Pancreatic Adenocarcinoma Therapeutics Targeting RTK and TGF Beta Receptor

Yang, Hsin-Han; Liu, Jen‐Wei; Lee, Jui-Hao; Harn, Horng‐Jyh; Chiou, Tzyy‐Wen

doi:10.3390/ijms22158125

Cited by 17 publications

(5 citation statements)

References 102 publications

(111 reference statements)

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“…Its role in pancreatic cancer has not yet been reported. GSEA revealed that the high- and low-risk score groups showed significant differences in TGF-beta receptor signaling, the Wnt signaling pathway, senescence and autophagy in cancer, and the PI3K-Akt signaling pathway, which might account for the poor PAAD prognosis owing to risk modifiers ( Aguilera and Dawson, 2021 ; Cortesi et al, 2021 ; Yang et al, 2021 ; Stanciu et al, 2022 ; Yamamoto et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial energy metabolism-related gene signature as a prognostic indicator for pancreatic adenocarcinoma

Ma,

Tang,

Huang

et al. 2024

Front. Pharmacol.

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Background: Pancreatic adenocarcinoma (PAAD) is a highly malignant gastrointestinal tumor and is associated with an unfavorable prognosis worldwide. Considering the effect of mitochondrial metabolism on the prognosis of pancreatic cancer has rarely been investigated, we aimed to establish prognostic gene markers associated with mitochondrial energy metabolism for the prediction of survival probability in patients with PAAD.Methods: Gene expression data were obtained from The Cancer Genome Atlas and Gene Expression Omnibus databases, and the mitochondrial energy metabolism–related genes were obtained from the GeneCards database. Based on mitochondrial energy metabolism score (MMs), differentially expressed MMRGs were established for MMs-high and MMs-low groups using ssGSEA. After the univariate Cox and least absolute and selection operator (LASSO) analyses, a prognostic MMRG signature was used in the multivariate Cox proportional regression model. Survival and immune cell infiltration analyses were performed. In addition, a nomogram based on the risk model was used to predict the survival probability of patients with PAAD. Finally, the expression of key genes was verified using quantitative polymerase chain reaction and immunohistochemical staining. Intro cell experiments were performed to evaluated the proliferation and invasion of pancreatic cancer cells.Results: A prognostic signature was constructed consisting of two mitochondrial energy metabolism–related genes (MMP11, COL10A1). Calibration and receiver operating characteristic (ROC) curves verified the good predictability performance of the risk model for the survival rate of patients with PAAD. Finally, immune-related analysis explained the differences in immune status between the two subgroups based on the risk model. The high-risk score group showed higher estimate, immune, and stromal scores, expression of eight checkpoint genes, and infiltration of M0 macrophages, which might indicate a beneficial response to immunotherapy. The qPCR results confirmed high expression of MMP11 in pancreatic cancer cell lines, and IHC also verified high expression of MMP11 in clinical pancreatic ductal adenocarcinoma tissues. In vitro cell experiments also demonstrated the role of MMP11 in cell proliferation and invasion.Conclusion: Our study provides a novel two-prognostic gene signature—based on MMRGs—that accurately predicted the survival of patients with PAAD and could be used for mitochondrial energy metabolism–related therapies in the future.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial energy metabolism-related gene signature as a prognostic indicator for pancreatic adenocarcinoma

Ma,

Tang,

Huang

et al. 2024

Front. Pharmacol.

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“…However, it is not clear exactly how alcohol increases the expression of TGFβ in these cells. Further research is needed to determine the exact mechanisms by which alcohol may increase the expression of TGFβ in MIA-PaCa-2 and PANC1 cells, paving the way for novel therapies [ 40 , 41 , 42 , 43 , 44 ].…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Comparison between Alcohol-Exposed versus Not Exposed Pancreatic Ductal Adenocarcinoma Patients Reveals a Peculiar TGFβ-Related Phenotype: An Exploratory Analysis

Doronzo¹,

Porcelli

Marziliano

et al. 2023

Medicina

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Background: Over the past few decades, there has been much debate and research into the link between alcohol consumption and the development and progression of pancreatic ductal adenocarcinoma (PDAC). Objectives: To contribute to the ongoing discussion and gain further insights into this topic, our study analysed the gene expression differences in PDAC patients based on their alcohol consumption history. Methods: To this end, we interrogated a large publicly available dataset. We next validated our findings in vitro. Results: Our findings revealed that patients with a history of alcohol consumption showed significant enrichment in the TGFβ-pathway: a signaling pathway implicated in cancer development and tumor progression. Specifically, our bioinformatic dissection of gene expression differences in 171 patients with PDAC showed that those who had consumed alcohol had higher levels of TGFβ-related genes. Moreover, we validated the role of the TGFβ pathway as one of the molecular drivers in producing massive stroma, a hallmark feature of PDAC, in patients with a history of alcohol consumption. This suggests that inhibition of the TGFβ pathway could serve as a novel therapeutic target for PDAC patients with a history of alcohol consumption and lead to increased sensitivity to chemotherapy. Our study provides valuable insights into the molecular mechanisms underlying the link between alcohol consumption and PDAC progression. Conclusions: Our findings highlight the potential significance of the TGFβ pathway as a therapeutic target. The development of TGFβ-inhibitors may pave the way for developing more effective treatment strategies for PDAC patients with a history of alcohol consumption.

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“…41 In addition, since the stromal plays a relatively important role in PDAC, and TGF-β plays an important role in tumor angiogenesis, cell apoptosis, collagen synthesis, and stromal cell differentiation, more attention should be given to these nonimmune related aspects to comprehensively evaluate the effect of TGF-β blockade in PDAC. 42 Moreover, a recent report revealed that the tumor-promoting function of TGF-β was induced by MUC1 overexpression. 43 As MUC1 is not expressed in the Panc02 cell line, the function of TGF-β requires further investigation in this model.…”

Section: Discussionmentioning

confidence: 99%

Limited Efficacy of Decreased Tumor-infiltrating Regulatory T Cells after Transforming Growth Factor-beta Blockade in Murine Pancreatic Ductal Adenocarcinoma

Zhao¹,

Pu²,

Nuerxiati³

et al. 2022

Cancer Screen Prev

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Background and objectives: Regulatory T cells (Tregs) are a vital cell subset that induces immune tolerance in the tumor microenvironment by secreting suppressive cytokines and inhibiting innate immune cells. Transforming growth factor-beta (TGF-β) plays an important role in this process. However, the effect of TGF-β blockade on intratumoral Tregs and its specific biological role remains unclear.Methods: Quantitative and functional changes in Tregs were evaluated after TGF-β blockade with gradient doses of monoclonal antibody 1D11 in a murine pancreatic ductal adenocarcinoma model. Results:The number of tumor infiltrating Tregs decreased significantly (high dose, low dose and control, 38.6 ± 8.1, 38.6 ± 1.8, 74.6 ± 4.9 /40× field, p = 0.024) after 1D11 administration, while CD8 + T cells in the tumor microenvironment significantly increased in the low dose group but reversed in the high dose group (3.1 ± 1.4, 12.3 ± 2.1, 5.4 ± 0.5 /40× field, p = 0.016). The frequency of CD4 + , CD8 + or Treg cells in the peripheral blood and spleen showed no significant change. The typical cytokines TGF-β and inerleukin-10 secreted by Tregs as well as interferon-γ produced by cytotoxic T cells in tumor tissues did not change compared with the controls.Conclusions: TGF-β blockade with a monoclonal antibody can reduce Tregs in the tumor niche, however, its therapeutic efficacy in PDAC patients remains limited. Further investigation of combination therapies is required.

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Pancreatic Adenocarcinoma Therapeutics Targeting RTK and TGF Beta Receptor

Cited by 17 publications

References 102 publications

Mitochondrial energy metabolism-related gene signature as a prognostic indicator for pancreatic adenocarcinoma

Mitochondrial energy metabolism-related gene signature as a prognostic indicator for pancreatic adenocarcinoma

Gene Expression Comparison between Alcohol-Exposed versus Not Exposed Pancreatic Ductal Adenocarcinoma Patients Reveals a Peculiar TGFβ-Related Phenotype: An Exploratory Analysis

Limited Efficacy of Decreased Tumor-infiltrating Regulatory T Cells after Transforming Growth Factor-beta Blockade in Murine Pancreatic Ductal Adenocarcinoma

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