3:59 PM
Nov 09, 2017
 |  BC Innovations  |  Targets & Mechanisms

Vesicular fuel

Exosomes may reawaken breast cancer by transmitting mitochondrial DNA

A study from Memorial Sloan Kettering Cancer Center has shown for the first time that fibroblasts can cause drug resistance by revving up the metabolism of dormant cancer cells. But the authors’ proposal that exosomes carrying mitochondrial DNA underlie the mechanism has met preliminary skepticism from some in the field.

If true, however, the findings would ascribe an entirely new function to exosomes, which are emerging as a new modality in drug discovery for their potential to act as delivery vehicles in cancer and other diseases.

Exosomes are vesicles shed from cells, that mediate intercellular communication by carrying proteins and nucleic acids. This study suggests a new type of cargo should be added to the list, and places the vesicles in the crosshairs of cancer metabolism -- another key field of oncology research.

And regardless of how the vesicles are classified, detecting them could help predict who will develop drug resistance.

The study, published last month in Proceedings of the National Academy of Sciences, showed that cancer-associated (stromal) fibroblasts release vesicles containing mitochondrial DNA, and in some cases full mitochondrial genomes, which reignited oxidative phosphorylation in dormant breast cancer cells and led to hormone therapy-resistant growth.

Jacqueline Bromberg, a medical oncologist at MSKCC who led the study, told BioCentury she thinks mitochondrial DNA-carrying exosomes could be used to create diagnostics that predict development of drug-resistance across a range of cancers.

“One of the things we know is that cancers that are resistant to therapies are metabolically more active,” said Bromberg. “You often hear about cancers being glycolytic. But in fact, many cancers -- breast, lung, colorectal cancers -- are dependent on very functional active mitochondria.”

However, some exosome biologists question whether the vesicles were correctly classified as exosomes as opposed to a larger type of extracellular vesicle, in part because of the size of the cargo.

“It’s kind of a surprising observation that you’d have the entirety of the 16.5 kb mitochondrial genome in an exosome, that’s a pretty big chunk of DNA,” said Douglas Williams, CEO of exosome player Codiak BioSciences Inc.

Williams added that the lack of a clear definition of an exosome that is accepted across all labs remains a challenge in the field. “There’s still no real convention,” he said. “With the differences in the size and purification methods that people use for isolating exosomes it’s hard to read across what different groups are doing.”

Still, Bromberg is standing by her assertion. She noted mitochondrial...

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