Autophagic degradation of focal adhesions underlies metastatic cancer dissemination

Abstract

Autophagy inhibition is being evaluated as a novel therapeutic strategy in multiple tumor types, but little is known about its implications for metastatic dissemination. We recently reported that autophagic degradation of paxillin through direct interaction with the autophagy protein LC3B is required for focal adhesion disassembly, Src-stimulated tumor cell motility, and metastasis. KEYWORDSAutophagy; cell motility; metastasis; paxillin; Src Despite decades of research, the treatment of metastatic disease remains an extremely challenging clinical problem and metastasis is still the cause of more than 90% of cancer-related mortality. Metastasis is a highly inefficient process as disseminating tumor cells must survive severe cellular stresses and selective pressures in different microenvironments that are part of the metastatic cascade in order to successfully reach and colonize a metastatic site.1 Autophagy is a conserved intracellular degradative pathway utilizing the endolysosomal machinery that plays a major role in cellular survival under stresses such as growth factor withdrawal and hypoxia 2 and is frequently coopted by tumor cells to support their proliferation and survival.3 Intriguingly, increased staining for the autophagy marker microtubule associated protein 1 light chain 3 beta (MAP1LC3B), hereafter referred to as LC3B, has been associated with lymph node metastasis in breast cancer, and increased levels of LC3B staining are observed in melanoma metastases compared to matched primary samples, 4 suggesting that autophagy is upregulated during metastatic dissemination. As a result, there has been increasing interest in investigating whether autophagy acts as a survival mechanism for disseminating tumor cells or has other prometastatic functions, and thus whether autophagy inhibition might represent a novel therapeutic strategy for targeting metastatic disease. Similar to the pleiotropic role of autophagy at earlier stages of tumorigenesis, 3 ex vivo studies identified several key functions for autophagy that are relevant to advanced metastatic disease, including the secretion of promigratory cytokines, 5 although the relevance of autophagy for metastatic dissemination and outgrowth in vivo remained unknown.In a recently published report, 6 we addressed this question through genetic and chemical inhibition of autophagy in the metastatic 4T1 mouse model of breast cancer, which undergoes robust basal autophagic flux. Intriguingly, we found that inhibition of autophagy in this model dramatically impaired spontaneous metastasis to the lungs and liver, but did not reduce cell proliferation or survival at the site of the primary tumor or indeed the ability of tumor cells to colonize the lungs after injection directly into the circulation. This suggested that autophagy-deficient cells were failing to metastasize due to their inability to escape from the primary tumor. Indeed, we found that autophagy-deficient 4T1 cells in vitro have a primary defect in cell migration and spreading that could also be fo...

The Double-Edge Sword of Autophagy in Cancer: From Tumor Suppression to Pro-tumor Activity

“…Autophagy participates in FA turnover in this context, by degrading paxillin in auto phagosomes and disrupting FA. Sharifi et al found that inhibiting autophagy suppresses metastasis to the lungs and liver without affecting tumor cell proliferation in a metastatic 4T1 mouse model of breast cancer ( 8 , 133 ). Paxillin in breast cancer and melanoma metastasis serves as FA scaffolding and contains a LIR.…”

Loss of the Essential Autophagy Regulators FIP200 or Atg5 Leads to Distinct Effects on Focal Adhesion Composition and Organization

“…This results in the encapsulation of cargo within an autophagosome, followed by their transport to the lysosome for degradation. It is thought that this selective process for the targeted turnover of focal adhesion components helps facilitate coordinated cell movement ( Kenific et al, 2016b ; Sharifi et al, 2017 ).…”

Dynamics of p14ARF and Focal Adhesion Kinase-Mediated Autophagy in Cancer

“…Loss of ECM–integrin engagement results in induced autophagy in several cellular models [ 62 , 63 ]. Furthermore, the basal level of autophagy regulates cell spreading by promoting cell protrusion extension [ 64 ] and is required for focal adhesion turnover and cell migration [ 65 ]. Interestingly, upon loss of ECM contact, the absence of nutrients does not per se induce autophagy, but rather a signaling mechanism that, “sensing” the cell environment, transduces the need for an alternative energy supply mechanism to the cell [ 66 ].…”