The Mutant p53-Driven Secretome Has Oncogenic Functions in Pancreatic Ductal Adenocarcinoma Cells

Abstract

The cancer secretome is a rich repository of useful information for both cancer biology and clinical oncology. A better understanding of cancer secretome is particularly relevant for pancreatic ductal adenocarcinoma (PDAC), whose extremely high mortality rate is mainly due to early metastasis, resistance to conventional treatments, lack of recognizable symptoms, and assays for early detection. TP53 gene is a master transcriptional regulator controlling several key cellular pathways and it is mutated in ~75% of PDACs. We report the functional effect of the hot-spot p53 mutant isoforms R175H and R273H on cancer cell secretome, showing their influence on proliferation, chemoresistance, apoptosis, and autophagy, as well as cell migration and epithelial-mesenchymal transition. We compared the secretome of p53-null AsPC-1 PDAC cells after ectopic over-expression of R175H-mutp53 or R273H-mutp53 to identify the differentially secreted proteins by mutant p53. By using high-resolution SWATH-MS technology, we found a great number of differentially secreted proteins by the two p53 mutants, 15 of which are common to both mutants. Most of these secreted proteins are reported to promote cancer progression and epithelial-mesenchymal transition and might constitute a biomarker secreted signature that is driven by the hot-spot p53 mutants in PDAC.

Cancer stem cell secretome in the tumor microenvironment: a key point for an effective personalized cancer treatment

“…Only one recent publication has related the inhibition of the HSP90 chaperone with a higher sensitivity to chemotherapy and a lower release of various cytokines (IL-8 and others) and, more interestingly, the HSP90 chaperone affected the survival of chemoresistant ALDH cell subpopulations [233]. In addition, there is little information available on oncogenic mutations associated with the influence of chemoresistance on CSC secretome, but p53 mutations have been reported to induce the release of an altered secretome by the tumor pool subpopulations that affects chemoresistance and other tumor processes [234,235]. For this reason, the epigenetic control of the secretome and oncogenic mutations seems plausible hypotheses related to chemoresistance generated by the secretome, but additional studies are necessary to confirm them.…”

From fuzziness to precision medicine: on the rapidly evolving proteomics with implications in mitochondrial connectivity to rare human disease

“…In addition, secretome profiling in rare cancer types, such as pancreatic cancer, can be achieved by SWATH-MS, which was applied for differential secretome mapping between two variants of the TP53 transcriptional regulator to fine-tune variant-specific biomarker discovery outputs ( Butera et al., 2020 ). Another important yet significantly understudied area of clinical research is metabolomics and their linkage to human disease.…”

Tumor Suppressor Role of Wild-Type P53-Dependent Secretome and Its Proteomic Identification in PDAC

“…A growing importance is emerging to consider not only the intracellular roles of p53 but also its extracellular impact in the regulation of the cancer microenvironment, which is important also for the identification of targeted cancer therapies and novel serum biomarkers. Our previous study reveals the functional effect of hot-spot p53 mutants on cancer cell secretome which promote oncogenic roles as chemoresistance, cell migration and epithelial-mesenchymal transition [ 16 , 17 ].…”