Abstract
Cancer recurrence after initial diagnosis and treatment is a major cause of breast cancer (BC) mortality, which results from the metastatic outbreak of dormant tumour cells. Alterations in the tumour microenvironment can trigger signalling pathways in dormant cells leading to their proliferation. However, processes involved in the initial and the long-term survival of disseminated dormant BC cells remain largely unknown. Here we show that autophagy is a critical mechanism for the survival of disseminated dormant BC cells. Pharmacologic or genetic inhibition of autophagy in dormant BC cells results in significantly decreased cell survival and metastatic burden in mouse and human 3D in vitro and in vivo preclinical models of dormancy. In vivo experiments identify autophagy gene autophagy-related 7 (ATG7) to be essential for autophagy activation. Mechanistically, inhibition of the autophagic flux in dormant BC cells leads to the accumulation of damaged mitochondria and reactive oxygen species (ROS), resulting in cell apoptosis.
Highlights
Cancer recurrence after initial diagnosis and treatment is a major cause of breast cancer (BC) mortality, which results from the metastatic outbreak of dormant tumour cells
We demonstrate that pharmacologic or genetic inhibition of autophagy greatly impairs the survival of dormant BC cells in vitro and in vivo, but has minimal effect on metastatic growth once dormant cells have transitioned to a proliferative state
D2.0 R cells in basal membrane extract (BME) plus collagen 1 (COL1) exhibited much lower levels of Lysosomal-associated membrane protein 1 (LAMP1) and LC3 staining throughout the 8-day time course (Fig. 1a, b)
Summary
Cancer recurrence after initial diagnosis and treatment is a major cause of breast cancer (BC) mortality, which results from the metastatic outbreak of dormant tumour cells. Pharmacologic or genetic inhibition of autophagy in dormant BC cells results in significantly decreased cell survival and metastatic burden in mouse and human 3D in vitro and in vivo preclinical models of dormancy. D2.0 R and MCF-7 cells remain quiescent on basal membrane extract (BME) matrices for 12 days whereas the highly metastatic D2A1, MDA-MB-231 and 4T1 cells spontaneously outbreak into a proliferative state between day 1 and 6 of culture on BME8 These studies demonstrated that changes in the microenvironment, including exposure to collagen 1 (COL1) or fibronectin, induce the dormant-to-proliferative switch of D2.0 R cells[8,10]. We demonstrate that pharmacologic or genetic inhibition of autophagy greatly impairs the survival of dormant BC cells in vitro and in vivo, but has minimal effect on metastatic growth once dormant cells have transitioned to a proliferative state.
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