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Editor | xi Pancreatic cancer is the third leading cause of cancer-related deaths, of which approximately 90% are Pancreatic Ductal Adenocarcinoma (Pancreatic Ductal Adenocarcinoma)
.
At present, the lack of effective early diagnosis methods for pancreatic ductal adenocarcinoma results in the vast majority of patients (80-85%) being diagnosed in the middle and late stages of the disease, so they cannot receive surgical treatment
.
Although chemotherapy has a certain effect on patients with pancreatic ductal adenocarcinoma, the median overall survival is still less than 12 months
.
The gene mutations that drive the occurrence and development of pancreatic ductal adenocarcinoma are mainly KRAS activating point mutations.
However, apart from the specific mutation form G12C, KRAS is considered to be a non-drugable target
.
Since KRAS mutations have a wide range of effects on the tumor microenvironment and the occurrence and development of tumors, the identification of key signaling pathways downstream of KRAS is of great significance for the treatment of this disease
.
In addition, the vast majority of pancreatic ductal adenocarcinomas are immune "cold" tumors, so specific molecular targets are needed to identify immune "hot" patients who may benefit from immunotherapy, and reveal that immune "cold" pancreatic ductal adenocarcinoma drives immune rejection Mechanism
.
On September 16, 2021, a collaborative team from Johns Hopkins University, Baylor College of Medicine, and Washington University in St.
Louis published an article Proteogenomic characterization of pancreatic ductal adenocarcinoma in Cell, using proteogenomics big data to comprehensively analyze pancreatic ductal adenocarcinoma Identification, identification of new potential therapeutic targets and early diagnosis markers
.
The researchers identified 140 pancreatic cancer tumor samples, 67 paired adjacent samples, and 9 normal pancreatic duct tissue protein genomes, including whole genome sequencing, whole exome sequencing, and DNA DNA methylation, RNA sequencing, miRNA sequencing, proteomics, phosphoproteomics, and glycoproteomics
.
In order to solve the problem of low tumor cell abundance in pancreatic ductal adenocarcinoma tumor tissue, the researchers used a variety of deconvolution methods based on tumor molecular characteristics and tissue imaging on tumor tissue samples, and identified 105 cells containing enough A sample of tumor cell abundance is used for downstream analysis
.
The integration of protein genomics data allows researchers to link gene variants associated with pancreatic ductal adenocarcinoma to the functional modules that drive the disease phenotype
.
For example, TP53 gene variants with extensive trans effects are associated with increased phosphorylation of proteins involved in DNA damage repair (MSH6, TP53, and TP53BP1), indicating that these changes play a role in maintaining genome integrity and preventing apoptosis
.
In TP53 mutant tumors, the researchers also observed increased phosphorylation of the cell proliferation marker MKI67, indicating that these mutations may lead to an increase in cell growth rate
.
The differential expression analysis of the proteome (tumor group vs.
paired adjacent group) identified 27 proteins that were significantly overexpressed in pancreatic ductal adenocarcinoma.
Among them, 21 proteins were further verified in the comparative analysis of tumor group and normal pancreatic duct tissue.
And these 21 proteins are also significantly overexpressed in early pancreatic ductal adenocarcinoma
.
The researchers used independent data to verify 14 of these proteins, demonstrating the reliability of the reported tumor-associated proteins
.
Among these 21 proteins, 12 are secreted proteins, which can be used as potential diagnostic targets for early pancreatic ductal adenocarcinoma
.
The integrated analysis of phosphorylated proteomics and proteomics identified five pairs of kinase-phosphorylated substrates (CDK7-MCM2, AKT1-FLNA, PAK1-BAD, PAK2-MAPK6, and SRC-STAT3) in pancreatic ductal adenocarcinoma Significantly overexpression
.
Among them, the phosphorylation of phosphorylated protein (BAD) S134 by kinase PAK1 can inhibit BAD-induced cell apoptosis, thereby promoting cell proliferation and survival
.
In addition, PAK1 is an important effector of a variety of receptor tyrosine kinases, such as MET
.
Researchers found that MET and PAK1 are simultaneously upregulated in tumors, and drive pancreatic cancer by regulating cell proliferation, movement, and cytoskeleton remodeling
.
The kinase PAK2 was found to promote the formation of MAPK6-Prak complex by phosphorylating MAPK6, indicating that PAK2 activity plays an important role in regulating atypical MAPK signaling
.
In view of the importance of PAK1/2 for pancreatic ductal adenocarcinoma, combined inhibition of PAK1/2 and KRAS downstream pathways, such as MAPK/ERK and PI3K/AKT/mTOR, can maximize the inhibition of tumor cell proliferation
.
The researchers used a deconvolution method based on transcriptomics to identify the cell composition in the tumor and identified four subtypes
.
One of the interesting subtypes has relatively high immune cell infiltration and high endothelial cell expression.
Researchers call this subtype immune "hot" subtype
.
Endothelial cells connect the circulatory system and tumor cells.
Endothelial cell adhesion proteins are essential for immune cell infiltration and are often down-regulated in the vascular system associated with tumors
.
Correspondingly, the researchers also found in this paper that immune "cold" tumors are associated with low endothelial cell adhesion proteins
.
In addition, immune "cold" tumors have also been shown to be associated with increased activity of VEGF and Hypoxia signaling pathways, and these two signaling pathways are related to endothelial cell remodeling during tumorigenesis, indicating that endothelial cell remodeling in immune "cold" tumors is related to There is an association between suppression of immune cell infiltration
.
In order to further study the mechanism of immune "cold" tumors, the researchers used transcriptome, proteome, and phosphorylation data to conduct signal pathway analysis
.
The results show that immune "cold" tumors have higher levels of glycolysis and phosphorylation of cell connexins, and cell connexins play an important role in regulating the permeability of endothelial cells
.
These data indicate that immune "hot" subtypes may benefit from immunotherapy, while immune "cold" subtypes are related to endothelial cell remodeling, increased glycolysis, and cellular connexin disorders
.
Dr.
Liwei Cao from Johns Hopkins University, Dr.
Chen Huang from Baylor College of Medicine, and Dr.
Daniel Cui Zhou from Washington University in St.
Louis are the co-first authors of the article
.
Dr.
Hui Zhang from Johns Hopkins University, Dr.
Zhang Bing from Baylor College of Medicine, and Dr.
Li Ding from Washington University in St.
Louis are the co-corresponding authors
.
Original link: https:// Reprinting instructions [Non-original article] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission , The author has all legal rights, and offenders must be investigated
.
.
At present, the lack of effective early diagnosis methods for pancreatic ductal adenocarcinoma results in the vast majority of patients (80-85%) being diagnosed in the middle and late stages of the disease, so they cannot receive surgical treatment
.
Although chemotherapy has a certain effect on patients with pancreatic ductal adenocarcinoma, the median overall survival is still less than 12 months
.
The gene mutations that drive the occurrence and development of pancreatic ductal adenocarcinoma are mainly KRAS activating point mutations.
However, apart from the specific mutation form G12C, KRAS is considered to be a non-drugable target
.
Since KRAS mutations have a wide range of effects on the tumor microenvironment and the occurrence and development of tumors, the identification of key signaling pathways downstream of KRAS is of great significance for the treatment of this disease
.
In addition, the vast majority of pancreatic ductal adenocarcinomas are immune "cold" tumors, so specific molecular targets are needed to identify immune "hot" patients who may benefit from immunotherapy, and reveal that immune "cold" pancreatic ductal adenocarcinoma drives immune rejection Mechanism
.
On September 16, 2021, a collaborative team from Johns Hopkins University, Baylor College of Medicine, and Washington University in St.
Louis published an article Proteogenomic characterization of pancreatic ductal adenocarcinoma in Cell, using proteogenomics big data to comprehensively analyze pancreatic ductal adenocarcinoma Identification, identification of new potential therapeutic targets and early diagnosis markers
.
The researchers identified 140 pancreatic cancer tumor samples, 67 paired adjacent samples, and 9 normal pancreatic duct tissue protein genomes, including whole genome sequencing, whole exome sequencing, and DNA DNA methylation, RNA sequencing, miRNA sequencing, proteomics, phosphoproteomics, and glycoproteomics
.
In order to solve the problem of low tumor cell abundance in pancreatic ductal adenocarcinoma tumor tissue, the researchers used a variety of deconvolution methods based on tumor molecular characteristics and tissue imaging on tumor tissue samples, and identified 105 cells containing enough A sample of tumor cell abundance is used for downstream analysis
.
The integration of protein genomics data allows researchers to link gene variants associated with pancreatic ductal adenocarcinoma to the functional modules that drive the disease phenotype
.
For example, TP53 gene variants with extensive trans effects are associated with increased phosphorylation of proteins involved in DNA damage repair (MSH6, TP53, and TP53BP1), indicating that these changes play a role in maintaining genome integrity and preventing apoptosis
.
In TP53 mutant tumors, the researchers also observed increased phosphorylation of the cell proliferation marker MKI67, indicating that these mutations may lead to an increase in cell growth rate
.
The differential expression analysis of the proteome (tumor group vs.
paired adjacent group) identified 27 proteins that were significantly overexpressed in pancreatic ductal adenocarcinoma.
Among them, 21 proteins were further verified in the comparative analysis of tumor group and normal pancreatic duct tissue.
And these 21 proteins are also significantly overexpressed in early pancreatic ductal adenocarcinoma
.
The researchers used independent data to verify 14 of these proteins, demonstrating the reliability of the reported tumor-associated proteins
.
Among these 21 proteins, 12 are secreted proteins, which can be used as potential diagnostic targets for early pancreatic ductal adenocarcinoma
.
The integrated analysis of phosphorylated proteomics and proteomics identified five pairs of kinase-phosphorylated substrates (CDK7-MCM2, AKT1-FLNA, PAK1-BAD, PAK2-MAPK6, and SRC-STAT3) in pancreatic ductal adenocarcinoma Significantly overexpression
.
Among them, the phosphorylation of phosphorylated protein (BAD) S134 by kinase PAK1 can inhibit BAD-induced cell apoptosis, thereby promoting cell proliferation and survival
.
In addition, PAK1 is an important effector of a variety of receptor tyrosine kinases, such as MET
.
Researchers found that MET and PAK1 are simultaneously upregulated in tumors, and drive pancreatic cancer by regulating cell proliferation, movement, and cytoskeleton remodeling
.
The kinase PAK2 was found to promote the formation of MAPK6-Prak complex by phosphorylating MAPK6, indicating that PAK2 activity plays an important role in regulating atypical MAPK signaling
.
In view of the importance of PAK1/2 for pancreatic ductal adenocarcinoma, combined inhibition of PAK1/2 and KRAS downstream pathways, such as MAPK/ERK and PI3K/AKT/mTOR, can maximize the inhibition of tumor cell proliferation
.
The researchers used a deconvolution method based on transcriptomics to identify the cell composition in the tumor and identified four subtypes
.
One of the interesting subtypes has relatively high immune cell infiltration and high endothelial cell expression.
Researchers call this subtype immune "hot" subtype
.
Endothelial cells connect the circulatory system and tumor cells.
Endothelial cell adhesion proteins are essential for immune cell infiltration and are often down-regulated in the vascular system associated with tumors
.
Correspondingly, the researchers also found in this paper that immune "cold" tumors are associated with low endothelial cell adhesion proteins
.
In addition, immune "cold" tumors have also been shown to be associated with increased activity of VEGF and Hypoxia signaling pathways, and these two signaling pathways are related to endothelial cell remodeling during tumorigenesis, indicating that endothelial cell remodeling in immune "cold" tumors is related to There is an association between suppression of immune cell infiltration
.
In order to further study the mechanism of immune "cold" tumors, the researchers used transcriptome, proteome, and phosphorylation data to conduct signal pathway analysis
.
The results show that immune "cold" tumors have higher levels of glycolysis and phosphorylation of cell connexins, and cell connexins play an important role in regulating the permeability of endothelial cells
.
These data indicate that immune "hot" subtypes may benefit from immunotherapy, while immune "cold" subtypes are related to endothelial cell remodeling, increased glycolysis, and cellular connexin disorders
.
Dr.
Liwei Cao from Johns Hopkins University, Dr.
Chen Huang from Baylor College of Medicine, and Dr.
Daniel Cui Zhou from Washington University in St.
Louis are the co-first authors of the article
.
Dr.
Hui Zhang from Johns Hopkins University, Dr.
Zhang Bing from Baylor College of Medicine, and Dr.
Li Ding from Washington University in St.
Louis are the co-corresponding authors
.
Original link: https:// Reprinting instructions [Non-original article] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission , The author has all legal rights, and offenders must be investigated
.
