richpossemato.bsky.social
Associate Professor at NYU Grossman School of Medicine. Cellular metabolism, iron, cancer research. 🏳️🌈Father of two possematolab.org
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I created a brief spreadsheet of reductions I've heard of so far. Any additions you know of (especially if you have the links/receipts) would be great: docs.google.com/spreadsheets...
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Congrats! Any truth to the idea that this supports iron sulfur cluster synthesis?
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What a cool concept. Congrats!
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We’re grateful to our collaborators Jessica Spinelli at UMASS Worcester and Tony Huang NYU Langone, and support from the Perlmutter Cancer Center and NYUGSOM Pathology. Come find us at possematolab.org for more on our work!
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Upon inhibition of replication in cancer cells, activation of the ATR/CHK1 pathway helps maintain viability. ATR/CHK1 inhibition cooperates strongly with pyrimidine synthesis inhibitors. However, current ATR and CHK1 inhibitors are not well-tolerated.
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Because many of the enzymes in de novo pyrimidine synthesis are current and proposed anti-cancer targets and the glucose level in tumors is typically low, this work might indicate a key mode of failure for such treatments.
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Thus, Minwoo concluded that glucose level impacts a nuclear to mitochondrial signal that triggers intrinsic apoptosis in these p53-null cancer cells. Future work in the lab will hopefully uncover that unknown mechanism!
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Deleting BAK or Caspase 9 could completely block apoptosis induced by pyrimidine synthesis inhibitors. Moreover, Bcl2 inhibitors or death receptor-dependent methods of inducing apoptosis were not affected by glucose levels.
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Blocking pyrimidine synthesis potently triggered apoptosis even when we targeted steps after the UDP-glucose shunt. Culture in low glucose potently suppressed apoptosis induced by inhibiting pyrimidine synthesis, indicating a second effect of glucose on apoptosis signaling.
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Minwoo found that in high glucose, UDP-glucose synthesis was maintained at a much higher level, shunting pyrimidines away from DNA and RNA synthesis. Blocking nucleotide sugar synthesis permitted cells to maintain replication longer when pyrimidines were limiting.
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Remarkably, Minwoo found that targeting de novo pyrimidine synthesis, but not other metabolic pathways, was much more effective in high (10mM) glucose conditions. Cells in high glucose halted replication faster and underwent apoptosis more rapidly.
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In this study postdoc Minwoo Nam used a continuous flow cell culture system that we developed over 10 years ago with Kivanc Birsoy to maintain cells at tumor-relevant concentrations of glucose (1 mM) and perform CRISPR-based genetic screening.
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Congrats I enjoyed reading this!
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Can I join Christian?
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There are a few republican senators who don't want to destroy science, right?
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Would love to join! Thanks for making this!