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Published on: January 12, 2020
A new tumor suppressor role for the Notch pathway in bladder cancer
Theodoros Rampias1, Paraskevi Vgenopoulou1, Margaritis Avgeris2
1Biomedical Research Foundation Academy of Athens, Athens, Greece.
Abstract:
The Notch signaling pathway controls cell fates through interactions between neighboring cells by positively or negatively affecting the processes of proliferation, differentiation and apoptosis in a context-dependent manner. This pathway has been implicated in human cancer as both an oncogene and a tumor suppressor. Here we report new inactivating mutations in Notch pathway components in over 40% of human bladder cancers examined. Bladder cancer is the fourth most commonly diagnosed malignancy in the male population of the United States. Thus far, driver mutations in fibroblast growth factor receptor 3 (FGFR3) and, less commonly, in RAS proteins have been identified. We show that Notch activation in bladder cancer cells suppresses proliferation both in vitro and in vivo by directly upregulating dual-specificity phosphatases (DUSPs), thus reducing the phosphorylation of ERK1 and ERK2 (ERK1/2). In mouse models, genetic inactivation of Notch signaling leads to Erk1/2 phosphorylation, resulting in tumorigenesis in the urinary tract. Collectively our findings show that loss of Notch activity is a driving event in urothelial cancer.
Insights
Loss of Notch signaling activity drives bladder cancer by increasing cell proliferation. Inactivating mutations in Notch pathway components are found in over 40% of human bladder cancers, highlighting its role in urothelial cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- The Notch signaling pathway regulates cell fate and is implicated in cancer as both an oncogene and tumor suppressor.
- Bladder cancer, a common malignancy in men, has known driver mutations in FGFR3 and RAS.
- The precise role of Notch signaling in bladder cancer development remains to be fully elucidated.
Purpose of the Study:
- To investigate the role of Notch signaling pathway mutations in human bladder cancers.
- To determine the functional consequences of Notch pathway alterations on cancer cell proliferation and signaling.
- To explore the therapeutic potential of targeting Notch signaling in urothelial cancers.
Main Methods:
- Genomic analysis of Notch pathway components in human bladder cancer samples.
- In vitro and in vivo experiments using bladder cancer cell lines and mouse models.
- Assessment of cell proliferation, apoptosis, and signaling pathway activation (ERK1/2, DUSPs).
Main Results:
- Inactivating mutations in Notch pathway components were identified in over 40% of examined human bladder cancers.
- Notch activation suppressed bladder cancer cell proliferation by upregulating dual-specificity phosphatases (DUSPs), reducing ERK1/2 phosphorylation.
- Genetic inactivation of Notch signaling in mouse models promoted tumorigenesis in the urinary tract due to increased Erk1/2 phosphorylation.
Conclusions:
- Loss of Notch signaling activity is a significant driving event in urothelial cancer development.
- The Notch pathway acts as a tumor suppressor in bladder cancer by inhibiting proliferation via DUSP upregulation.
- Targeting Notch signaling may offer a novel therapeutic strategy for bladder cancer.
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