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Lucas Sullivan

@lucasbsullivan.bsky.social
797 followers 594 following 67 posts

Associate Professor @ Fred Hutch Studying metabolic constraints of cancer cell proliferation research.fredhutch.org/sullivan/en.… On a mote of dust suspended in a sunbeam

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Reposted by Lucas Sullivan
Yasemin Sancak @yasesancak.bsky.social · 05/08/2026
Excited to share our new preprint! biorxiv.org/content/10.6... We know that mitochondria make contacts with organelles, but determining whether these contacts establish functionally distinct mitochondrial populations has been challenging.
biorxiv.org
A Modular Platform for Purification of Organelle-associated Mitochondria Reveals Functional Specialization at Organelle Contact Sites
Mitochondria perform diverse metabolic and signaling functions, yet how these activities are spatially organized within the mitochondrial network of cells remains poorly understood. Organelle contact ...
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Lucas Sullivan @lucasbsullivan.bsky.social · 29/07/2026
Notably, this study is still a preprint and a more complete story will be coming as we addressed reviewer comments with respect to therapeutic relevance and biochemical mechanisms. Check out the full reviewed preprint at eLife: doi.org/10.7554/eLif...
doi.org
Adaptive plasticity of aspartate metabolism in succinate dehydrogenase-deficient cancer cells
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Lucas Sullivan @lucasbsullivan.bsky.social · 29/07/2026
This work was driven by David Sokolov, with support from from @serwah.bsky.social, Eric Zheng and @madelouhart.bsky.social. Many thanks to NIGMS and NCI for funding and to eLife reviewers for helpful feedback.
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Lucas Sullivan @lucasbsullivan.bsky.social · 29/07/2026
This work helps reconcile years of conflicting reports how SDH-deficient cells rewire their metabolism to support proliferation: Two adaptive routes, gated by mitochondrial redox state, can drive SDH-independent aspartate production, with implications for targeting SDH deficient cancers.
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Lucas Sullivan @lucasbsullivan.bsky.social · 29/07/2026
We recently found SDH loss starves cells of pyrimidines via competition between aspartate & succinate at ATCase, causing ATR inhibitor sensitization. Notably, either route produces more aspartate and partially restores pyrimidine synthesis + lowers ATR inhibitor sensitivity. doi.org/10.1038/s422...
doi.org
Succinate dehydrogenase loss suppresses pyrimidine biosynthesis via succinate-mediated inhibition of aspartate transcarbamylase - Nature Metabolism
Succinate acts as a competitive inhibitor of mammalian aspartate transcarbamylase (ATCase), leading to impaired pyrimidine biosynthesis and reduced proliferation under SDH inhibition.
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Lucas Sullivan @lucasbsullivan.bsky.social · 29/07/2026
What drives the CI-independent route? PC! Adapted clones increase in PC expression >2 fold, and simply overexpressing PC in unadapted cells is enough to phenocopy CI-intact adaptation.
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Lucas Sullivan @lucasbsullivan.bsky.social · 29/07/2026
Digging into the dependencies, both routes require the mitochondrial pyruvate carrier (MPC). However, PC is essential in CI-intact cells but only partly needed for CI-suppressed cells. Interestingly, GOT1 vs. GOT2 usage is a strict either/or and inhibition of CI flips GOT dependency.
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Lucas Sullivan @lucasbsullivan.bsky.social · 29/07/2026
These two adapted states, arising from the same parental clone, are metabolically distinct: CI-suppressed cells primarily rely on reductive carboxylation of glutamine and cytosolic GOT1, while CI-intact cells rely on a route using pyruvate carboxylase (PC) and GOT2.
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Lucas Sullivan @lucasbsullivan.bsky.social · 29/07/2026
Interestingly, only a subset of adapted clones suppressed CI, while others kept full CI activity and yet have overcome aspartate limitation - suggesting a second, CI-independent route to adaptation.
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Lucas Sullivan @lucasbsullivan.bsky.social · 29/07/2026
To examine adaptation behaviors, PhD student David Sokolov evolved 5 clonal SDHB-KO cell lines over months, tracking proliferation rates and finding recurrent (& aspartate-dependent) adaptation.
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Lucas Sullivan @lucasbsullivan.bsky.social · 29/07/2026
We & others have found SDH-deficient cells are limited for aspartate and that mito complex I (CI) loss can drive alternative aspartate routes to restore proliferation. However, others have also described SDH-deficient models with intact CI, suggesting heterogeneity. doi.org/10.7554/eLif...
doi.org
Mitochondrial redox adaptations enable alternative aspartate synthesis in SDH-deficient cells
SDH-null cancer cells decrease mitochondrial complex I to drive rewired aspartate synthesis through reductive carboxylation and pyruvate carboxylase, supporting cell proliferation and tumor growth.
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Lucas Sullivan @lucasbsullivan.bsky.social · 29/07/2026
A new preprint from our lab is out today at @elife.bsky.social! Our lab has focused on mechanisms by which mitochondrial metabolism supports cell proliferation. However, the observation that succinate dehydrogenase (SDH) mutations drive tumorigenesis seems paradoxical. doi.org/10.7554/eLif...
elifesciences.org
Adaptive plasticity of aspartate metabolism in succinate dehydrogenase-deficient cancer cells
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Reposted by Lucas Sullivan
Nature Metabolism @natmetabolism.nature.com · 16/07/2026
RESEARCH | (FHCC, US) ML Hart D Sokolov @lucasbsullivan.bsky.social et al Succinate acts as a competitive inhibitor of mammalian aspartate transcarbamylase leading to impaired pyrimidine biosynthesis and reduced proliferation under SDHi 🧪
dlvr.it
Succinate dehydrogenase loss suppresses pyrimidine biosynthesis via succinate-mediated inhibition of aspartate transcarbamylase - Nature Metabolism
Succinate acts as a competitive inhibitor of mammalian aspartate transcarbamylase (ATCase), leading to impaired pyrimidine biosynthesis and reduced proliferation under SDH inhibition.
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Lucas Sullivan @lucasbsullivan.bsky.social · 09/07/2026
cc: @serwah.bsky.social
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Lucas Sullivan @lucasbsullivan.bsky.social · 06/07/2026
Check out our recent Spotlight article in @cp-trendsendomet.bsky.social discussing intriguing new findings in mitochondrial lactate metabolism, written by graduate student Serwah Danquah! Paywall bypass link: authors.elsevier.com/a/1nNcv3jDgW...
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Reposted by Lucas Sullivan
Fusion Conferences @fusionconf.bsky.social · 24/06/2026
📢SAVE THE DATE! 2nd Redox Biology in Health & Disease Conference 📅Date: 25 - 28 May 2027 🌏Location: Durrës, Albania Sign up for updates to find out more information on the conference: bit.ly/4eF65xf #FusionCancerResearch #FusionMetabolism #FusionHumanDisease #RedoxBio
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Lucas Sullivan @lucasbsullivan.bsky.social · 03/06/2026
Very cool work (and helpful thread)!
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Reposted by Lucas Sullivan
Payam Gammage @mito-oncogene.bsky.social · 02/06/2026
🚨Excited to announce a new preprint from our lab, where we describe an ancient metabolic axis that controls mitochondrial genome copy number; a mechanism we uncovered in human cells that stretches through evolution to control mtDNA in flies, yeast and even plants!
biorxiv.org
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Reposted by Lucas Sullivan
Ram Chakrabarty @rpc3312.bsky.social · 21/05/2026
Very happy to share our new paper. Together with our wonderful collaborators, we found that L-2-HG, a metabolite often viewed as “toxic,” also has an essential physiological function in mice. www.nature.com/articles/s41...
nature.com
Mitochondrial l-2-hydroxyglutarate is a physiological signalling metabolite - Nature
l-2-Hydroxyglutarate is identified as a legitimate physiological signalling metabolite, and control of its levels is essential for postnatal growth and survival and correct renal development and funct...
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Reposted by Lucas Sullivan
Nature Metabolism @natmetabolism.nature.com · 09/05/2026
dlvr.it
Metformin lowers blood glucose by targeting intestinal mitochondrial complex I
Nature Metabolism, Published online: 08 May 2026; doi:10.1038/s42255-026-01532-wMetabolomic analysis of plasma from metformin-treated humans, together with mechanistic studies in mouse models, reveals that metformin selectively inhibits mitochondrial complex I in the intestinal epithelium. This mechanism unifies multiple clinical effects of metformin, including enhanced intestinal glucose use, improved postprandial glycaemic control and increased production of GDF15 and N-lactoyl-phenylalanine.
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Lucas Sullivan @lucasbsullivan.bsky.social · 09/05/2026
I guess we’ll have to team up for the next one. 👀
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Lucas Sullivan @lucasbsullivan.bsky.social · 09/05/2026
Also, check out this excellent N&V writeup from @frezzalab.bsky.social that nicely summarizes our findings and contextualizes them with other fascinating work on succinate interactions with nucleotide synthesis from the @bensahralab.bsky.social and Hirschey Labs! www.nature.com/articles/s42...
nature.com
Succinate calls a time-out on pyrimidine biosynthesis - Nature Metabolism
Cell metabolism is a dynamic network of highly interconnected biochemical reactions. In this issue of Nature Metabolism, time-lapse analysis of the amino acid aspartate revealed an unexpected regulati...
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Lucas Sullivan @lucasbsullivan.bsky.social · 09/05/2026
Many thanks to the team, including first authors @madelouhart.bsky.social and David Sokolov, and to @davidmacphersonlab.bsky.social for a huge assist with mouse modeling. Also thanks to @jeannakhle.bsky.social for shepherding this story through the publication process and to NIGMS/NCI for funding.
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Lucas Sullivan @lucasbsullivan.bsky.social · 09/05/2026
This paper greatly expands our earlier preprint findings, including: Enzyme assays demonstrating competitive inhibition of human ATCase activity by succinate. Demonstrating impaired pyrimidine synthesis in a mouse model of SDHB deficient pituitary tumors. And much more!
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Lucas Sullivan @lucasbsullivan.bsky.social · 09/05/2026
New out this week in @natmetabolism.nature.com – We measured dynamic aspartate changes following mitochondrial inhibition, finding that SDH inhibition causes a counterintuitive "aspartate rebound" effect, mediated by succinate impairing pyrimidine synthesis. www.nature.com/articles/s42...
nature.com
Succinate dehydrogenase loss suppresses pyrimidine biosynthesis via succinate-mediated inhibition of aspartate transcarbamylase - Nature Metabolism
Succinate acts as a competitive inhibitor of mammalian aspartate transcarbamylase (ATCase), leading to impaired pyrimidine biosynthesis and reduced proliferation under SDH inhibition.
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Reposted by Lucas Sullivan
Cristina Muñoz Pinedo @crismunozp.bsky.social · 04/05/2026
Very interesting articles about cancer metabolism this month, and insightful reviews. Highlighting fresh articles and comments about cysteine and glutathione from @lucasbsullivan.bsky.social @ginadenicola.bsky.social @harrislab.bsky.social and others metabolist.wordpress.com/2026/05/04/m...
metabolist.wordpress.com
MetaboList – April 2026
Cystine / Glutathione / NADPH SLC33A1 exports oxidized glutathione to maintain endoplasmic reticulum redox homeostasis Shanshan Liu  (刘珊珊), Mark Gad, Caifan Li  (李采蘩), Kevin Cho, Yuyang Liu  (刘雨洋),…
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Lucas Sullivan @lucasbsullivan.bsky.social · 14/04/2026
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...
annualreviews.org
Mitochondria, OXPHOS, and Cancer Progression: A Modular View
Mitochondrial oxidative phosphorylation (OXPHOS) is an ancient metabolic process that is increasingly recognized as an important player in cancer onset, progression, and treatment resistance. In this ...
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Lucas Sullivan @lucasbsullivan.bsky.social · 08/04/2026
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."
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Lucas Sullivan @lucasbsullivan.bsky.social · 08/04/2026
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.
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Reposted by Lucas Sullivan
Nature Metabolism @natmetabolism.nature.com · 07/04/2026
dlvr.it
Drowning in cysteine
Nature Metabolism, Published online: 07 April 2026; doi:10.1038/s42255-026-01511-1In this issue of Nature Metabolism, Brain, Vigil et al. show that NRF2-induced cystine uptake drives the formation of several cysteine–sugar metabolites. This process acts as a ‘sink’ for free cysteine and can lead to metabolic vulnerabilities and toxicity in NRF2-activated tumours.
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Reposted by Lucas Sullivan
Jen Brain (Crainic) @jenniferabrain.bsky.social · 07/04/2026
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!!
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Lucas Sullivan @lucasbsullivan.bsky.social · 08/04/2026
Also, check out this great N&V write up from the PapaG lab: www.nature.com/articles/s42...
nature.com
Drowning in cysteine - Nature Metabolism
In this issue of Nature Metabolism, Brain, Vigil et al. show that NRF2-induced cystine uptake drives the formation of several cysteine–sugar metabolites. This process acts as a ‘sink’ for free cystein...
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Lucas Sullivan @lucasbsullivan.bsky.social · 08/04/2026
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!
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Lucas Sullivan @lucasbsullivan.bsky.social · 08/04/2026
Overall, this study reveals “excess cysteine stress” as an underappreciated vulnerability in NRF2-driven cancers and expands the landscape of cysteine metabolism.
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Lucas Sullivan @lucasbsullivan.bsky.social · 08/04/2026
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.
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Lucas Sullivan @lucasbsullivan.bsky.social · 08/04/2026
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.
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Lucas Sullivan @lucasbsullivan.bsky.social · 08/04/2026
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.
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Lucas Sullivan @lucasbsullivan.bsky.social · 08/04/2026
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.
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Lucas Sullivan @lucasbsullivan.bsky.social · 08/04/2026
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?
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Julia S. Brunner @juliabrunner.bsky.social · 26/02/2026
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/
cell.com
Aspartate availability drives differential engagement of the malate-aspartate shuttle
Brunner et al. report that malate-aspartate shuttle engagement is cell-state dependent and can be modulated by the availability of the amino acid aspartate. In differentiated cells, malate-aspartate s...
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Reposted by Lucas Sullivan
Jason Cantor @jasonrcantor.bsky.social · 16/01/2026
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. 🧵
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Barbara Marte @barbmarte.bsky.social · 07/01/2026
new out in Nature www.nature.com/articles/s41...
nature.com
Nutrient requirements of organ-specific metastasis in breast cancer - Nature
How the complex interplay between multiple nutrients within the microenvironment dictates potential sites of metastatic cancer growth is explored.
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Lucas Sullivan @lucasbsullivan.bsky.social · 13/10/2025
cc: @olivernewsom.bsky.social
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Lucas Sullivan @lucasbsullivan.bsky.social · 13/10/2025
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!
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.
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Lucas Sullivan @lucasbsullivan.bsky.social · 13/10/2025
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...
sciencedirect.com
Defined media reveal the essential role of lipid scavenging in supporting cancer cell proliferation
Fetal bovine serum (FBS) is an undefined additive that is ubiquitous to mammalian cell culture media and whose functional contributions to promoting c…
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Lucas Sullivan @lucasbsullivan.bsky.social · 15/07/2025
Check out this great interview with a true rising star in metabolism research (and lab alumni)! 🙌
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Yasemin Sancak @yasesancak.bsky.social · 31/05/2025
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/...
science.org
Mitochondrial calcium signaling regulates branched-chain amino acid catabolism in fibrolamellar carcinoma
Mitochondrial Ca2+ signaling regulates branched-chain amino acid catabolism in an adolescent liver cancer.
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Randall Munroe @xkcd.com · 29/05/2025
Mass Spec xkcd.com/3094/
[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.
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Natalie Niemi @nieminm.bsky.social · 26/05/2025
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!
bit.ly
Succinate Dehydrogenase loss causes cascading metabolic effects that impair pyrimidine biosynthesis - preLights
Not all aspartate limitation is created equal: An aspartate biosensor reveals that inhibiting succinate dehydrogenase results in defects in pyrimidine synthesis and replication stress, unique from oth...
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David MacPherson Lab @davidmacphersonlab.bsky.social · 29/04/2025
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
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