The Vault Complex Is Significantly Involved in Therapeutic Responsiveness of Endocrine Tumors and Linked to Autophagy under Chemotherapeutic Conditions

Abstract

Cancers display dynamic interactions with their complex microenvironments that influence tumor growth, invasiveness, and immune evasion, thereby also influencing potential resistance to therapeutic treatments. The tumor microenvironment (TME) includes cells of the immune system, the extracellular matrix, blood vessels, and other cell types, such as fibroblasts or adipocytes. Various cell types forming this TME secrete exosomes, and molecules thereby released into the TME have been shown to be important mediators of cellular communication and interplay. Specific stressors in the TME, such as hypoxia, starvation, inflammation, and damage, can furthermore induce autophagy, a fundamental cellular process that degrades and recycles molecules and subcellular components, and recently it has been demonstrated that the small non-coding vault RNA1-1 plays a role as a regulator of autophagy and the coordinated lysosomal expression and regulation (CLEAR) network. Here, we demonstrate for the first time that intra-tumoral damage following effective therapeutic treatment is linked to specific intracellular synthesis and subsequent exosomal release of vault RNAs in endocrine tumors in vitro and in vivo. While we observed a subsequent upregulation of autophagic markers under classical chemotherapeutic conditions, a downregulation of autophagy could be detected under conditions strongly involving inflammatory cascades.