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Published on: November 5, 2020
Tumor Suppressor Role of Wild-Type P53-Dependent Secretome and Its Proteomic Identification in PDAC
Giovanna Butera1, Marcello Manfredi2,3,4, Alessandra Fiore1
1Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biochemistry, University of Verona, 37134 Verona, Italy.
Abstract:
The study of the cancer secretome is gaining even more importance in cancers such as pancreatic ductal adenocarcinoma (PDAC), whose lack of recognizable symptoms and early detection assays make this type of cancer highly lethal. The wild-type p53 protein, frequently mutated in PDAC, prevents tumorigenesis by regulating a plethora of signaling pathways. The importance of the p53 tumor suppressive activity is not only primarily involved within cells to limit tumor cell proliferation but also in the extracellular space. Thus, loss of p53 has a profound impact on the secretome composition of cancer cells and marks the transition to invasiveness. Here, we demonstrate the tumor suppressive role of wild-type p53 on cancer cell secretome, showing the anti-proliferative, apoptotic and chemosensitivity effects of wild-type p53 driven conditioned medium. By using high-resolution SWATH-MS technology, we characterized the secretomes of p53-deficient and p53-expressing PDAC cells. We found a great number of secreted proteins that have known roles in cancer-related processes, 30 of which showed enhanced and 17 reduced secretion in response to p53 silencing. These results are important to advance our understanding on the link between wt-p53 and cancer microenvironment. In conclusion, this approach may detect a secreted signature specifically driven by wild-type p53 in PDAC.
Insights
Wild-type p53 suppresses pancreatic cancer by altering secreted proteins. Loss of p53 impacts the cancer secretome, affecting invasiveness and treatment response.
Area of Science:
- Oncology
- Proteomics
- Cancer Biology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is highly lethal due to late detection.
- Wild-type p53 protein is crucial for tumor suppression, acting both intracellularly and extracellularly.
- Loss of p53 function in PDAC significantly alters the cancer cell secretome and promotes invasiveness.
Purpose of the Study:
- To investigate the tumor-suppressive role of wild-type p53 on the cancer cell secretome in PDAC.
- To identify specific secreted proteins regulated by wild-type p53.
- To understand the impact of p53 status on the PDAC tumor microenvironment.
Main Methods:
- Utilized high-resolution SWATH-MS technology to analyze secretomes.
- Compared secretomes of p53-deficient and p53-expressing PDAC cells.
- Assessed the effects of wild-type p53-driven conditioned medium (anti-proliferative, apoptotic, chemosensitivity).
Main Results:
- Characterized significant differences in secreted proteins between p53-deficient and p53-expressing PDAC cells.
- Identified 30 secreted proteins with enhanced secretion and 17 with reduced secretion upon p53 silencing.
- Demonstrated anti-proliferative, apoptotic, and chemosensitivity effects mediated by wild-type p53 conditioned medium.
Conclusions:
- Wild-type p53 exerts tumor-suppressive functions by modulating the PDAC secretome.
- p53 status profoundly influences the extracellular environment of PDAC cells.
- The study may lead to the discovery of a secreted biomarker signature for wild-type p53 in PDAC.
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