I do believe the part about embracing the mothers
I still like small data but I'm not opposed to big data. We study #metabolism, #genetics, #pediatric inborn errors & cancer.
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I do believe the part about embracing the mothers
I’m thrilled to share that I have been awarded an NIH/NIGMS K99 Pathway to Independence Award. I’m deeply grateful to everyone who has supported me along the way, especially @rjdlab.bsky.social @cri-utsw.bsky.social
🍹 @walterwchen.bsky.social et al show that PEX39 cooperates with PEX7 in the peroxisomal import of proteins containing a PTS2 site and uncover an (R/K)PWE motif in PEX39 and PEX13 that binds to PEX7 and facilitates the import of PTS2-containing proteins. bit.ly/4lmjv2l
Congrats! 👏👏👏 Two CRI scientists named 2025 Pew-Stewart & Pew Scholars — Javier Garcia-Bermudez, Ph.D. & @hrshin.bsky.social — to advance cancer, biomedical research 🧪 Read more about their #relentlessdiscovery ⬇️ cri.utsw.edu/two-children... @pewtrusts.org
I’ve been fortunate to have many great collaborations over the years, and I hope you will too. The best are where different scientists bring complementary skills and everyone is working towards a common goal - as we all did in this case.
10/For more breakthroughs in peroxisomal biology, see this recent work from Michael Skowyra and Tom Rapoport: www.nature.com/articles/s41...
9/I will always be grateful for this collaboration with Daniel, Tony, Jorge and Bettina, and all the co-authors, for an experience that reinforces the value of openness in science.
8/There was no quibbling over who would get credit for what. Everyone just wanted to make as complete a story as possible, as efficiently as possible. We agreed on an authorship structure early on and stuck to it.
7/The collaboration allowed us to incorporate mammalian cell biology, yeast genetics and elegant biochemistry all in one paper. The end product was much greater than the sum of the parts because the technical expertise and perspectives of these different scientists all come through in the paper.
6/So Walter reached out to them to share his work. They were receptive and generous. This led to remarkably open, productive collaboration with true experts in peroxisomal biology, including Tony Rodrigues, Daniel Wendscheck (@dwendscheck.bsky.social), Jorge Azevedo, and Bettina Warscheid.
5/It was immediately clear to Walter that another team of scientists had found the yeast ortholog of C6ORF226 and were working on its role in peroxisome biology.
4/Walter had worked for a couple of years on C6ORF226 in human cells and learned quite a bit about its function when he noticed that an online resource for peroxisomal biologists had provisionally identified a “PEX39” (peroxins are named in the order of their discovery).
3/The cell biology and biochemistry of what PEX39 does and how it works are fascinating. But I want to focus on the collaborative aspects of this study.
2/Walter began this project by searching interactome databases for proteins of unknown function that seemed to interact with known proteins localized to metabolic organelles, like the peroxisome. That led him to C6ORF226, eventually renamed PEX39.
1/New paper on peroxisome assembly, reporting the detailed mechanism of PEX39, a new peroxin involved in PTS2 protein transport. Fantastic work by @walterwchen.bsky.social and a dream team of collaborators, as explained below. www.nature.com/articles/s41...
Congrats @dwendscheck.bsky.social - what a pleasure it was to work with you on this project.
4/Congrats to Jennifer Gill, Aparna Rao, Ling Cai, and the entire team for this study.
3/If metabolic pathways are not conserved between patient and PDX, we shouldn't use PDXs to test metabolic therapies. We hope the paper will improve the efficiency of cancer metabolism studies in PDXs by showing which pathways withstand transplantation.
2/The metabolic features we analyzed include isotope tracing with 13C-glucose (performed in patients and mice) and metabolomic profiling, evaluated over 6 passages in mice to assess both the fidelity and durability of PDX metabolic heterogeneity.
1/Patient-derived xenografts (PDXs) are used in preclinical testing of cancer therapies, including metabolic therapies. We determined which metabolic properties are retained, and which are lost, when melanomas from patients are implanted and passaged as PDXs in mice. www.nature.com/articles/s42...
And I mean that with the greatest respect for Ozzy.
If Ozzy Osbourne could write Crazy Train, I can write one more paragraph of a research summary.
I ❤️ SCD1. Congrats!
It's a pleasure Walter - keep up the great work!
Apologies for the massive photo of my face.
Thanks Nature Cancer for the chance to reflect on some factors that led me to study cancer metabolism. For the trainees and other young scientists: the critical events that shape your career might not be obvious while they are happening. Keep an open mind and trust your instincts. rdcu.be/evi4I
Just in case the grad school or postdoc office see this post ... I would like to clarify that none of the *trainees* are still here after 10 years.
The photo reminds me of the benefits of continuity. Several of these folks were here when Pei graduated 10 yrs ago. Jessica (behind me) and Chendong (front row, right) have been in the lab since 2008. I'm lucky to work with such talented and patient people. And how great to have a reunion with Pei.
Welcome back Pei-Hsuan! (Front row, 2nd from right.) Pei was one of my first PhD students. She stopped by on a visit to Dallas to say hello. I am not sure anyone in the lab has generated quite as much data as Pei. Her remarkable paper: pubmed.ncbi.nlm.nih.gov/31564558/
But oddly I can't fully commit to the Oxford comma.
I still use them; I'm OK with people knowing I went to college. www.washingtonpost.com/opinions/202...
Today in @dallasnews.com by @sodendritic.bsky.social: "Dallas researchers find cancer’s secret weapon to defeat death" ⬇️ read more www.dallasnews.com/news/2025/06... 🧪 #relentlessdiscovery @rjdlab.bsky.social
Excellent news for a fantastic young scientist and colleague. Congrats @walterwchen.bsky.social !
GAGs regulate LDL uptake and protect cells from lipid oxidation - new from Javier Garcia-Bermudez.
🎥 Now On Demand! Catch the Keystone Symposium: Metabolic & Nutritional Control of Development and Cell Fate—featuring top researchers at the intersection of metabolism, diet & development. 🎓 Stream now: keysym.us/KSMetabDev25OD #KSMetabDev @rjdlab.bsky.social @lydiafiney.bsky.social
Thanks Shuyuan Zhang and Biochemistry PhD students for inviting me to Case Western Reserve University for the Harlan G Wood lecture. It was an honor and pleasure. See you all soon!
12/So in these patient-derived models of neuronal stem cell renewal and differentiation, the inborn metabolic defect promotes an epigenetic state that induces oncogene expression and interferes with terminal differentiation – in a cellular lineage with high relevance to the disease.
11/Wen’s analysis revealed thousands of differentially expressed genes and differentially methylated loci in the mutant cells. But MYC was the key. Reducing MYC to levels seen in L2HGDH-wild type cells completely reversed the differentiation defects of L2HGDH-mutant cells.
10/In studying why this happens, Wen discovered profound overexpression of MYC in the mutants, and high levels of H3K4 di- and trimethylation in MYC regulatory regions. These marks are associated with active gene expression, and their removal by KDM5 histone demethylases is blocked by L-2HG.
9/When NPCs were induced to differentiate into neurons, the ones with mutant L2HGDH had reduced neurite length and failed to achieve the excitatory phenotype of mature neurons, indicating a defect in terminal differentiation.
8/Neural progenitor cells (NPCs) derived from mutant iPSCs had markedly enhanced self-renewal capacity compared to NPCs from cells in which the L2HGDH locus was “corrected” to wild-type. The mutants also produced much larger cerebral organoids.
7/iPSCs were generated from two siblings with L2HGDH deficiency, then the L2HGDH locus was edited with CRISPR to create isogenic lines containing mutant or wild-type L2HGDH at the native genomic locus.
6/Wen used patient-derived cell lines from CRI’s Genetic and Metabolic Disease Program to study epigenetics, stem cell properties and differentiation capacity in L2HGDH deficiency.
5/D-2HG’s impact on epigenetics, gene expression and cellular differentiation has been widely studied in IDH1/2-mutant cancers. There has been much less attention on the impact of L-2HG accumulation in human L2HGDH deficiency.
4/Both D-2HG and L-2HG interfere with epigenetic regulation of gene expression by altering (usually inhibiting) AKG-dependent dioxygenases involved in demethylation of histones, DNA and RNA.
3/L2HGDH converts L-2-hydroxyglutarate (L-2HG) to alpha-ketoglutarate (AKG). L-2HG is the opposite enantiomer of D-2HG, which accumulates in tumors with mutations in IDH1 or IDH2.
2/L2HGDH deficiency is a rare, autosomal recessive inborn error of metabolism (IEM) characterized by severe and progressive neurodevelopmental disability, seizures, and (unique among IEMs) an elevated risk of brain tumors.
1/New pre-print from Wen Gu reporting enhanced self-renewal and defective neuronal differentiation in neural progenitor cells from patients with L-2-hydroxyglutaric acid dehydrogenase (L2HGDH) deficiency. @cri-utsw.bsky.social. www.biorxiv.org/cgi/content/...
Happy to share that our very own Justin Engel (@justeng95.bsky.social) received the 2025 Nominata Award, the highest honor for a graduate student at UT Southwestern. He also received the Kirkpatrick Prize, which is given to the student with the most meritorious NIH NRSA proposal. Congrats Justin! 🎉
Finally
Happy Prom night from Dallas.
Colossal says they resurrected the direwolf. Why not bring back Jerry instead? www.youtube.com/watch?v=uejA...
It took me 5 tries to get a 200-word project description down to an 8th grade reading level (Flesch Reading Ease Score 64.3). Maybe I really am elitist.
What can I tell you. Dallas public school education.
Ha! Yes, I believe you have! I read about it.
Once she watched me give a lecture and said, "I really liked that one slide with NAD." I was surprised. So I gave her chapter and verse about redox until she said, "yeah, but did you ever notice it has the first three letters of my name?" (Nadine.) Nope. I had not put those two together.
6/The worst part was when I sheepishly closed the laptop and she says, "It's OK, Dad, I thought that was REALLY interesting."
5/She starts staring off and says, "yeah, but I am supposed to be doing the metalloids ..."
4/But no. Lost her by trying to explain too many details about glycolysis. Panicked. Pivoted to 15N for some reason.
3/You'd think after giving this talk 1,000 times I could deliver the message clearly when it really matters.
2/"Here, let me show you ..." (fumbles through laptop folders to find the right Power Point)
1/My 7th grader's science homework is to learn the elements Memorize atomic masses. She points out that carbon has a mass of 12. My life passes before my eyes. Finally, my chance to explain what I've been doing for 20 yrs. So I say, kind of casually, "you know, sometimes carbon has a mass of 13..."
300+ papers, first research article to hit the cover. Thank you Cancer Discovery!
Hope we don’t need you for the revisions.
Farewell to our QTOF after many years. So much data. Adios amigo.
www.quantamagazine.org/how-metaboli... Seems like a good time to remind you of an upcoming meeting on this exact topic: www.keystonesymposia.org/conferences/...
You don’t want a day by day update of Alex Reese’s 3PT%?
Surprisingly few.
Been on Bluesky for a few months now. My feed: 25% science, 25% “world news” (let’s call it that) and 50% pictures of owls and red foxes. It’s pretty good so far.
If you are immigrant into the US and work in the biomedical sciences (like me) and are still young (not like me), please apply for the Vilcek prizes for Creative Promise founded by an inspiring immigrant couple, Marica and Jan Vilcek. vilcek.org/prizes/vilce...
Thanks @frezzalab.bsky.social. Refs to lipoylation started to spike when it was connected to cuproptosis by Peter Tsvetkov, Todd Golub and colleagues. But lipoylation is connected to many interesting processes. Special shout out to John Cronan at U Illinois for pioneering work on this pathway.
12/This is also a nice example of how insights from inborn errors can inform research in cancer metabolism. These diseases share responses to metabolic perturbation, and that helps us think about how to reverse pathological processes. More to come on the many effects of L-2HG accumulation.
11/Congrats to Faith and her team on a very interesting paper describing a mechanistic connection between intermediary metabolism and DNA damage responses that could possibly be exploited for therapy.
10/The effects of LIPT1 inhibition on radiosensitization could be mitigated by providing more AKG to the cells or, strikingly, by simply over-expressing the dehydrogenase that converts excess L-2HG to AKG.
9/Faith showed that LIPT1 blockade enhances histone methylation through KDM4B inhibition, and that this results in a homologous recombination repair defect, potentiating the effects of ionizing radiation.
8/Elevated 2HG matters, a lot. Both isomers of this metabolite (D- and L-2HG) can inhibit the many demethylases that use AKG as a substrate. These include histone demethylases like KDM4B, which is required for homologous recombination repair after radiation.
7/Faith found that LIPT1 blockade causes many metabolic anomalies in lung cancer cells too, including elevated 2HG, very similar to what occurs in patients with LIPT1 deficiency.
6/Oxidation of AKG in the TCA cycle requires a LIPT1-dependent enzyme, the AKGDH complex. AKGDH inhibition likely explains why 2HG accumulates in LIPT1 deficiency.
5/Why does this work? We reported a few years ago that human LIPT1 deficiency causes dozens of metabolic anomalies in the blood, including accumulation 2-hydroxyglutarate, the reduced form of the TCA cycle intermediate AKG. www.cell.com/cell-reports...
4/Lipoylation, the metabolic pathway Faith uncovered in her screen, involves synthesizing a lipoic acid cofactor and then transferring it to 2-ketoacid dehydrogenases related to the TCA cycle. LIPT1 catalyzes the final step.
3/Blocking this pathway in vivo, either through genetic silencing of LIPT1 or with a drug that suppresses lipoylation, improved the therapeutic effect of radiation on lung tumor xenograft growth in mice.
2/Faith performed a CRISPR loss of function screen in the presence and absence of ionizing radiation. Components of the lipoylation pathway, including the enzyme LIPT1, emerged as top hits (i.e. blocking lipoylation enhanced the efficacy of radiation).
1/Happy to share a new paper reporting a metabolic approach to radiosensitization in lung cancer, from Rachel Chiang, Faith Zhang and colleagues at UT Southwestern Radiation Oncology and @cri-utsw.bsky.social www.science.org/doi/10.1126/...
Metabolic & Nutritional Control of Development and Cell Fate is just around the corner. Register by March 20 (11:59pm MST) and snag a $200 discount! Don't miss our incredible speaker lineup! 👉 keysym.us/KSMetabDev25. #KSMetabDev25 youtu.be/CSto4rJv40I @lydiafinley.bsky.social @rjdlab.bsky.social
Save the Date! Cancer Molecular Therapeutics Research Association Annual Meeting in Utah July 13-17. Please register today. Incredible line up of speakers: RT! @andreaventura.bsky.social @rjdlab.bsky.social #lcsm
So … anybody know what’s up with NCBI today?
Recognizing Rare Disease Awareness Day 2025 at UT Southwestern, with teams from the Genetic & Metabolic Disease Program @cri-utsw.bsky.social and the McDermott Center. We work to find causes & treatments for rare diseases. 25-30 million Americans have a "rare" disease - our mission is to help them.
Another great day for #relentlessdiscovery & #CancerResearch: 🟠 Sam McBrayer, Ph.D., received $1.19M to study developmental origins of IDH-mutant glioma in adolescents 🟠 Michalis Agathocleous, Ph.D., received $900K to study role of glutathione in leukemia development from CPRIT 🧪 shorturl.at/pgKmG
12/Many thanks to Dr. Kemp Kernstine, our incredible surgical collaborator for more than a decade, the UTSW Lung SPORE, the Simmons Comprehensive Cancer Center, and most of all the patients who participated in this research.
11/There’s much more to do, starting with understanding exactly what underlies this context-dependent need for the ETC/TCA cycle during metastasis. And of course whether we can do anything to safely and durably target this essential pathway.
10/Altogether, the data indicate that glucose oxidation involving the TCA cycle promotes NSCLC progression in both humans and mice. A recent study in renal cancer came to similar conclusions, in part by comparing labeling features between primary and metastatic ccRCC. www.nature.com/articles/s41...
9/It also reduced the abundance of viable circulating tumor cells, and metastatic dissemination from the subcutaneous site of implantation, although growth of the subcutaneous tumors was unaffected.
8/In these PDX models, modest suppression of Complex I of the electron transport chain reduced 13C labeling in tumor-derived TCA cycle intermediates after infusion with 13C-glucose, as expected.
7/ Most patients who progressed did so through metastatic disease, so we next asked whether metabolism related to the TCA cycle promotes metastasis. We tested this in PDX models derived from subjects enrolled in the study.
6/Very important that the abundance of these same metabolites did NOT predict cancer progression/early demise, emphasizing that 13C labeling reports different and clinically relevant information. Labeling and abundance of glycolytic intermediates were also not predictive in this cohort.
5/In a nutshell, the metabolic features that best predicted poor outcomes (by far) were related to 13C enrichment in the tricarboxylic acid (TCA) cycle. These features predicted shorter times to cancer recurrence and death.
4/Then the patients were followed – for many years. This allowed us to ask which metabolic processes in the tumor best predicted favorable or poor outcomes in the patients.
3/Over 90 patients with solitary lung nodules (mostly NSCLC) were invited to receive infusions with 13C-labeled nutrients during surgical tumor resection. Labeling in metabolites extracted from the tumor allowed us to infer metabolic processes within the tumor.
2/This is the result of an 11-year effort to connect metabolic features of human NSCLC, obtained through clinical intra-operative 13C-glucose tracing, with overall and recurrence-free survival.
1/I am delighted to share a new Cancer Discovery paper about metabolism and clinical outcomes in patients with non-small cell lung cancer (NSCLC). From Ling Cai and Brandon @faubert.bsky.social, @cri-utsw.bsky.social and UT Southwestern McDermott Center.