From Malignant Progression to Therapeutic Targeting: Current Insights of Mesothelin in Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC), accounting for 90% of all pancreatic tumors, is a highly devastating disease with poor prognosis and rising incidence. The lack of available specific diagnostics tests and the limited treatment opportunities contribute to this pejorative issue. Over the last 10 years, a growing interest pointing towards mesothelin (MSLN) as a promising PDAC-associated antigen has emerged. The limited expression of MSLN in normal tissues (peritoneum, pleura and pericardium) and its overexpression in 80 to 90% of PDAC make it an attractive candidate for therapeutic management of PDAC patients. Moreover, its role in malignant progression related to its involvement in tumor cell proliferation and resistance to chemotherapy has highlighted the relevance of its targeting. Hence, several clinical trials are investigating anti-MSLN efficacy in PDAC. In this review, we provide a general overview of the different roles sustained by MSLN during PDAC progression. Finally, we also summarize the different MSLN-targeted therapies that are currently tested in the clinic.

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High HDAC9 is associated with poor prognosis and promotes malignant progression in pancreatic ductal adenocarcinoma

Molecular Medicine Reports ◽

10.3892/mmr.2019.10869 ◽

2019 ◽

Cited By ~ 1

Author(s):

He Li ◽

Xiaocheng Li ◽

Huapeng Lin ◽

Jianping Gong

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Poor Prognosis ◽

Malignant Progression ◽

Ductal Adenocarcinoma

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Stroma Involvement in Pancreatic Ductal Adenocarcinoma: An Overview Focusing on Extracellular Matrix Proteins

Frontiers in Immunology ◽

10.3389/fimmu.2021.612271 ◽

2021 ◽

Vol 12 ◽

Author(s):

Sophie Liot ◽

Jonathan Balas ◽

Alexandre Aubert ◽

Laura Prigent ◽

Perrine Mercier-Gouy ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Poor Prognosis ◽

Matrix Proteins ◽

Ductal Adenocarcinoma ◽

Pancreatic Tumors ◽

Industrialized Countries ◽

Pancreatic Cancers ◽

Current State ◽

Combined Features ◽

Specific Symptoms

Pancreatic cancer is the seventh leading cause of cancer-related deaths worldwide and is predicted to become second in 2030 in industrialized countries if no therapeutic progress is made. Among the different types of pancreatic cancers, Pancreatic Ductal Adenocarcinoma (PDAC) is by far the most represented one with an occurrence of more than 90%. This specific cancer is a devastating malignancy with an extremely poor prognosis, as shown by the 5-years survival rate of 2–9%, ranking firmly last amongst all cancer sites in terms of prognostic outcomes for patients. Pancreatic tumors progress with few specific symptoms and are thus at an advanced stage at diagnosis in most patients. This malignancy is characterized by an extremely dense stroma deposition around lesions, accompanied by tissue hypovascularization and a profound immune suppression. Altogether, these combined features make access to cancer cells almost impossible for conventional chemotherapeutics and new immunotherapeutic agents, thus contributing to the fatal outcomes of the disease. Initially ignored, the Tumor MicroEnvironment (TME) is now the subject of intensive research related to PDAC treatment and could contain new therapeutic targets. In this review, we will summarize the current state of knowledge in the field by focusing on TME composition to understand how this specific compartment could influence tumor progression and resistance to therapies. Attention will be paid to Tenascin-C, a matrix glycoprotein commonly upregulated during cancer that participates to PDAC progression and thus contributes to poor prognosis.

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Single-Cell RNA-Seq Reveals Dynamic Change in Tumor Microenvironment During Pancreatic Ductal Adenocarcinoma Malignant Progression

SSRN Electronic Journal ◽

10.2139/ssrn.3745132 ◽

2020 ◽

Author(s):

Kai Chen ◽

Qi Wang ◽

Mingzhe Li ◽

Huahu Guo ◽

Weikang Liu ◽

...

Keyword(s):

Tumor Microenvironment ◽

Single Cell ◽

Pancreatic Ductal Adenocarcinoma ◽

Dynamic Change ◽

Malignant Progression ◽

Ductal Adenocarcinoma ◽

Rna Seq

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Low expression of tRF‐Pro‐CGG predicts poor prognosis in pancreatic ductal adenocarcinoma

Journal of Clinical Laboratory Analysis ◽

10.1002/jcla.23742 ◽

2021 ◽

Author(s):

Jun Li ◽

Lei Jin ◽

Yuan Gao ◽

Peng Gao ◽

Le Ma ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Poor Prognosis ◽

Ductal Adenocarcinoma ◽

Low Expression

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Aberrant methylation ofReprimo correlates with genetic instability and predicts poor prognosis in pancreatic ductal adenocarcinoma

Cancer ◽

10.1002/cncr.21977 ◽

2006 ◽

Vol 107 (2) ◽

pp. 251-257 ◽

Cited By ~ 24

Author(s):

Norihiro Sato ◽

Noriyoshi Fukushima ◽

Hiroyuki Matsubayashi ◽

Christine A. Iacobuzio-Donahue ◽

Charles J. Yeo ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Genetic Instability ◽

Poor Prognosis ◽

Ductal Adenocarcinoma ◽

Aberrant Methylation

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High expression of ErbB3 binding protein 1 (EBP1) predicts poor prognosis of pancreatic ductal adenocarcinoma (PDAC)

Tumor Biology ◽

10.1007/s13277-015-3625-6 ◽

2015 ◽

Vol 36 (12) ◽

pp. 9189-9199 ◽

Cited By ~ 2

Author(s):

Chen Gong ◽

Yixin Zhang ◽

Yinji Chen ◽

Haifeng Zhang ◽

Xiaorong Liu ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Poor Prognosis ◽

Binding Protein ◽

High Expression ◽

Ductal Adenocarcinoma

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Therapeutic Targeting of Autophagy in Pancreatic Ductal Adenocarcinoma

Frontiers in Pharmacology ◽

10.3389/fphar.2021.751568 ◽

2021 ◽

Vol 12 ◽

Author(s):

Alexander G. Raufi ◽

Nicholas R. Liguori ◽

Lindsey Carlsen ◽

Cassandra Parker ◽

Liz Hernandez Borrero ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Alternative Energy ◽

Mapk Pathway ◽

Ductal Adenocarcinoma ◽

Therapeutic Targeting ◽

Aggressive Disease ◽

Alternative Energy Sources ◽

Novel Treatment ◽

Late Detection ◽

Autophagy Inhibition

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by early metastasis, late detection, and poor prognosis. Progress towards effective therapy has been slow despite significant efforts. Novel treatment approaches are desperately needed and autophagy, an evolutionary conserved process through which proteins and organelles are recycled for use as alternative energy sources, may represent one such target. Although incompletely understood, there is growing evidence suggesting that autophagy may play a role in PDAC carcinogenesis, metastasis, and survival. Early clinical trials involving autophagy inhibiting agents, either alone or in combination with chemotherapy, have been disappointing. Recently, evidence has demonstrated synergy between the MAPK pathway and autophagy inhibitors in PDAC, suggesting a promising therapeutic intervention. In addition, novel agents, such as ONC212, have preclinical activity in pancreatic cancer, in part through autophagy inhibition. We discuss autophagy in PDAC tumorigenesis, metabolism, modulation of the immune response, and preclinical and clinical data with selected autophagy modulators as therapeutics.

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SLC39A1 Contributes to Gemcitabine Resistance of Pancreatic Ductal Adenocarcinoma by Activating AMPK Signaling

10.21203/rs.3.rs-856017/v1 ◽

2021 ◽

Author(s):

Hao Yu ◽

Xiaoping Mei ◽

Xueming Zhang ◽

Neng Qian ◽

Qingjiang Yu ◽

...

Keyword(s):

Cell Proliferation ◽

Protein Expression ◽

Pancreatic Ductal Adenocarcinoma ◽

Western Blotting ◽

Poor Prognosis ◽

Ductal Adenocarcinoma ◽

Tumor Type ◽

Ampk Signaling ◽

Gemcitabine Resistance ◽

Mrna And Protein Expression

Abstract Objective: Pancreatic ductal adenocarcinoma (PDAC) serves as a prevailing tumor type with high mortality and poor prognosis. The study aims to explore the mechanism of gemcitabine resistance in PDAC patients. Methods: Immunohistochemistry(IHC)was used to analyze the expression of SLC39A1 in PDAC samples. PDAC cells were culture and transfected with siSLC39A1 and siNC, respectively. Cell proliferation analysis was performed using CCK-8 assay. And qPCR and Western blotting was used to analysis the expression level of SLC39A1 and related signal molecular in cells. Results: IHC results demonstrated that the SLC39A1 expression was significantly up-regulated in the gemcitabine-resistant PDAC samples compared with gemcitabine-sensitive PDAC samples. The treatment of gemcitabine dose-dependently inhibited the viability of the PDAC cells. Meanwhile, the mRNA and protein expression of SLC39A1 were elevated in the gemcitabine-resistant PDAC. The treatment of gemcitabine remarkably decreased viability of PDACs, in which SLC39A1 depletion could reverse this effect. SLC39A1 knockdown could reverse the gemcitabine-induced phosphorylation of AMPK enhanced and gemcitabine-inhibited S6K expression. Conclusion: SLC39A1 contributed to gemcitabine resistance of PDAC by activating AMPK signaling.

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