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Lucas Sullivan

@lucasbsullivan.bsky.social

730 followers 540 following 34 posts

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

research.fredhutch.org

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Lucas Sullivan @lucasbsullivan.bsky.social · Feb 20

Next, our 2nd preprint of the week (!), this one driven by @madelouhart.bsky.social

Previously: Mitochondrial inhibition impairs cell proliferation by constraining aspartate (ASP) availability.

Here: we investigate the kinetics of ASP depletion/ proliferation impairments and...surprises ensue!

bioRxivpreprint @biorxivpreprint.bsky.social · Feb 19

Succinate Dehydrogenase loss causes cascading metabolic effects that impair pyrimidine biosynthesis https://www.biorxiv.org/content/10.1101/2025.02.18.638948v1

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Lucas Sullivan @lucasbsullivan.bsky.social · Jul 15

Check out this great interview with a true rising star in metabolism research (and lab alumni)! 🙌

Shefali @iamshef.bsky.social · Jul 15

#MetabolismMondays
Meet Anna Vigil, #PhD student in @justinmcrocker.bsky.social lab @embl.org @embldbunit.bsky.social, discussing her work on how #metabolism impacts cell fate, development & #evolution #Drosophila.
#theNodeCorrespondents #ecr @the-node.bsky.social #DevBio

Currents of Change: Metabolism shaping cell fate and evolution #MetabolismMondays - the Node

All the world's a metabolic dance, early career scientists are leading the way! Emerging perspectives in metabolism Anna-Lena Brigitte Gunda VigilPhD

thenode.biologists.com

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Reposted by Lucas Sullivan

Yasemin Sancak @yasesancak.bsky.social · May 31

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/...

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.

www.science.org

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Reposted by Lucas Sullivan

Randall Munroe @xkcd.com · May 29

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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Reposted by Lucas Sullivan

Natalie Niemi @nieminm.bsky.social · May 26

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!

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...

bit.ly

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Reposted by Lucas Sullivan

David MacPherson Lab @davidmacphersonlab.bsky.social · Apr 29

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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Reposted by Lucas Sullivan

Jen Crainic @jen-crainic.bsky.social · Apr 25

Overjoyed to have the opportunity to present my work orally at the Cancer Metabolism Showcase! Hope to see you there virtually!

Isaac Harris @harrislab.bsky.social · Apr 24

Less than two weeks until the 2025 Cancer Metabolism Showcase and Workshops!

Speaker lineup now online! Register today!

www.cancermetabolismshowcase.org

9:30 AM - 3 PM EST, May 5th and 6th, 2025

www.cancermetabolismshowcase.org

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Reposted by Lucas Sullivan

Rich Possemato @richpossemato.bsky.social · Apr 18

From Nobel prize winning cancer researcher Bill Kaelin
Killing the Science Golden Goose - The American Journal of Medicine www.amjmed.com/article/S000...

Killing the Science Golden Goose

In the 1970’s I was probably one of the last American high school students who was told that if you wanted to go to medical school, you should learn to speak German. This was because in the late 19th ...

www.amjmed.com

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Reposted by Lucas Sullivan

Jen Crainic @jen-crainic.bsky.social · Apr 3

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...

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Lucas Sullivan @lucasbsullivan.bsky.social · Mar 30

Hello, can you add me please?

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Reposted by Lucas Sullivan

Jen Crainic @jen-crainic.bsky.social · Mar 13

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

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Reposted by Lucas Sullivan

Jason Cantor @jasonrcantor.bsky.social · Mar 12

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...

Seeing the world through the eyes of cultured cells

The metabolic environment experienced by cultured cells often differs from physiological conditions. Here, we highlight the effects that the microenvironment can have on cultured cell behavior and adv...

www.cell.com

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Reposted by Lucas Sullivan

Tina Termini @cterminiphd.bsky.social · Mar 7

We were delighted to have @king5news.com.web.brid.gy visit us in the Termini Lab to discuss how NIH funding cuts could affect cancer research:

m.youtube.com/watch?v=Szo9...

We NEED indirect costs to provide funding needed complete research studies that will lead to life saving discoveries.

Potential NIH funding cuts could affect local cancer research

YouTube video by KING 5 Seattle

m.youtube.com

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Lucas Sullivan @lucasbsullivan.bsky.social · Feb 22

Thanks Jakub!

Lucas Sullivan @lucasbsullivan.bsky.social · Feb 22

Thank you!

Lucas Sullivan @lucasbsullivan.bsky.social · Feb 20

Thanks to Madeleine for wanting to stick around post-graduation to figure out “the boomerang” and the rest of the team for support, esp Kristian for quantitative efforts. Thanks to NIGMS and NCI for funding. Also, watch out for Madeleine's next act with @saranowinski.bsky.social!

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Lucas Sullivan @lucasbsullivan.bsky.social · Feb 20

TLDR – we find that, upon SDH loss, the combined effects of ASP depletion and succinate accumulation profoundly inhibit ATCase. Pyrimidine loss impairs ASP consumption for biosynthesis, causing ASP to accumulate until it outcompetes succinate to restart pyrimidines/biosynthesis once again.

Lucas Sullivan @lucasbsullivan.bsky.social · Feb 20

The full paper has plenty more (ASP flux measurements, succinate sufficiency, replication stress), so I invite you to give it a full read. There are also fun phenotypes that epitomize some of the logical pitfalls that we metabolism nerds often warn about (e.g. levels =/= flux).

Lucas Sullivan @lucasbsullivan.bsky.social · Feb 20

We found SDH impaired cells can reach >10 mM!

Conclusion: succinate competes with diminished ASP at ATCase, blocking pyrimidine synthesis. To our knowledge the first description of this relationship in cells + revealing another potential regulatory function of succinate.

Lucas Sullivan @lucasbsullivan.bsky.social · Feb 20

A literature search found a goldmine: E Coli ATCase was a workhorse of biochemistry for decades (e.g. ⬇️) One compound used to impair its function in vitro? Succinate! While the concentrations needed to impair ATCase in vitro seemed unrealistic at ~1+ mM...

pubmed.ncbi.nlm.nih.gov/3894357/

Substrate specificity of aspartate transcarbamylase. Interaction of the enzyme with analogs of aspartate and succinate - PubMed

The ability of aspartate transcarbamylase from Escherichia coli to catalyze carbamylation of amino acids other than the natural substrate, L-aspartate, was examined. Cysteine, cysteate, cysteinesulfin...

pubmed.ncbi.nlm.nih.gov

Lucas Sullivan @lucasbsullivan.bsky.social · Feb 20

SDH inhibition is distinct from other mitochondrial impairments due to the accumulation of succinate, which we hypothesized to play a role. First, we decreased succinate production by cotreating with the CI inhibitor rotenone. Result: restoration of pyrimidine synthesis, even with comparable ASP.

Rotenone treatment restores carb-Asp levels in AA5 treated cells (at a time point where Asp levels are near identical).

Lucas Sullivan @lucasbsullivan.bsky.social · Feb 20

So, what happens if we restore pyrimidines to these cells?

A complete loss of the ASP rebound and a return to the (very reasonable) phenotype of monotonic ASP depletion.

So, SDH loss causes a disproportionate effect on pyrimidine synthesis by impairing ATCase, but why?

Supplementing AA5 treated cells with uridine (Uri) but not asparagine (Asn) or adenine (Ade) prevents the ASP rebound effect.

Lucas Sullivan @lucasbsullivan.bsky.social · Feb 20

We next investigated the biosynthetic fates of aspartate and found:

Aspartyl tRNA charge = OK

Purine nucleotides = OK

ASN = OK - Rebounds with ASP

Pyrimidine nucleotides = Depleted at the first step (ATCase, which makes Carb-ASP) - and stays depleted even with rebounding ASP:

Carbamoyl-Aspartate (carb-ASP) levels are depleted by AA5 treatment at 24 hours and remain depleted at 44 hours, when ASP levels had partially recovered.

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Lucas Sullivan @lucasbsullivan.bsky.social · Feb 20

When we did the same experiment with the SDH inhibitor AA5, we get a strange result:
ASP declines for ~24 hours until proliferation slows, then..ASP rebounds???

Even stranger:
Proliferation doesn't recover with ASP even though we know ASP supplementation would solve the proliferation defect!

Aspartate levels, measured by the GFP/NucRFP ratio, fall for about 24 hours upon AA5 treatment, then rebound.

Lucas Sullivan @lucasbsullivan.bsky.social · Feb 20

Deploying our ASP biosensor, jAspSnFR3, Madeleine & co used live cell imaging to continuously measure ASP levels (GFP) and cell number. In two cases – CI inhibition and GOT1/2 DKO cells, ASP levels crash over 24 hours then cell proliferation decays, leading to a new ~steady state.

Very reasonable.

ASP (measured by GFP) declines proportionally to environmental ASP availability in ASP auxotrophs (GOT1/2 DKO cells)

Lucas Sullivan @lucasbsullivan.bsky.social · Feb 20

bioRxivpreprint @biorxivpreprint.bsky.social · Feb 19

Succinate Dehydrogenase loss causes cascading metabolic effects that impair pyrimidine biosynthesis https://www.biorxiv.org/content/10.1101/2025.02.18.638948v1

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