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| Staphylococcus epidermidis |
Download Episode (9.2 MB, 10 minutes)
Show notes:
Microbe of the episode: Hamiltonella virus APSE1
News item
Journal Paper:
Nakatsuji T, Chen TH, Butcher AM, Trzoss LL, Nam S-J, Shirakawa KT, Zhou W, Oh J, Otto M, Fenical W, Gallo RL. 2018. A commensal strain of Staphylococcus epidermidis protects against skin neoplasia. Sci Adv 4:eaao4502.
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Episode outline:
- Background: Microbiota important for most parts of body, function of immune system
- Gut but also skin and others
- Help defend against pathogens like Staphylococcus aureus
- Can also help regulate inflammation after injury
- What’s new: Now, scientists publishing in Science Advances have discovered another useful function of skin microbes—protecting against cancer!
- Methods: Were testing strains of Staphylococcus that live on healthy skin for antimicrobials
- Found one S. epidermidis that can secrete inhibitor of Streptococcus pathogens
- Purified and identified as a small molecule, not a protein: 6-N-hydroxyaminopurine
- Or 6-HAP
- Synthesized specifically by the bacteria, not byproduct of metabolism
- 6-HAP similar in structure to nucleic acid base, adenine, or A of AGCT
- Might interact with DNA/RNA metabolism somehow
- So tested with DNA polymerase
- 6-HAP inhibited DNA synthesis when addition of adenine nucleotide required
- So can prevent DNA synthesis and therefore can prevent cell replication/proliferation
- Possibly useful against cancer, since it proliferates much more than normal skin cells?
- Tested against several cancer lines and normal cells with BrdU
- fluorescent tag similar to thymine, shows DNA synthesis
- 6-HAP prevented cancer lines from incorporating it (and thus making DNA)
- But didn't prevent normal cells
- Why the selectiveness? Mediated by mARCs
- Mitochondrial amidoxime reducing components – convert stuff like 6-HAP to normal bases
- More activity in normal cells than cancer
- When inhibited in normal, reduced resistance to 6-HAP to be more like cancer cells
- Still, important to ensure 6-HAP doesn't interfere with DNA; could cause mutations
- Tested with a couple mutagenesis tests, in mouse cells and bacteria
- But found no mutagenic activity
- Then actually tested in a live context - in mice with tumors
- In healthy mice, 6-HAP alone didn't show toxicity even at max dose for 2 weeks injected
- So then gave to mice inoculated with melanoma cell line to induce tumors
- Despite aggressive tumors, size suppressed by >60%
- So molecule works, but what about bacteria that make it?
- Induced tumors on mouse skin with UV+carcinogen
- And colonized mouse skin with S. epidermidis, either producing 6-HAP or not
- Producers had fewer tumors, non-producers had normal number
- Finally looked in human microbiome datasets, found 6-HAP producers common in humans
- Summary: Healthy skin bacteria produce compound with antitumor properties, could help prevent skin cancer
- Applications and implications: Maybe new treatment for cancer
- Or basis for developing one
- Useful for research too, when selectively inhibiting DNA synthesis is desired
- Clarifications if necessary: Seems like resistance could evolve fairly easily
- Seems already present in healthy cells, in enzymes that degrade 6-HAP
- So just need for cancer not to inactivate enzymes; not so hard?
- What do I think: Shows importance of healthy microbiota, even on skin
- Some evidence that disruptions increase risk of cancer, at least in gut
- This anticancer molecule production could contribute to effect
- In addition to immune modulation
- And maybe disruption of other microbes that increase risks
- Need to understand better
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