Abstract
SummaryCancer metastasis depends on cell survival following loss of extracellular matrix attachment and dissemination through the circulation. The metastatic spread can be enhanced by the clustering of detached cancer cells and increased antioxidant defense. Here, we link these responses by describing how cell clustering limits reactive oxygen species (ROS). Loss of attachment causes mitochondrial perturbations and increased ROS production. The formation of cell clusters induces a hypoxic environment that drives hypoxia-inducible factor 1-alpha (Hif1α)-mediated mitophagy, clearing damaged mitochondria and limiting ROS. However, hypoxia and reduced mitochondrial capacity promote dependence on glycolysis for ATP production that is supported by cytosolic reductive metabolism. Preventing this metabolic adaptation or disruption of cell clusters results in ROS accumulation, cell death, and a reduction of metastatic capacity in vivo. Our results provide a mechanistic explanation for the role of cell clustering in supporting survival during extracellular matrix detachment and metastatic spread and may point to targetable vulnerabilities.
Highlights
The metastatic spread of tumors to distant sites is responsible for most cancer-related deaths (Eccles and Welch, 2007)
Loss of Attachment Induces Reductive Carboxylation into Malate and 2HG Production To assess metabolic changes that may contribute to cancer cell survival during anchorage independent growth, we compared cells grown in monolayers to cells grown on ultralow attachment plates that prevent cell adhesion and force cells to grow in suspension
While this cytosolic citrate can shuttle to the mitochondria to support mitochondrial NADPH production (Jiang et al, 2016), our further analysis of TCA cycle intermediates revealed an increase in M + 3 and a decrease in M + 4 malate and fumarate in detached cells (Figures 1B and S1B)
Summary
The metastatic spread of tumors to distant sites is responsible for most cancer-related deaths (Eccles and Welch, 2007) While this invasive process remains poorly understood, it is clear that the metastasizing cell must overcome numerous hurdles associated with movement out of the primary tumor, entry into the circulation, and re-establishment within a distant organ (Fidler, 2003; Hunter et al, 2008). These barriers make metastasis a highly inefficient process. One factor that can enhance the metastatic capacity of cancers is the ability of detached cells to form clusters or aggregates (Aceto et al, 2014; Gkountela et al, 2019), the underlying mechanism by which aggregation supports metastatic capacity is not well understood
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