title: Autophagy-dependent production of secreted factors facilitates oncogenic RAS-driven invasion.
abstract: The tumor-promoting functions of autophagy are primarily attributed to its ability to promote cancer cell survival. However, emerging evidence suggests that autophagy plays other roles during tumorigenesis. Here, we uncover that autophagy promotes oncogenic RAS-driven invasion. In epithelial cells transformed with oncogenic RAS, depletion of autophagy-related genes suppresses invasion in three-dimensional culture, decreases cell motility, and reduces pulmonary metastases in vivo. Treatment with conditioned media from autophagy-competent cells rescues the invasive capacity of autophagy-deficient cells, indicating that these cells fail to secrete factors required for RAS-driven invasion. Reduced autophagy diminishes the secretion of the promigratory cytokine interleukin-6 (IL-6), which is necessary to restore invasion of autophagy-deficient cells. Moreover, autophagy-deficient cells exhibit reduced levels of matrix metalloproteinase 2 and WNT5A. These results support a previously unrecognized function for autophagy in promoting cancer cell invasion via the coordinate production of multiple secreted factors.
  
  
  CONCLUSIONS
  Our results delineate a previously unrecognized function for autophagy in facilitating oncogenic RAS-driven invasion. We demonstrate that an intact autophagy pathway is required for the elaboration of multiple secreted factors favoring invasion, including IL-6.
authors: Department of Pathology, Helen Diller Family Comprehensive Cancer Center and Biomedical Science Graduate Program, University of California San Francisco, San Francisco, California.
authors: Rebecca
authors: R
authors: Lock
authors: Candia M
authors: CM
authors: Kenific
authors: Andrew M
authors: AM
authors: Leidal
authors: Eduardo
authors: E
authors: Salas
authors: Jayanta
authors: J
authors: Debnath
mesh_terms: D000818:Animals; D001343:Autophagy; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D051153:Wnt Proteins / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics*
chemical_list: D015850:Interleukin-6; D051153:Wnt Proteins; D020778:Matrix Metalloproteinase 2; D018631:ras Proteins