Cell-autonomous circadian DNA damage response

3718 Cell Cycle Volume 11 Issue 20 Of the hallmarks of cancer,1 the process of invasion and metastases is arguably the least well-understood and therefore least drugable. Invasion through the extracellular matrix is arguably the critical distinction between carcinoma in situ and carcinoma with metastatic potential. Efforts to understand targetable mechanisms of cancer invasiveness are sorely needed. In a recent issue, Macintosh et al. provided evidence that autophagy, the degradative process by which cells sequester and recycle cytoplasmic components, plays a role in tumor cell invasion.2 Using a glioma cell line expressing a doxycycline-inducible shRNA directed against the essential autophagy gene ATG12, the effects of autophagy inhibition in two-dimensional (2D) culture and a three-dimensional (3D) organotypic culture system was studied. Knockdown of ATG12 had no significant impact on many cellular functions in 2D culture, including profileration, vaibility and migration. However, knockdown of ATG12, compared with non-target knockdown, resulted in a reduced capacity to invade an organotypic matrix consisting of human fibroblasts embedded in polymerized collagen (Fig. 1). Since efforts are underway to target autophagy therapeutically in cancer,3 the authors conclude that autophagy represents a drugable mechanism of tumor cell invasion. This study provides further evidence that autophagy can contribute to the malignant phenotype of cancer cells and could be a therapeutic target in certain cancers. The results also underscore a recurring theme in autophagy research, that cellular phenotypes of autophagy modulation are more pronounced within the tumor microenvironment than in traditional 2D culture. In an ovarian cancer model, acute activation of the ARHI tumor suppressor gene induced autophagic cell death in vitro but autophagic cell survival in vivo.4 In a study of aggressive and indolent melanoma cell lines, elevated autophagy levels did not Cell Cycle News & Views