Autophagy and Extracellular Vesicles, Connected to rabGTPase Family, Support Aggressiveness in Cancer Stem Cells

Abstract

Even though cancers have been widely studied and real advances in therapeutic care have been made in the last few decades, relapses are still frequently observed, often due to therapeutic resistance. Cancer Stem Cells (CSCs) are, in part, responsible for this resistance. They are able to survive harsh conditions such as hypoxia or nutrient deprivation. Autophagy and Extracellular Vesicles (EVs) secretion are cellular processes that help CSC survival. Autophagy is a recycling process and EVs secretion is essential for cell-to-cell communication. Their roles in stemness maintenance have been well described. A common pathway involved in these processes is vesicular trafficking, and subsequently, regulation by Rab GTPases. In this review, we analyze the role played by Rab GTPases in stemness status, either directly or through their regulation of autophagy and EVs secretion.

Keywords: autophagy; cancer stem cells; extracellular vesicles; rab family.

Figure 1

Screening of some Rab GTPases involved in autophagy (red), EVs secretion (green) and other Rab proteins involved in other cellular processes (blue). Inspired from [25,26].

Figure 2

(A)—Comparison of human genes associated with Gene Ontology terms related to autophagy, extracellular vesicles and/or exosomes biogenesis and stem cells biological process (http://geneontology.org/ and https://www.ebi.ac.uk/QuickGO/, accessed on 26 March 2021) using Venn diagram. In fact, 543 different genes were categorized into GO-BP related to autophagy (GO:0006914 and GO:0010506), 31 different genes were categorized into GO-BP related to extracellular vesicles/exosomes (GO:0140112, GO:0097734, GO:0099156, GO:1990182, GO:0071971 and GO:1903551) and 424 different genes were categorized into GO-BP related to stem cells (GO:0019827, GO:0017145, GO:0048863, GO:0072089 and GO:0048864). Few genes were commonly associated with three biological process, and among Rab identified in these processes, only Rab7A was common to 2 processes. (B)—Main terms of Gene Ontology-Biological Process (GO-BP) associated with Homo Sapiens Rab proteins. GO-BP terms associated with the 70 human Rab proteins were retrieved from the DAVID database (https://david.ncifcrf.gov/ accessed on 26 March 2021) by focusing on level 5 of the GO hierarchy. Among 81 enriched terms (p adjusted ≤ 0.05), 33 terms were associated with more than 10% of Rab. After removing redundant GO terms using REVIGO (http://revigo.irb.hr/ accessed on 26 March 2021) according to functional similarity, we selected a short list of 23 terms summarized in the above graphic, illustrating the functional diversity of the Rab protein family.