The pleiotropic functions of autophagy in metastasis

Abstract

Autophagy is deregulated in many cancers and represents an attractive target for therapeutic intervention. However, the precise contributions of autophagy to metastatic progression, the principle cause of cancer-related mortality, is only now being uncovered. While autophagy promotes primary tumor growth, metabolic adaptation and resistance to therapy, recent studies have unexpectedly revealed that autophagy suppresses the proliferative outgrowth of disseminated tumor cells into overt and lethal macrometastases. These studies suggest autophagy plays unexpected and complex roles in the initiation and progression of metastases, which will undoubtedly impact therapeutic approaches for cancer treatment. Here, we discuss the intricacies of autophagy in metastatic progression, highlighting and integrating the pleiotropic roles of autophagy on diverse cell biological processes involved in metastasis.

Keywords: Autophagy; Cancer; Metastasis; Selective Autophagy.

Fig. 1.

Stage-specific roles for autophagy during metastatic progression. Pre-clinical evidence demonstrates that autophagy can both suppress and promote tumor progression at distinct steps of the metastatic cascade. Autophagy hinders cancer initiation, but critically supports the growth and metabolic fitness of advanced primary tumors. In primary tumors, autophagy limits hypoxic and necrotic cell death, which might influence critical tumor–stroma interactions that initiate metastatic spread. Moreover, tumor cells utilize autophagy for migration, invasion and anoikis resistance. Upon initial seeding of distant metastatic sites, disseminated tumor cells (DTCs) utilize autophagy to facilitate dormant and quiescent cell survival, which may facilitate clinically undetectable metastatic disease resistant to therapeutic intervention. As DTCs erupt into a proliferative growth phase, autophagy can limit the emergence of aggressive subpopulations of tumor cells with high proliferative potential. Finally, autophagy selectively degrades MHC-I, which is crucial for immune recognition of tumor cells.

Fig. 2.

Autophagic regulation of tumor cell biological functions that influence metastatic progression. Autophagy supports multiple pro-metastatic cellular functions in primary tumors and during the early stages of metastasis, namely metabolic recycling and homeostasis, invasion and migration, and resistance to anoikis and chemotherapy, as well as cancer stem cell survival and fitness (arrows). In contrast, especially during the late stage of metastasis, such as colonization, autophagy has been found to be anti-metastatic by restricting the proliferation of disseminated tumor cells and inhibiting pro-metastatic differentiation programs (inhibitory arrows). How these paradoxical autophagy-regulated phenotypes coalesce during in vivo metastasis remains an area of intense investigation and clinical significance.

Fig. 3.

Pleiotropic functions of autophagy receptors in cancer. Selective autophagy is mediated by receptors, such as p62 and NBR1, which recognize ubiquitylated substrates and target them to the autophagosome for degradation. As a result, autophagy receptors are themselves degraded via autophagy. (A) Upon inhibition of autophagy, p62 and NBR1 accumulate within cells and act as scaffolds for components that are critical for MAPK and NFκB signaling cascades. (B) Elevated levels of cytosolic autophagy receptors in autophagy-deficient cells may also stabilize pro-metastatic transcription factors (NRF2, TP63 and TWIST1) or metabolic enzymes (PFKFB3) by sequestrating molecules that would normally promote the proteasomal degradation of these metastasis-promoting factors in autophagy-competent cells. (C) In autophagy-competent cells, NBR1 selectively removes MHC-I from the cell surface for autophagic degradation, thereby facilitating tumor cell immune evasion. aPKC, atypical protein kinase C; Ub, ubiquitin.