Functions of autophagy in the tumor microenvironment and cancer metastasis

Abstract

Macro-autophagy is an ancient and highly conserved self-degradative process that plays a homeostatic role in normal cells by eliminating organelles, pathogens, and protein aggregates. Autophagy, as it is routinely referred to, also allows cells to maintain metabolic sufficiency and survive under conditions of nutrient stress by recycling the by-products of autophagic degradation, such as fatty acids, amino acids, and nucleotides. Tumor cells are more reliant than normal cells on autophagy for survival in part due to their rapid growth rate, altered metabolism, and nutrient-deprived growth environment. How this dependence of tumor cells on autophagy affects their progression to malignancy and metastatic disease is an area of increasing research focus. Here, we review recent work identifying critical functions for autophagy in tumor cell migration and invasion, tumor stem cell maintenance and therapy resistance, and cross-talk between tumor cells and their microenvironment.

Keywords: autophagy; invasion; metastasis; mitophagy; tumor cell migration; tumor microenvironment; tumor stem cells.

Figure 1. Autophagy overview

Autophagy is exquisitely sensitive to amino acid deprivation in addition to other nutrient stresses. Amino acid deprivation induces AMPK and suppresses mTORC1 to promote Ulk1 kinase activity as part of the pre-initiation complex (Ulk1/FIP200/Atg13) that in turn activates the lipid kinase activity of the initiation complex (Beclin1/VPS34 and associated proteins). This is turn recruits the Atg12/Atg5/Atg16L conjugation complex that promotes processing and insertion of lipid conjugated LC3 into nascent phagophore membranes. LC3 and related proteins interact with cargo to be turned over via autophagy and also promotes closure of the autophagosome around the cargo. Fusion of these double-membraned autophagosomes with the lysosome results in proteolytic degradation of the cargo and release from the autophagolysosome of amino acids, nucleotides and lipids derived from degraded cargo. In addition to induction of autophagy by these post-translational mechanisms, autophagy is also stimulated by transcriptional control of Atg genes, notably by ATF4 and MiT/TFE transcription factors that are activated by amino acid deprivation amongst other stresses.

Figure 2. Coordinate control of autophagy and cell migration

Autophagy and cellular motility are coordinated at the molecular level through reciprocal control of both processes by common modulators including Focal adhesion kinase (FAK), FAK-Interacting Protein 200 kD (FIP200) and Paxillin (PXN). Autophagy promotes cell motility through turnover of focal adhesion complexes and specifically via degradation of focal adhesion component, Paxillin (PXN). Autophagy also promotes turnover of SRC in response to FAK inhibition to prevent cell death in response to cell detachment. Both FAK (through TSC2) and PXN (through ill-defined mechanisms) feed back to modulate autophagic flux. Similarly, there is a reciprocal interaction between autophagy and members of the Rho family of small G proteins involved in cell migration. Autophagy promotes Rho turnover via p62/Sqstm1 while ROCK1 that acts downstream of Rho stimulates autophagy through phosphorylation of Beclin1.

Figure 3. Requirement for autophagy in stem cell maintenance

Autophagy is required for maintenance of a stem-like phenotype both in normal tissue stem cells but also in certain types of cancer stem cells. Stresses (hypoxia, TGF-β) that induce stem-like properties, including self-renewal capability, EMT, up-regulation of CD44, also induce autophagy that is required for many of these stem-like features, including up-regulation of CD44. Recent work has highlighted a specific role for mitophagy in promoting a stem-like state in cancers, possibly by limiting ROS production and promoting glycolytic metabolism that may limit differentiation.

Figure 4. Autophagy in the tumor microenvironment supports tumor cell growth through supply of nutrients and other factors

The growth of pancreatic ductal adenocarcinoma (PDAC) is supported by a highly complex and dense desmoplastic stroma that includes pancreatic stellate cells (PSCs). Autophagy plays a critical role in the tumor-promoting activity of PSCs that supply associated PDAC tumor cells with the breakdown products of autophagy, including amino acids such as alanine. Inhibition of alanine metabolism in tumor cells neutralized the pro-tumor activity of PSCs. Autophagy is induced in PSCs by their association with PDAC cells although how tumor cells signal to PSCs to induce autophagy is not yet clear. Autophagy in PSCs was also required for production of pro-inflammatory cytokines such as IL-6, that may be feeding back to both promote tumor cell motility and mobilization of metabolites systemically in the animal, but also may also contribute to the signal that induces autophagy in PSCs in the first place. Additional metabolites and factors may also contribute to additional aspects of how autophagy in the tumor microenvironment promotes tumor growth and metastasis.