Payam Gammage
@mito-oncogene.bsky.social
Mitochondrial genetics, genome engineering, cancer metabolism. Lab supported by ERC, NCI, CRUK & EMBO YIP.
Lab website: https://shorturl.at/lowCL
Lab website: https://shorturl.at/lowCL
Now that’s the kind of reach we can only dream of! 😊 thanks
November 8, 2025 at 10:04 PM
Now that’s the kind of reach we can only dream of! 😊 thanks
This made my day :) thank you
November 7, 2025 at 9:22 AM
This made my day :) thank you
Thank you for your kind words Christian!
November 4, 2025 at 8:03 AM
Thank you for your kind words Christian!
Thank you Alexey, I think the functional data we generated bear out that point well.
November 3, 2025 at 11:51 AM
Thank you Alexey, I think the functional data we generated bear out that point well.
Oof - a bunch of those images didn't come out at all! If you want to see them all the more reason to go check out the paper!
November 3, 2025 at 11:19 AM
Oof - a bunch of those images didn't come out at all! If you want to see them all the more reason to go check out the paper!
Huge thanks to all of our fantastic collaborators (many of whom are not on Bsky) within @cruk-si.bsky.social @mskcancercenter.bsky.social @helsinki.fi @uofglasgow.bsky.social and more - this was a team effort, supported by @cancerresearchuk.org and the NIH/National Cancer Institute.
November 3, 2025 at 11:15 AM
Huge thanks to all of our fantastic collaborators (many of whom are not on Bsky) within @cruk-si.bsky.social @mskcancercenter.bsky.social @helsinki.fi @uofglasgow.bsky.social and more - this was a team effort, supported by @cancerresearchuk.org and the NIH/National Cancer Institute.
Sidebar 2: they also appear to be something of an Achilles heel for therapy - another conversation for another day.
www.nature.com/articles/s43...
www.nature.com/articles/s43...
Mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade response in melanoma - Nature Cancer
Gammage and colleagues find that mitochondrial DNA mutations induce alterations in redox metabolism, a remodeled tumor microenvironment characterized by a loss of neutrophils and consequently enhanced...
www.nature.com
November 3, 2025 at 11:15 AM
Sidebar 2: they also appear to be something of an Achilles heel for therapy - another conversation for another day.
www.nature.com/articles/s43...
www.nature.com/articles/s43...
I'll leave it to the readers to make up their own minds.
But we think it's because the metabolic consequences of mtDNA mutation are powerful drivers of tumor initiation and progression.
www.cell.com/trends/cance...
But we think it's because the metabolic consequences of mtDNA mutation are powerful drivers of tumor initiation and progression.
www.cell.com/trends/cance...
Mitochondrial DNA is a major source of driver mutations in cancer
Mitochondrial DNA (mtDNA) mutations are among the most common genetic events in all
tumors and directly impact metabolic homeostasis. Despite the central role mitochondria
play in energy metabolism an...
www.cell.com
November 3, 2025 at 11:15 AM
I'll leave it to the readers to make up their own minds.
But we think it's because the metabolic consequences of mtDNA mutation are powerful drivers of tumor initiation and progression.
www.cell.com/trends/cance...
But we think it's because the metabolic consequences of mtDNA mutation are powerful drivers of tumor initiation and progression.
www.cell.com/trends/cance...
Why this matters #2:
These mutations have never been seen in the human germline or in mito disease.
Clearly they are not compatible with life, but tumors are not only unfazed by this, they are happily selecting for the most deleterious mtDNA mutations observed on planet earth.
Why is that?
These mutations have never been seen in the human germline or in mito disease.
Clearly they are not compatible with life, but tumors are not only unfazed by this, they are happily selecting for the most deleterious mtDNA mutations observed on planet earth.
Why is that?
November 3, 2025 at 11:15 AM
Why this matters #2:
These mutations have never been seen in the human germline or in mito disease.
Clearly they are not compatible with life, but tumors are not only unfazed by this, they are happily selecting for the most deleterious mtDNA mutations observed on planet earth.
Why is that?
These mutations have never been seen in the human germline or in mito disease.
Clearly they are not compatible with life, but tumors are not only unfazed by this, they are happily selecting for the most deleterious mtDNA mutations observed on planet earth.
Why is that?
Why this matters #1:
Most mtDNA mutations in cancer have never been studied, and many are 5-50% heteroplasmy (VAF).
Because of the low heteroplasmy, they are often discounted as non-functional passengers.
The discoveries described in this paper establish that this is not a safe assumption.
Most mtDNA mutations in cancer have never been studied, and many are 5-50% heteroplasmy (VAF).
Because of the low heteroplasmy, they are often discounted as non-functional passengers.
The discoveries described in this paper establish that this is not a safe assumption.
November 3, 2025 at 11:15 AM
Why this matters #1:
Most mtDNA mutations in cancer have never been studied, and many are 5-50% heteroplasmy (VAF).
Because of the low heteroplasmy, they are often discounted as non-functional passengers.
The discoveries described in this paper establish that this is not a safe assumption.
Most mtDNA mutations in cancer have never been studied, and many are 5-50% heteroplasmy (VAF).
Because of the low heteroplasmy, they are often discounted as non-functional passengers.
The discoveries described in this paper establish that this is not a safe assumption.
rRNA hotspot mutations are clearly something else. Given their impact at very low heteroplasmy, we have termed these variants 'functionally dominant'.
November 3, 2025 at 11:15 AM
rRNA hotspot mutations are clearly something else. Given their impact at very low heteroplasmy, we have termed these variants 'functionally dominant'.
As I said about 5000 posts back, canonical mtDNA mutations associated with mitochondrial disease need heteroplasmies over 50% to become penetrant -this makes them 'functionally recessive'.
November 3, 2025 at 11:15 AM
As I said about 5000 posts back, canonical mtDNA mutations associated with mitochondrial disease need heteroplasmies over 50% to become penetrant -this makes them 'functionally recessive'.
This exemplar mutation we've been able to validate really matters, and not just because it's the first time anyone did it. Disease-associated mtDNA mutations having an impact below 50% heteroplasmy, and in this case quite a long way below, is very important for interpreting tumor genomics.
November 3, 2025 at 11:15 AM
This exemplar mutation we've been able to validate really matters, and not just because it's the first time anyone did it. Disease-associated mtDNA mutations having an impact below 50% heteroplasmy, and in this case quite a long way below, is very important for interpreting tumor genomics.
Congratulations if you made it this far! I know I've been going on for a while, so time to wrap up
a penguin is sticking its head out of a hole next to a piece of paper that says please wrap it up
ALT: a penguin is sticking its head out of a hole next to a piece of paper that says please wrap it up
media.tenor.com
November 3, 2025 at 11:15 AM
Congratulations if you made it this far! I know I've been going on for a while, so time to wrap up
And in a final flourish, one of my favourite analyses, using the DOGMA output, Sonia was able to establish that the heteroplasmy threshold for a transcriptional phenotype of our example rRNA hotspot was somewhere ~20-30%.
November 3, 2025 at 11:15 AM
And in a final flourish, one of my favourite analyses, using the DOGMA output, Sonia was able to establish that the heteroplasmy threshold for a transcriptional phenotype of our example rRNA hotspot was somewhere ~20-30%.
Using the powerful DOGMA-seq method from Leif Ludwig (no Bsky) and @caleblareau.bsky.social, we were able to tease apart heteroplasmic dosage of m.1227G>A on cellular transcriptional phenotype, showing a clear effect on mitochondrial transcripts, but also (gasp) non-mitochondrial ribosomes...
November 3, 2025 at 11:15 AM
Using the powerful DOGMA-seq method from Leif Ludwig (no Bsky) and @caleblareau.bsky.social, we were able to tease apart heteroplasmic dosage of m.1227G>A on cellular transcriptional phenotype, showing a clear effect on mitochondrial transcripts, but also (gasp) non-mitochondrial ribosomes...
This was coupled to a clearly perturbed mitoribosome assembly/translational profile, again from a low heteroplasmy (38%). If you're not seeing it immediately don't sweat - it took @mitogene.bsky.social ~5 years to teach me how to interpret these things
November 3, 2025 at 11:15 AM
This was coupled to a clearly perturbed mitoribosome assembly/translational profile, again from a low heteroplasmy (38%). If you're not seeing it immediately don't sweat - it took @mitogene.bsky.social ~5 years to teach me how to interpret these things
Interestingly, even after all that screening we couldn't get the bulk heteroplasmy of this recurrent mutation, m.1227G>A, above ~40%. And even more interesting, we saw massive effects of this mutation on metabolism, mitochondrial function and protein levels starting from heteroplasmy of ~10%.
November 3, 2025 at 11:15 AM
Interestingly, even after all that screening we couldn't get the bulk heteroplasmy of this recurrent mutation, m.1227G>A, above ~40%. And even more interesting, we saw massive effects of this mutation on metabolism, mitochondrial function and protein levels starting from heteroplasmy of ~10%.
(This was painful - introducing any old mutation somewhere in mtDNA is one thing, but trying to edit a single, specific position while avoiding off-targets is still a major challenge. In this case we had a 2% hit rate from candidate reagents to lead reagent. You have been warned!) #sorryjacqueline
a man in a suit and tie stands next to another man in a yellow shirt and tie
ALT: a man in a suit and tie stands next to another man in a yellow shirt and tie
media.tenor.com
November 3, 2025 at 11:15 AM
(This was painful - introducing any old mutation somewhere in mtDNA is one thing, but trying to edit a single, specific position while avoiding off-targets is still a major challenge. In this case we had a 2% hit rate from candidate reagents to lead reagent. You have been warned!) #sorryjacqueline
Employing fantastic mitochondrial base editing tools developed in David Liu's lab @broadinstitute.org institute.org, we engineered in vitro models to bear recurrent rRNA mutations, which we then profiled extensively to see what was happening.
November 3, 2025 at 11:15 AM
Employing fantastic mitochondrial base editing tools developed in David Liu's lab @broadinstitute.org institute.org, we engineered in vitro models to bear recurrent rRNA mutations, which we then profiled extensively to see what was happening.
Now, because nobody has really had cause or means to study mutations in these positions, the impact of a 'low heteroplasmy' mutation in one of these positions was a total unknown. They seemed pretty likely to do something, but it was validation time.
November 3, 2025 at 11:15 AM
Now, because nobody has really had cause or means to study mutations in these positions, the impact of a 'low heteroplasmy' mutation in one of these positions was a total unknown. They seemed pretty likely to do something, but it was validation time.
However, the heteroplasmy of these genetically recurrent and structurally clustered rRNA mutations was pretty low - rarely rising over 30% in the bulk sequencing from tumor genomes (probably an underestimate, given how much of a tumor isn’t cancer cells, but still rather low).
November 3, 2025 at 11:15 AM
However, the heteroplasmy of these genetically recurrent and structurally clustered rRNA mutations was pretty low - rarely rising over 30% in the bulk sequencing from tumor genomes (probably an underestimate, given how much of a tumor isn’t cancer cells, but still rather low).