“These awardees stood out for their scientific originality, rigor and dedication to asking important scientific questions. They reflect the strength and promise of the next generation of scientific leaders.” - Dr. Bai, director of the Weintraub Award. www.fredhutch.org/en/news/rele...
Thanks Indigo!
This project has been an incredibly fun collaboration, and I’m grateful to have had the opportunity to work on this alongside Brandon Chew, Benedict Choi, Timmy Suh, and Chris Carpenter! Huge thank you to many others @gladstoneinst.bsky.social, @arcinstitute.bsky.social, and @ucsfhealth.bsky.social
But treating real patients with hypoxia would pose practical challenges. Recently, we showed that HypoxyStat, a small molecule that increases hemoglobin’s binding affinity for oxygen, can mimic the effects of hypoxia. And this drug also slowed tumor growth!
So it looks like hypoxia slows tumor growth, but could it be used alongside existing cancer therapies? We found that hypoxia could augment the tumor suppressive effects of the chemotherapy drug gemcitabine and of anti-CTLA4 immunotherapy.
Nucleotides can come from two sources: de novo synthesis, which is energetically demanding, and salvage, which requires abundant nucleobase substrates. We measured the contribution of each pathway; hypoxic tumors suppressed de novo synthesis, resulting in smaller purine pools.
Coinciding with the transcriptomics data, we observed that the smaller tumors in hypoxic mice had lower levels of purine nucleotides, which could contribute to decreased cancer cell proliferation.
Using the GENEVA data, we found that a few cell lines out-competed others in hypoxia, and those cell lines tended to activate genes involved in the synthesis of new purine nucleotides.
To see how hypoxia would affect different cancer cell lines, we used a platform called GENEVA, developed by
@thejohnnyyu.bsky.social and @genophoria.bsky.social . We implanted 20 pooled cancer cell lines into normoxic and hypoxic mice, and performed single-cell RNA-sequencing after 8 days.
But little is known about how systemic hypoxia affects tumor progression, so we exposed mice with solid tumors to different oxygen levels: 21% (normoxia), 11% (moderate hypoxia) and 8% O2 (hypoxia). The tumors grew much less in the hypoxic mice!
We started investigating this question based on two seemingly conflicting observations:
1. Tumor-localized hypoxia is associated with worse prognosis
2. People who live at altitude (where the air is thinner) have lower cancer mortality
I am excited to share our latest preprint showing that systemic hypoxia suppresses solid tumor growth: www.biorxiv.org/content/10.6...
This has been a tremendous collaborative effort in the labs of Isha Jain @ishahjain.bsky.social and Hani Goodarzi @genophoria.bsky.social.
The latest from our group, led by Megan Ostrowski and @martyyang.bsky.social, is now published in final form (www.cell.com/cell/fulltex...! Many thanks to our excellent peer reviewers for suggesting several experiments (including CAF-1 perturbation) to really improve the study =) #epigenetics
