karrethlab.bsky.social
We study how melanomas progress and metastasize at Moffitt Cancer Center. Current focus on TFs and ncRNAs. Account managed by Florian.
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Not far at all! If you're down here and tired of cooking lemme know and Gina and I will take you to dinner
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I much prefer looking at food pics than reading the news these days, so thank you 😁
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Aren't mice obligated nasal breathers? How would CPR work in that case?
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More work is needed, but asRNA appear to be key regulators of mRNA translation, potentially to deal with secondary structures in the mRNA 5'UTRs.
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Ribosome profiling confirmed the effects of CDH3-AS1 on P-cad translation but also uncovered a global effect of asRNAs: transcripts, especially those with longer 5'UTR, that have an asRNA overlapping with the 5'UTR, are translated more efficiently.
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CDH3-AS1 increases P-cadherin without affecting CDH3 transcription, splicing, localization, or stability. CDH3 harbors secondary structures in its 5'region that reduce translation. CDH3-AS1 overlaps with this region and enhances P-cadherin translation.
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Like CDH3, CDH3-AS1 acts as a tumor suppressor, and we show the TS effects of CDH3-AS1 require CDH3/P-cadherin expression. CDH3-AS1 interacts with CDH3, preferntially when expressed in cis from a common locus.
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We profiled deregulated noncoding RNAs in melanoma cells and found hundreds of asRNAs. CDH3-AS1, the most downregulated asRNA, overlaps CDH3, which encodes P-cadherin and which is also robustly reduced in melanoma. Both CDH3-AS1 and CDH3 are suppressed my MAPK signaling.
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There are a few unanswered questions, which we plan to address in follow up studies with recently awarded NCI funding. Neel graduated and will move on soon - if you are interested in carrying on this work as a postdoc in the lab, email me. We are hiring.
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This was a fun project, and Neel was brave to take it on as it was our first foray into metabolic enzymes, even if we used our strengths to analyze PHGDH: signaling and mouse modeling.
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This created a melanoma-specific metabolic vulnerability where melanoma cells can be starved of serine by combining dietary serine restriction with BRAF inhibitor-mediated reduction of PHGDH. This combo kills melanoma cells in vitro and reduces tumor growth in vivo.
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He went on to delineate a MAPK-mTORC1-ATF-PHGDH regulatory pathway. Surprisingly, this pathway still controls PHGDH levels when melanoma cells are starved of extracellular serine (typically, this would turn on the integrated stress response pathway to regulate ATF4 and turn off mTORC1)
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Using two genetically engineered mouse models, Neel showed that PHGDH is essential for melanomagenesis. He also noted that PHGDH is generally upregulated in melanoma cells compared to melanocytes. He hypothesized that this could be due to MAPK hyperactivation in melanoma cells.
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The PHGDH gene, encoding the rate limiting enzyme of the serine synthesis pathway, is amplified in melanoma, making melanoma cells addicted to it. Neel wanted to know if PHGDH is important also in non-amplified melanoma cells.
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Looks like expertly peeled, cored, and sliced apples and pears were used here
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Congrats Anna and team!
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Only because it was the weekend