The proteome and secretome analyses were performed using Perseus v. software (20). Before uploading the data to Perseus, the proteins were filtered based on a 1% false discovery rate. Only proteins assigned to a given protein group (Master protein) with a minimum of 2 unique proteins were included for the Perseus analysis. This filter was performed using R v.3.6.2 through R Studio v.1.2.5019 software (R Foundation for Statistical Computing, Vienna, Austria). Contaminated proteins were filtered out. The data were log2 transformed and normalized using z-score normalization. Proteins present in at least 1 of the groups analyzed were kept for statistical testing. Student's t-test was applied to compare each pair of groups. Proteins with a false discovery rate <0.05 between 2 groups were considered significant. The Venn diagrams were plotted using the web-based tool InteractiVenn (21). The plots were created using R v.3.6.2 software, and publication quality images were generated with Inkscape software (Free Software Foundation, Boston, Massachusetts) when possible.

For the aforementioned in vitro studies, statistical analyses were performed with the Prism software package (GraphPad Version 7, GraphPad Software, San Diego, California). Differences between 2 means were assessed by a 2-tailed paired or unpaired Student's t-test. Values of p < 0.05 were considered significant. For evaluating morphological, histological, and survival data, analysis of variance followed by Bonferroni correction was used to compare 3 groups. When sample number is not suffice to test for normality, nonparametric tests (Mann-Whitney U test or 1-way analysis of variance followed by Holm-Sidak’s test analysis) were used.

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