Our review dissecting the nuanced roles of mitochondria during cancer progression, was just published in @annualreviews.bsky.social. This one was written by David Sokolov with his approachable and entertaining writing style. Check it out:
www.annualreviews.org/content/jour...
The second was adding NAC (in Ext Data). We also blocked GSH synth, which increased Cys and showed similar effects. As you know, working with ROS/thiols is tricky and, while each treatment has caveats and nuances, we think they collectively they argue for xCT-independent effect of "Excess cysteine."
Thanks Antonio!
Yes! While we found adding cysteine directly wouldn't work since it rapidly autooxidized, we took a couple of approaches to orthogonally supply cysteine without xCT. First was BME in the media to catalytically reduce cystine to cysteine for uptake, which showed similar effects.
Check out our latest work out today in @natmetabolism.nature.com in which we describe a new metabotype (metabolic phenotype): excess cysteine stress. We discovered novel cysteine conjugates and show how pyruvate modulates free intracellular cysteine levels. Grateful for an awesome team!!
This work was driven by two fantastic #CysTeam trainees – @jenniferabrain.bsky.social and Anna Vigil – with support from lab members (incl. @ayahai.bsky.social, @madelouhart.bsky.social, and others) + collaborators.
Thx to NIGMS, Emerson Coll. for funding and @jeannakhle.bsky.social for editing!
Overall, this study reveals “excess cysteine stress” as an underappreciated vulnerability in NRF2-driven cancers and expands the landscape of cysteine metabolism.
Functionally, high environmental cystine was toxic to NRF2-activated cells: excess cystine uptake impaired proliferation, which was rescued by xCT inhibition or by sequestering cysteine into a subset of non-toxic conjugates.
These cysteine-derived conjugates weren’t just cell culture artifacts. With help from @ginadenicola.bsky.social we detected them in murine lung tumors and in primary human lung cancer samples, where they were enriched in NRF2-activated tumors.
We determined many unknown metabolites to be cysteine conjugates formed with endogenous sugar metabolites, including irreversible conjugates reactions with sugar phosphates and reversible products from carbonyl-containing metabolites.
To map cysteine’s metabolic fates, we developed an untargeted isotope tracing strategy (inspired by credentialing approaches by @gjpattij.bsky.social and others), which uncovered 29 cysteine-derived features, with most being unknown and enriched in NRF2 activated cells.
Pleased to share our recent work out today in @natmetabolism.nature.com. This study addresses a longstanding mystery - NRF2-driven cancers increase cysteine acquisition (via xCT) by ~5x - so where does all that cysteine go?
A big chunk of my postdoctoral work on cell-state dependent metabolism is now out at @cp-molcell.bsky.social: www.cell.com/molecular-ce... 1/
For ~century, we’ve asked: why do proliferating cells ferment glucose even when O2 is around? I’m thrilled to share our latest work @natmetabolism.nature.com, led by @thebiokimist.bsky.social. By leveraging conditional essentiality in HPLM, we propose a provocative new answer to this classic Q. 🧵
cc: @olivernewsom.bsky.social
Comparison of proliferation rates in serum free vs 10% FBS media formulations. Transformed cells maintain proliferation in both contexts while non-transformed cells proliferate slower in serum free conditions.
One new reviewer-initiated experiment: Unlike cancer cells, non-transformed cells grow poorly in serum free conditions. Highlights the fact that cancer cells are defined, in part, by the lack of requirement for exogenous growth factors. Makes fetal serum use for cancer cells all the more absurd!
Our work detailing the metabolic roles of serum for cancer cell proliferation is now out at JBC, @asbmbjournals.bsky.social!
Congrats to Oliver and Eric and many thanks to the editor and reviewers for a thoughtful and efficient review process.
See here:
www.sciencedirect.com/science/arti...
Check out this great interview with a true rising star in metabolism research (and lab alumni)! 🙌
Our paper on regulation of BCAA catabolism by mitochondrial calcium signaling is out!
Mitochondrial calcium signaling regulates branched-chain amino acid catabolism in fibrolamellar carcinoma | Science Advances www.science.org/doi/10.1126/...
![[Person with ponytail wearing lab coat hands balloon to another person in front of a springboard, a magnet hanging from above, and then a target] PERSON WITH PONYTAIL to Person 2: Rub this balloon against your head, then go jump past that magnet toward the target on the wall. [caption] Before the bathroom scale was invented, the only way to weigh people was mass spectrometry.](https://cdn.bsky.app/img/feed_thumbnail/plain/did:plc:cz73r7iyiqn26upot4jtjdhk/bafkreid7lnvd7afmasx3nxi6anxmyhbatpaw54za3kiw3eaoclrf722faq)
[Person with ponytail wearing lab coat hands balloon to another person in front of a springboard, a magnet hanging from above, and then a target] PERSON WITH PONYTAIL to Person 2: Rub this balloon against your head, then go jump past that magnet toward the target on the wall. [caption] Before the bathroom scale was invented, the only way to weigh people was mass spectrometry.
Mass Spec
xkcd.com/3094/
Niemi lab graduate student Hannah Pletcher recently joined @prelights.bsky.social and wrote nice highlight of recent work from @lucasbsullivan.bsky.social - check it out here!
Our latest, in Science Advances: In vivo CRISPR screen revealed sgRNAs that switch chemosensitive SCLC PDXs to become resistant.We validated KEAP1 as key hit and found KEAP1 alterations in IMpower133 trial, where active NRF2 links to reduced survival in chemo arm www.science.org/doi/10.1126/... 1/2
Overjoyed to have the opportunity to present my work orally at the Cancer Metabolism Showcase! Hope to see you there virtually!
From Nobel prize winning cancer researcher Bill Kaelin
Killing the Science Golden Goose - The American Journal of Medicine www.amjmed.com/article/S000...
Obliteride registeration opens today!!! Join the @lucasbsullivan.bsky.social team and help to CURE CANCER FASTER! See you August 9th at the starting line!! @obliteride.bsky.social #Obliteride #Obliteride2025 secure.fredhutch.org/goto/sulliva...
Hello, can you add me please?
Poster is printed! Looking forward to going to the Keystone Tumor Metabolism meeting next week in Vancouver. Come talk to me about NRF2, cysteine, and novel metabolite discovery! #KSTumorMetab25 #cancermetabolism #keystonesymposia
happy to share our forum now online @Cell_Metabolism! fun for us (Guy & myself) to collaborate with @dfazakerley.bsky.social, Joycelyn, & Sam in putting together what we hope will be a useful piece for the broad metabolism community re: in vitro modeling! www.cell.com/cell-metabol...
