Caleb Cheng

In a recent Nature paper, @djcalebc.bsky.social et al. explore how PIKfyve regulates lysosomal lipid recycling in PDAC. This opens up a therapeutic window: co-inhibition of PIKfyve and the KRAS–MAPK pathway leads to synthetic lethality & tumor regression.

View it here >>> nature.com/articles/s41...

Targeting PIKfyve-driven lipid metabolism in pancreatic cancer - Nature A study of human and mouse models of pancreatic cancer finds that inhibiting the lipid kinase PIKfyve interferes with the cancer’s lipid homeostasis, making it a potential target for drug development.

more from last week www.nature.com/articles/s41...

My team and I are at #AACR25 and have posters to discuss parts of the project (and some future directions) tomorrow! Rüya Pakkan will present on Tuesday AM Abstract #4158 Sec 13 board 8. I will present on Tuesday PM #5384 Sec 12 board 12. Come visit!

Thank you!! And thank you for all your help and support along the way 😊

Thanks @bryantkl.bsky.social for the shoutout!! Look forward to seeing your future work including target PIKfyve as well as RAS in PDAC 💪

Thanks so much Siva!!! Look forward to seeing yours out soon 🫡

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Thanks for this writeup and for highlighting our work!!

Thanks so much!!

🔥Smoking hot new paper and tweetorial from @djcalebc.bsky.social (collab with Chinnaiyan Lab)! 🔥

We are over the moon about this new work and its therapeutic implications for pancreatic cancer. Please have a read and share your thoughts/feedback! 🙏🏼

Excited to be part of this #AACR25 (@theaacr.bsky.social @rickbuck.bsky.social) Social Media Ambassadorship!!

Look out for updates on the #Tumor-microenvironment ( #TME )-relevant events and highlights. I’ll be posting from Sunday afternoon to midday Wednesday 😎

Thank you for the highlight!!

Thanks for the highlight!!!

13/ Finally thanks to the many friends for your support from both @lyssiotislab.bsky.social and the Chinnaiyan lab @brandontwchen.bsky.social @radykm.bsky.social @juliaugras.bsky.social @ja-nietocarrion.bsky.social @mruckert.bsky.social @shiva251993.bsky.social @federicadanzi.bsky.social 💜💜

12/ Also very grateful to officially have my first paper out in the pancreatic cancer field! This community has been so welcoming, and I look forward to working on PDAC throughout my training and career! @pancan.bsky.social

11/ THANK YOU to all the many contributors to this project, collaborators, mentors, and leaders. I am so honored to have been a part of this exciting study @awaddomi.bsky.social @lyssiotislab.bsky.social Arul Chinnaiyan and Yuanyuan Qiao.

10/ We’re extremely excited about this potential therapeutic strategy given all the RAS inhibitors coming out. This also complements another recent story showing that PIKfyve inhibition synergizes with RAS-MAPK through disrupting autophagy @bryantkl.bsky.social

aacrjournals.org/cancerres/ar...

We show this concept in efficacy studies using xenografts, orthotopic allografts, and KPC models in which the combo of RAS-MAPK and PIKfyve inhibitors resulted in regression/cures! Thanks especially to @jenmorton.bsky.social @macleanoncology.bsky.social @cruk-si.bsky.social @uofglasgow.bsky.social

a man in a leather jacket is making a funny face while looking at the camera . ALT: a man in a leather jacket is making a funny face while looking at the camera .

8/ These suggest that co-targeting KRAS-MAPK and PIKfyve may result in synergistic effects through opposing effects on lipid metabolism!

7/ We then found that KRAS can regulate de novo lipid synthesis through regulating genes such as FASN and ACC1 through MAPK signaling, and that KRAS-MAPK inhibition partially reverses the transcriptional and metabolic adaptation that PIKfyve inhibition elicits on PDAC cells.

6/ RNA-seq, metabolomics, lipidomics, and stable isotope tracing strongly corroborated these results and suggested that PIKfyve inhibition triggers an adaptive lipogenic transcriptional and metabolic program. Special thanks to Dr. Pietro Morlacchi from Agilent for their help with the lipidomics!

5/ To assess the metabolic effect of inhibiting PIKfyve in PDAC, we ran a metabolism-focused CRISPR screen using PIKfyve inhibition as a selective pressure. The screen strongly demonstrated that PIKfyve inhibition forces PDAC cells rely on de novo lipid biosynthesis.

4/ We started with a GEMM developed by Yuanyuan Qiao demonstrating that loss of Pikfyve slows PDAC development in KC/KPC models while preserving pancreas function. Using a phase 1 cleared inhibitor ESK981, we also found that PIKfyve inhibition slows PDAC development and growth.

3/ Here, we show that inhibiting PIKfyve slows PDAC growth and induces an adaptive lipogenesis that can be blocked by KRAS inhibition. Follow along below for more in-depth tweetorial!

Targeting PIKfyve-driven lipid metabolism in pancreatic cancer - Nature A study of human and mouse models of pancreatic cancer finds that inhibiting the lipid kinase PIKfyve interferes with the cancer’s lipid homeostasis, making it a potential target for drug development.

Link to paper: www.nature.com/articles/s41...

Beyond grateful to share that my main PhD thesis project, Targeting PIKfyve-driven lipid metabolism in pancreatic cancer (@lyssiotislab.bsky.social + Arul Chinnaiyan lab), has just been published in @nature.com!

Targeting PIKfyve-driven lipid metabolism in pancreatic cancer - Nature A study of human and mouse models of pancreatic cancer finds that inhibiting the lipid kinase PIKfyve interferes with the cancer’s lipid homeostasis, making it a potential target for drug development.

Congrats to @djcalebc.bsky.social and @lyssiotislab.bsky.social for this awesome work🤩

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

Thank you!!!!

Mitochondria-organelle crosstalk in establishing compartmentalized metabolic homeostasis Mitochondria serve as central hubs in cellular metabolism by sensing, integrating, and responding to metabolic demands. This integrative function is a…

Happy to share our most recent review on mitochondria-organelle metabolic communication with Yatrik Shah and Costas Lyssiotis now online at Molecular Cell!

We explored aspect of lipid transfer, organelle membrane contacts, ROS, metabolites, and metals!

www.sciencedirect.com/science/arti...

Excited for this!