Thanks Federica 😊

7/ Congrats to leads: Dr Nneka Mbah & Damien Sutton! Thanks to collaborators, supporters, and funders 🙏

6/ In summary, while we potently induced ICD DAMPs in vitro, these did not translate to ICD in vivo.
These findings suggest that, on balance, the effects of ferroptotic tumor cell death help to establish a tumor-protective, immune-tolerant microenvironment in murine PDAC.

5/ But ferroptosis released “brakes.” Metabolomic/lipidomic profiling revealed selective release of immunosuppressive metabolites & oxidized phospholipids. Conditioned media impaired T cells, and in vivo ferroptotic cells skewed tumors toward immunosuppressive myeloid enrichment w/ reduced T cells

4/ Maybe the Cys deprivation is inducing ferroptosis? Ferroptosis with GPX4 inhibition similarly elicited ICD-associated features, and these were reversed by Ferrostatin-1, linking cysteine deprivation → lipid peroxidation/ferroptosis → DAMP signaling.

3/ Cys-deprived tumor cells also activated innate immunity in co-culture: they increased dendritic cell phagocytosis, maturation (e.g., MHCII/CD80/CD86), and pro-inflammatory cytokine production, all consistent with an ICD-like program. Evidence is mounting in support of a metabolic form of ICD!

2/ In a focused amino-acid dropout screen across syngeneic murine cancer cell lines, one hit stood out: cystine/cysteine restriction robustly induced multiple ICD hallmarks in vitro: canonical DAMPs like ecto-calreticulin, extracellular ATP, and HMGB1.

New study from the lab 🧵
1/ Pancreatic cancer is metabolically rewired and immunosuppressive. We asked: can targeting metabolism trigger immunogenic cell death (ICD) to boost anti-tumor immunity? Key twist: ferroptosis shows ICD signals in vitro, but is largely tumor-protective in vivo rdcu.be/fc55T

Thanks Buddy!

11/ Huge congrats to lead author @radykm.bsky.social! She just started her own lab at @roswellpark.bsky.social (Buffalo, NY). Excited to see what’s next from her team. radyklab.org

10/ Thanks Wellen Lab for the News & Views: “Metabolism modulates stress and neoplasia”.
They synthesize both papers around a shared model: NADPH-producing enzymes constrain ROS and pancreatic neoplasia, while ROS→NRF2 signaling helps drive ADM.
www.nature.com/articles/s42...

ALDH1L2 regulates reactive oxygen species and acinar-to-ductal metaplasia in the pancreas - Nature Metabolism In the early stages of pancreatic ductal adenocarcinoma (PDAC) development, loss of ALDH1L2 expression elevates reactive oxygen species levels, driving accelerated acinar-to-ductal metaplasia. Decreas...

9/ Co-published study from Vousden Lab identifies ALDH1L2 as acinar-enriched mitochondrial one-carbon NADPH enzyme, which also regulates ROS and ADM. ALDH1L2 loss elevates ROS, accelerates ADM/PanIN, and links to rising circulating formate as a PDAC biomarker.
www.nature.com/articles/s42...

8/ Notable experiments demonstrate antioxidant treatment (e.g. NAC or glutathione) dampens accelerated lesion formation ex vivo and in vivo. Conversely, weakening endogenous antioxidant capacity (e.g., glutathione depletion) promotes ADM in primary human acinar cells and increases lesions in mice.

7/ Mechanism: our work supports a large body of work that oxidative stress is required for ADM, e.g. Vousden Lab, Storz Lab, DeNicola Lab, et al.

Our key contributions are in identifying target enzymes and functions.

6/ ME1 loss also increases oxidative stress and promotes ADM/PanIN, but with a key difference: Me1 loss accelerates malignant progression, with faster PDAC development over time. Same redox theme at initiation, distinct requirements once lesions evolve.

5/ G6PD deficiency decreases oxidative PPP flux and increases oxidative stress markers. In KRAS-driven KC mice, it accelerates ADM and PanIN formation. But in KPC it doesn’t shorten survival, suggesting oxidative PPP/NADPH can be a brake early, without being the limiting factor later.

4/ NRF2 target genes stoodout during ADM. Among them are NADPH-producing enzymes from two major routes:
1) G6PD (oxidative PPP)
2) ME1 (cytosolic malic enzyme)
We asked whether these NADPH “buffers” actively restrain oxidative-stress–driven neoplasia.

3/ We started with a time course of primary acinar cells undergoing KRAS-driven ADM, with paired transcriptomics + metabolomics. Transcripts and metabolites shift together, revealing dynamic remodeling of central carbon metabolism and antioxidant pathways as acinar identity is lost.

2/ ADM is a reversible wound-healing state after pancreatic injury. But w/ oncogenic KRAS (in >90% of PDAC), ADM can persist, transform into PanIN, and sometimes PDAC. Many PanINs persist for years/decades, so understanding what governs initiation vs progression is key

Fig ref: Chuvin, et al CMGH

NADPH-producing enzymes restrict the formation of pancreatic precancerous lesions - Nature Metabolism Temporal profiling of central carbon metabolism during KrasG12D-driven acinar-to-ductal metaplasia reveals that disruptions in NADPH-producing enzymes accelerate the formation of pancreatic precancero...

1/ We map metabolic rewiring during the earliest stage of pancreatic cancer transformation (acinar-to-ductal metaplasia, ADM) and show that NADPH/redox buffering acts as a barrier to early lesion formation with stage-specific differences that matter for progression.
www.nature.com/articles/s42...

🚨New @lyssiotislab.bsky.social paper led by @radykm.bsky.social in @NatureMetabolism
"NADPH-producing enzymes restrict the formation of pancreatic precancerous lesions"
🧵Follow for a tweetorial... and bonus highlight of Vousden Lab co-published study and News & Views link from Wellen Lab!

I do! Thanks to @megankillian.bsky.social

Email me and I’ll forward. clyssiot@umich.edu

The Shingles vaccine has outperformed all expectations. Why?
erictopol.substack.com/p/spotlight-...

Your email = life saver. TY so much🙏😊

🙌🏼 TY so much! I have since found out that other html tricks also apply.

Just spoke to The Hill about how the dismantling of the NIH is impacting science in America. We still face a cliff of unfathomable heights, w easily 1000+ labs poised to close in the next year due to funding ending. A generation of young scientists lost because there is nowhere for them to train.

Who is loving (the wasted hours) reformatting their Biosketch in sciENcv?! 🙋‍♂️

The formatting is atrocious. Anyone identify hacks to make it more palatable?

Interested in stable isotope infusions but daunted by jugular catheter surgery? New from postdoc @kimyumi0201.bsky.social: our simple tail vein catheter method enables anesthesia-free infusions in awake, freely moving mice. 🧵

q.e.d Science Critical Thinking AI for constructive criticism and science evaluation

Here's the link to the system, try it! qedscience.com
@qedscience.bsky.social

Rewiring of cortical glucose metabolism fuels human brain cancer growth - Nature The cortex fuels essential physiological processes with glucose-derived carbon, while gliomas fuel their aggressiveness by rerouting glucose carbon pathways and scavenging alternative carbon sources such as environmental amino acids, providing a potential therapeutic target.

#NatMetabPicks | In @nature.com led by @danwahlmd.bsky.social‬ @lyssiotislab.bsky.social @dnagrathlab.bsky.social WN Al-Holou ( @umich.edu )

Gliomas take up serine from the tumor microenvironment, and can be targeted with dietary serine restriction.

🧪

www.nature.com/articles/s41...