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Autophagy in cell migration and metastasis.

“Autophagy promotes focal adhesion disassembly and cell motility of metastatic tumor cells through the direct interaction of paxillin with LC3”.

Sharifi et al, Cell Reports 15 (7) 1-13 (2016).

Autophagy is a conserved catabolic process that plays a housekeeping role in eliminating protein aggregates and organelles and is activated during nutrient deprivation to generate metabolites and energy. Autophagy plays a significant role in tumorigenesis, although opposing context-dependent functions of autophagy in cancer have complicated efforts to target autophagy for therapeutic purposes. Work from our lab has demonstrated that autophagy inhibition reduces tumor cell migration and invasion in vitro and attenuates metastasis in vivo. Numerous abnormally large focal adhesions (FAs) accumulate in autophagy-deficient tumor cells, reflecting a role for autophagy in FA disassembly through targeted degradation of paxillin. We demonstrate that paxillin interacts with processed LC3 through a conserved LIR motif in the amino terminal end of paxillin and that this interaction is regulated by oncogenic SRC activity. Together, these data establish a function for autophagy in FA turnover, tumor cell motility and metastasis.


  • Autophagy is required for the migration and invasion of metastatic tumor cells.
  • Autophagy promotes the degradation of paxillin and focal adhesion turnover.
  • Paxillin interacts with LC3B through a conserved LIR in a Src-regulated manner.
  • Autophagy is required for Src-regulated tumor cell motility.
  • These studies validate targeting autophagy to inhibit metastatic disease.



The image (right) shows mApple-Paxillin (red) in close association with processed GFP-LC3B-II (green) as focal adhesions are turned over by autophagy.

BNIP3 and mitophagy control in cancer.

“Mitophagy defects arising from BNip3 loss promote mammary tumor progression to metastasis”

Chourasia et al, EMBO Rep. 16 (9) 1145-1163 (2015).

bnip3BNip3 is a hypoxia-inducible protein that targets mitochondria for autophagosomal degradation. We have identified a novel tumor suppressor role for BNip3 in a clinically relevant mouse model of mammary tumorigenesis. We have demonstrated a functional link between the activity of BNip3 in retarding primary mammary tumor growth and progression to preventing the accumulation of dysfunctional mitochondria and resultant excess ROS production. In the absence of BNip3, mammary tumor cells are unable to reduce mitochondrial mass effectively and increased mitochondrial ROS caused elevated expression of Hif-1a and Hif target genes, including those involved in glycolysis and angiogenesis, two processes that are also markedly increased in BNip3 null tumors. Glycolysis inhibition attenuated growth of BNip3 null tumor cells revealing increased dependence on autophagy for survival. Our data also demonstrates that BNIP3 deletion can be used as a prognostic marker of tumor progression to metastasis in human triple negative breast cancer (TNBC). Our work reveals how mitochondrial dysfunction due to defects in mitophagy can promote the Warburg effect and tumor progression, and also suggest better approaches to stratifying TNBC for treatment.


  • Loss of BNip3 promotes tumor cell growth and progression to metastasis in the MMTV-PyMT mammary tumor model;
  • Elevated ROS production by dysfunctional mitochondria in BNip3 null tumors results in increased Hif-1a levels and increased tumor progression to invasiveness;
  • This defines a novel negative feedback loop between BNip3 and Hif-1a that limits the oncogenic activity of Hif-1 in glycolysis and angiogenesis;
  • Defective mitochondria and increased aerobic glycolysis arising from loss of BNip3 induces greater dependence on autophagy for survival;
  • BNIP3 is focally deleted in triple negative breast cancer and together with high HIF-1a levels strongly predicts progression to metastasis in TNBC patients.