YAP in pancreatic cancer: oncogenic role and therapeutic strategy

Mao, Wenhao; Mai, Jia; Peng, Hui; Wan, Junhu; Sun, Ting

doi:10.7150/thno.53438

Cited by 30 publications

(14 citation statements)

References 126 publications

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“…YAP has been reported to be overexpressed in pancreatic cancer 26 , 38 , 39 . To validate the mRNA expression of YAP in PDAC, we analyzed the RNA-sequencing data from the TCGA and GTEx databases using the web-based tool GEPIA (Gene Expression Profiling Interactive Analysis, http://gepia.cancer-pku.cn/ ) 40 .…”

Section: Resultsmentioning

confidence: 99%

Autophagy-mediated negative feedback attenuates the oncogenic activity of YAP in pancreatic cancer

Sun¹,

Peng²,

Mao³

et al. 2021

Int. J. Biol. Sci.

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Pancreatic ductal adenocarcinoma (PDAC) is the most lethal malignancy in humans, and new therapeutic targets are urgently needed. Yes-associated protein (YAP) plays a significant role in cancer progression. Autophagy is also closely associated with various human cancers. However, the interplay between YAP and autophagy in PDAC remains poorly understood. In this study, we found that YAP was upregulated and activated in PDAC. Further analysis revealed that there is a YAP-autophagy feedback loop in pancreatic cancer. Mechanistically, YAP activates autophagy by promoting Atg5 transcription via TEAD1-mediated binding, while autophagy negatively regulates YAP through autophagic degradation. The hyperactivation of YAP in PDAC unbalances the YAP-autophagy circuit and promotes cancer progression. Inhibition of autophagy enhances the oncogenic activity of YAP in PDAC. The autophagy activator rapamycin promotes the antitumor effect of verteporfin, a YAP inhibitor. Therefore, our study elucidated the interaction between YAP and autophagy in PDAC and our results suggest that targeting the YAP-autophagy circuit may be a new therapeutic strategy for pancreatic cancer.

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Section: Resultsmentioning

confidence: 99%

Autophagy-mediated negative feedback attenuates the oncogenic activity of YAP in pancreatic cancer

Sun¹,

Peng²,

Mao³

et al. 2021

Int. J. Biol. Sci.

Self Cite

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“…In recent years, accumulated evidence has shown that dysfunctional YAP is highly associated with human malignancies, including pancreatic cancer [15,16]. YAP acts as an oncogenic transcription factor and is required for tumor initiation and the development of pancreatic cancer [17]. Furthermore, aberrant YAP activation leads to the highly metastatic characteristic of tumor cells, thus promoting pancreatic cancer invasion and metastasis [18].…”

Section: Introductionmentioning

confidence: 99%

A Novel Small Molecular Prostaglandin Receptor EP4 Antagonist, L001, Suppresses Pancreatic Cancer Metastasis

Lin

Meng

et al. 2022

Molecules

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Metastatic pancreatic cancer remains a major clinical challenge, emphasizing the urgent need for the exploitation of novel therapeutic approaches with superior response. In this study, we demonstrate that the aberrant activation of prostaglandin E2 (PGE2) receptor 4 (EP4) is a pro-metastatic signal in pancreatic cancer. To explore the therapeutic role of EP4 signaling, we developed a potent and selective EP4 antagonist L001 with single-nanomolar activity using a panel of cell functional assays. EP4 antagonism by L001 effectively repressed PGE2-elicited cell migration and the invasion of pancreatic cancer cells in a dose-dependent manner. Importantly, L001 alone or combined with the chemotherapy drug gemcitabine exhibited remarkably anti-metastasis activity in a pancreatic cancer hepatic metastasis model with excellent tolerability and safety. Mechanistically, EP4 blockade by L001 abrogated Yes-associated protein 1 (YAP)-driven pro-metastatic factor expression in pancreatic cancer cells. The suppression of YAP’s activity was also observed upon L001 treatment in vivo. Together, these findings support the notions that EP4–YAP signaling axis is a vital pro-metastatic pathway in pancreatic cancer and that EP4 inhibition with L001 may deliver a therapeutic benefit for patients with metastatic pancreatic cancer.

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“…Then, we merged the cells from the two libraries by each cell type (Figure 6 B). Overall, the downregulation of CSC markers, including CD44, KLF4 and YAP1 48 - 51 , was observed in CLS1 cells treated with digoxin (Figure 6 C). Furthermore, the overall scRNA-seq data revealed the downregulation of cytokine genes, including CXCL1, IL8 and IGFBP2, in the CAFs treated with digoxin (Figure 6 D).…”

Section: Resultsmentioning

confidence: 89%

Tumor microenvironment-based screening repurposes drugs targeting cancer stem cells and cancer-associated fibroblasts

Lee

et al. 2021

Theranostics

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The tumorous niche may drive the plasticity of heterogeneity and cancer stemness, leading to drug resistance and metastasis, which is the main reason of treatment failure in most cancer patients. The aim of this study was to establish a tumor microenvironment (TME)-based screening to identify drugs that can specifically target cancer stem cells (CSCs) and cancer-associated fibroblasts (CAFs) in the TME. Methods: Lung cancer patient-derived cancer cell and CAFs were utilized to mimic the TME and reproduce the stemness properties of CSCs in vitro and develop a high-throughput drug screening platform with phenotypical parameters. Limiting dilution assay, sphere-forming and ALDH activity assay were utilized to measure the cancer stemness characteristics. In vivo patient-derived xenograft (PDX) models and single-cell RNA sequencing were used to evaluate the mechanisms of the compounds in CSCs and CAFs. Results: The TME-based drug screening platform could comprehensively evaluate the response of cancer cells, CSCs and CAFs to different treatments. Among the 1,524 compounds tested, several drugs were identified to have anti-CAFs, anticancer and anti-CSCs activities. Aloe-emodin and digoxin both show anticancer and anti-CSCs activity in vitro and in vivo , which was further confirmed in the lung cancer PDX model. The combination of digoxin and chemotherapy improved therapeutic efficacy. The single-cell transcriptomics analysis revealed that digoxin could suppress the CSCs subpopulation in CAFs-cocultured cancer cells and cytokine production in CAFs. Conclusions: The TME-based drug screening platform provides a tool to identify and repurpose compounds targeting cancer cells, CSCs and CAFs, which may accelerate drug development and therapeutic application for lung cancer patients.

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YAP in pancreatic cancer: oncogenic role and therapeutic strategy

Cited by 30 publications

References 126 publications

Autophagy-mediated negative feedback attenuates the oncogenic activity of YAP in pancreatic cancer

Autophagy-mediated negative feedback attenuates the oncogenic activity of YAP in pancreatic cancer

A Novel Small Molecular Prostaglandin Receptor EP4 Antagonist, L001, Suppresses Pancreatic Cancer Metastasis

Tumor microenvironment-based screening repurposes drugs targeting cancer stem cells and cancer-associated fibroblasts

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