last, we showed that, age, tumor grade and REXO2 expression were independent prognostic factors in IDH wild type LGG.

scholarly journals Multiscale-omic assessment of EWSR1-NFATc2 fusion positive sarcomas identifies the mTOR pathway as a potential therapeutic target

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Nathan D. Seligson ◽  
Richard D. Maradiaga ◽  
Colin M. Stets ◽  
Howard M. Katzenstein ◽  
Sherri Z. Millis ◽  
...  
Keyword(s):  
Ewing Sarcoma ◽  
Additional Data ◽  
Gene Expression Omnibus ◽  
Mtor Pathway ◽  
The Cancer Genome Atlas ◽  
Molecular Characteristics ◽  
Potential Therapeutic Target ◽  
Disease Stabilization ◽  
Cancer Genome Atlas ◽  
Ewing Family Of Tumors

AbstractSarcomas harboring EWSR1-NFATc2 fusions have historically been categorized and treated as Ewing sarcoma. Emerging evidence suggests unique molecular characteristics and chemotherapy sensitivities in EWSR1-NFATc2 fusion positive sarcomas. Comprehensive genomic profiles of 1024 EWSR1 fusion positive sarcomas, including 14 EWSR1-NFATc2 fusions, were identified in the FoundationCore® database. Additional data from the Gene Expression Omnibus, the Genomics of Drug Sensitivity in Cancer and The Cancer Genome Atlas datasets were included for analysis. EWSR1-NFATc2 fusion positive sarcomas were genomically distinct from traditional Ewing sarcoma and demonstrated upregulation of the mTOR pathway. We also present a case of a 58-year-old male patient with metastatic EWSR1-NFATc2 fusion positive sarcoma who achieved 47 months of disease stabilization when treated with combination mTOR and VEGF inhibition. EWSR1-NFATc2 fusion positive sarcomas are molecularly distinct entities with overactive mTOR signaling; which may be therapeutically targetable. These findings support the use of precision medicine in the Ewing family of tumors.

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