S100A8 transported by SEC23A inhibits metastatic colonization via autocrine activation of autophagy

Abstract

Metastasis is the main cause of failure of cancer treatment. Metastatic colonization is regarded the most ratelimiting step of metastasis and is subjected to regulation by a plethora of biological factors and processes. On one hand, regulation of metastatic colonization by autophagy appears to be stage-and context-dependent, whereas mechanistic characterization remains elusive. On the other hand, interactions between the tumor cells and their microenvironment in metastasis have long been appreciated, whether the secretome of tumor cells can effectively reshape the tumor microenvironment has not been elucidated mechanistically. In the present study, we have identified "SEC23A-S1008-BECLIN1-autophagy axis" in the autophagic regulation of metastatic colonization step, a mechanism that tumor cells can exploit autophagy to exert self-restrain for clonogenic proliferation before the favorable tumor microenvironment is established. Specifically, we employed a paired lung-derived oligometastatic cell line (OL) and the homologous polymetastatic cell line (POL) from human melanoma cell line M14 that differ in colonization efficiency. We show that S100A8 transported by SEC23A inhibits metastatic colonization via autocrine activation of autophagy. Furthermore, we verified the clinical relevance of our experimental findings by bioinformatics analysis of the expression of Sec23a and S100A8 and the clinicalpathological associations. We demonstrate that higher Sec23a and Atg5 expression levels appear to be protective factors and favorable diagnostic (TNM staging) and prognostic (overall survival) markers for skin cutaneous melanoma (SKCM) and colon adenocarcinoma (COAD) patients. And we confirm the bioinformatics analysis results with SKCM biopsy samples.

Sec23a Inhibits The Self-Renewal of Melanoma Cancer Stem Cells via Inactivation of ER-Phagy

“…In our previous studies, we show that miR-200c augments melanoma metastasis by targeting Sec23a 25 . We further show that S100A8 transported by SEC23A inhibits melanoma metastatic colonization via autocrine activation of autophagy in extravasated tumor cells, thus have identi ed for the rst time the link between Sec23a and autophagy 27 .…”

“…While our prior work has shown for the rst time the link between Sec23a and autophagy in regulation of M14 metastatic colonization 27 , others have reported regulation of CSC stemness by autophagy 29,30 . These observations prompted us to test whether autophagic activities differ in M14-parental and M14-SE cell.…”

“…Consistent with the literature, we show that Sec23a inhibits metastatic colonization e ciency by changing the secretome to activate autophagic activity in melanoma cells. It is achieved via the Sec23a-S1008A-Beclin1 axis 27 . In a recent report, SEC23B, a homolog protein of the SEC23 family, can activate autophagy under nutrient deprivation condition 53 .…”

“…Western Blot (WB) analysis WB was conducted as we previously reported 27 . Cells were lysed in SDS lysis buffer (Beyotime, P0013G) containing 1% protease inhibitor PMSF (Beyotime, ST506).…”

“…Autophagy ux analysis of LC3B puncta was conducted as we previously reported 27 . Adenovirus expressing mCherry-GFP-LC3B fusion protein (Ad-mCherry-GFP-LC3B, C3011) was purchased from Beyotime.…”