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.

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.

5/ Using a mouse model, G6PD deficiency (physiologic model) 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.

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.

7/ Mechanism: our work supports a large body of work that oxidative stress is required for ADM, e.g. @LabVousden, @LabDeNicola, @LabStorz, et al. Our key contributions are in identifying target enzymes and functions. Notable phenotypic experiments demonstrate that 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. (Important: this is mechanistic biology in models, not personal medical advice.)

8/ Thanks for reading along! 1st- thank you to our incredible co-authors & collaborators! A few of us remain on twitter: @YatrikShahLab, @ruckertmt, @CJHPhD, @Fil_Bednar, @timofran1, @Pasca_Lab 2nd- Thanks to the Rogel and Blondy Center for Pancreatic Cancer (@UMICHpancreas), @UMRogelCancer, @UMPhysiology 3rd- Special thanks to our funding agencies. We couldn't have done it without you and are so grateful for the support! (this project goes back ~10 years): @theNCI, @DeptofDefense_, @PanCAN, @AACR, @TheVFoundation, @skyresearch

9/ Co-published companion study from @LabVousden identifies ALDH1L2 as an acinar-enriched mitochondrial one-carbon NADPH enzyme, which also regulates ROS and ADM. ALDH1L2 is suppressed during ADM; its loss elevates ROS, accelerates ADM/PanIN, and links to rising circulating formate as a potential PDAC burden/prognostic biomarker. So grateful to Karen and Marc for their support - congrats!! nature.com/articles/s42255-0…

10/ One more thank you to the @WellenLab 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, highlighting a dynamic feedback between stress signaling and antioxidant “brakes,” plus important cautions about antioxidant interventions. nature.com/articles/s42255-0…

11/ Huge congrats to our lead author Dr. Megan Radyk. She just started her own lab at @RoswellPark (Buffalo, NY). Excited to see what’s next from her team. radyklab.org/ [I'll link to her BlueSky account once I post there...]