Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 70,182 bioRxiv papers from 306,456 authors.
HIF-2α drives an intrinsic vulnerability to ferroptosis in clear cell renal cell carcinoma
Michael J Palte,
Amy A Deik,
John K. Eaton,
Elizaveta S Leshchiner,
Vasanthi S. Viswanathan,
Toni K Choueiri,
Jesse S. Boehm,
Bridget K. Wagner,
Clary B. Clish,
Paul A Clemons,
Stuart L Schreiber
Posted 09 Aug 2018
bioRxiv DOI: 10.1101/388041
Posted 09 Aug 2018
Kidney cancers are characterized by extensive metabolic reprogramming and resistance to a broad range of anti-cancer therapies. By interrogating the Cancer Therapeutics Response Portal compound sensitivity dataset, we show that cells of clear-cell renal cell carcinoma (ccRCC) possess a lineage-specific vulnerability to ferroptosis that can be exploited by inhibiting glutathione peroxidase 4 (GPX4). Using genome-wide CRISPR screening and lipidomic profiling, we reveal that this vulnerability is driven by the HIF-2α - HILPDA pathway by inducing a polyunsaturated fatty acyl (PUFA)-lipid-enriched cell state that is dependent on GPX4 for survival and susceptible to ferroptosis. This cell state is developmentally primed by the HNF-1β - 1-acylglycerol-3-phosphate O-acyltransferase 3 (AGPAT3) axis in the renal lineage. In addition to PUFA metabolism, ferroptosis is facilitated by a phospholipid flippase TMEM30A involved in membrane topology. Our study uncovers an oncogenesis-associated vulnerability, delineates the underlying mechanisms and suggests targeting GPX4 to induce ferroptosis as a therapeutic opportunity in ccRCC.
- Downloaded 1,785 times
- Download rankings, all-time:
- Site-wide: 3,104 out of 70,182
- In cancer biology: 78 out of 2,385
- Year to date:
- Site-wide: 5,340 out of 70,182
- Since beginning of last month:
- Site-wide: 6,369 out of 70,182
Downloads over time
Distribution of downloads per paper, site-wide
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!