Ral GTPases promote breast cancer metastasis by controlling biogenesis and organ targeting of exosomes

Ral GTPases promote breast cancer metastasis by controlling biogenesis and organ targeting of exosomes

Metastasis is a fundamental hallmark of cancer and the most closely aligned with poor prognosis.  The mechanisms that regulate metastasis; in particular, the cancer cell’s ability to communicate with the tumor microenvironment to colonize at distinct, distal organ sites remain an intense area of investigation. Recent studies suggest both soluble molecules as well as extracellular vesicles (EV) can play important roles towards seeding the pre-metastatic niche and creating a favorable tumor microenvironment for metastatic cancer cells. Preliminary work by Hyenne et al. identified Ral A/B as a participant in EV secretion in aggressive 4T1 mammary tumor cells; however, whether these EVs play a role in metastasis remained unknown. In this recent study, Ghoroghi et. al. identified Ral A/B as critical regulator of metastasis through control of exosome secretion and biogenesis.  Following up on their early studies, the group utilized chemical fixation and high-pressure freezing electron microscopy to validate that Ral A/B controls MVB homeostasis and regulation of EV secretion.  They then sought to analyze metastatic progression of mammary tumors in a syngeneic mouse model.  Interestingly, manipulation of Ral A or Ral B had opposing effects on the primary tumor cells, but depletion of either Ral A or Ral B reduced the metastatic burden in this model. They hypothesized it may be due to a non-cell autonomous mechanism; thus, they investigated whether Ral A/B regulated EVs may be altering the pre-metastatic niche.  They utilized Membright plasma membrane probes to label EVs +/- Ral A/B from 4T1 cells and injected them into the blood circulation to track their localization.  Interestingly, EVs from Ral A/B depleted cells failed to reach the lungs and liver like its wild type counterparts.  They went on to identify key proteins involved in both biogenesis and targeting of EVs to these pre-metastatic niches, and also found that Ral A/B are expressed at high levels in cancer patients with poor survival. Cytoskeleton’s Membright/Memglow plasma membrane probe (Cat. #MG04) was important for labeling and tracking EVs to distal organs where they contribute to metastasis progression.