Dataset Information

A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis.

ABSTRACT: Clear-cell carcinomas (CCCs) are a histological group of highly aggressive malignancies commonly originating in the kidney and ovary. CCCs are distinguished by aberrant lipid and glycogen accumulation and are refractory to a broad range of anti-cancer therapies. Here we identify an intrinsic vulnerability to ferroptosis associated with the unique metabolic state in CCCs. This vulnerability transcends lineage and genetic landscape, and can be exploited by inhibiting glutathione peroxidase 4 (GPX4) with small-molecules. Using CRISPR screening and lipidomic profiling, we identify the hypoxia-inducible factor (HIF) pathway as a driver of this vulnerability. In renal CCCs, HIF-2α selectively enriches polyunsaturated lipids, the rate-limiting substrates for lipid peroxidation, by activating the expression of hypoxia-inducible, lipid droplet-associated protein (HILPDA). Our study suggests targeting GPX4 as a therapeutic opportunity in CCCs, and highlights that therapeutic approaches can be identified on the basis of cell states manifested by morphological and metabolic features in hard-to-treat cancers.

SUBMITTER: Zou Y

PROVIDER: S-EPMC6453886 | biostudies-other | 2019 Apr

REPOSITORIES: biostudies-other

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A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis.

Zou Yilong Y Palte Michael J MJ Deik Amy A AA Li Haoxin H Eaton John K JK Wang Wenyu W Tseng Yuen-Yi YY Deasy Rebecca R Kost-Alimova Maria M Dančík Vlado V Leshchiner Elizaveta S ES Viswanathan Vasanthi S VS Signoretti Sabina S Choueiri Toni K TK Boehm Jesse S JS Wagner Bridget K BK Doench John G JG Clish Clary B CB Clemons Paul A PA Schreiber Stuart L SL

Nature communications 20190408 1

Clear-cell carcinomas (CCCs) are a histological group of highly aggressive malignancies commonly originating in the kidney and ovary. CCCs are distinguished by aberrant lipid and glycogen accumulation and are refractory to a broad range of anti-cancer therapies. Here we identify an intrinsic vulnerability to ferroptosis associated with the unique metabolic state in CCCs. This vulnerability transcends lineage and genetic landscape, and can be exploited by inhibiting glutathione peroxidase 4 (GPX4 ...[more]

PMID: 30962421

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Project description:Activating transcription factor 4 (ATF4) is a critical mediator of metabolic and oxidative homeostasis and cell survival. ATF4 is elevated in response to diverse microenvironmental stresses, including starvation, ER stress damages and exposure to toxic factors. Here we show that ATF4 expression fosters the malignancy of primary brain tumors (WHO grade III and IV gliomas) and increases proliferation and tumor angiogenesis. Hence, ATF4 expression promotes cell migration and anchorage-independent cell growth, whereas siRNA-mediated knockdown of ATF4 attenuates these features of malignancy in human gliomas. Further experiments revealed that ATF4-dependent tumor promoting effects are mediated by transcriptional targeting the glutamate antiporter xCT/SCL7A11 (also known as system Xc-). Thus, xCT is elevated as a consequence of ATF4 activation. We further found evidence that ATF4-induced proliferation can be attenuated by pharmacological or genetic xCT inhibition and ferroptosis inducers such as sorafenib, erastin and GPx4 inhibitor RSL3. Further, fostered xCT expression promotes cell survival and growth in ATF4 knockdown cells. Moreover, increased xCT levels ameliorate sorafenib and erastin-induced ferroptosis. Conversely, ATF4 knockdown renders cells susceptible for erastin, sorafenib and RSL3-induced ferroptosis. We further identified that ATF4 promotes tumor-mediated neuronal cell death which can be alleviated by xCT inhibition. Moreover, elevated ATF4 expression in gliomas promotes tumor angiogenesis. Noteworthy, ATF4-induced angiogenesis could be diminished by ferroptosis inducers erastin and by GPx4 inhibitor RSL3. Our data provide proof-of-principle evidence that ATF4 fosters proliferation and induces a toxic microenvironmental niche. Furthermore, ATF4 increases tumor angiogenesis and shapes the vascular architecture in a xCT-dependent manner. Thus, inhibition of ATF4 is a valid target for diminishing tumor growth and vasculature via sensitizing tumor cells for ferroptosis.

Project description:The small molecule YC-1 was identified as identified as a selectively active agent against subsets of the two major live cancer subtypes, intrahepatic cholangiocarcinoma and hepatocellular carcinoma. Response to YC-1 is dependent on the expression of the sulfotransferase SULT1A1, which activates YC-1 through sulfonation. The contributions of mass spectrometry to the study were: (i) identifying SULT1A1 as the key player in YC-1 response through observing the protein in a cell line with acquired resistance to the small molecule treatment, (ii) corroborating the role of SULT1A1 in the YC-1 activity by correlating protein expression profiles and drug responses across 37 biliary cancer cell lines, (iii) showing that SULT1A1 expression was associated with IDH mutations, FGFR2 fusion, and BAP1 loss in vivo studying patient-derived xenograft (PDX) models, and (iv) identifying protein targets in a protein enrichment experiment with an immobilized drug. (i) and (ii): Cell line samples from datasets (i) and (ii) were analyzed together in a set of 12 TMT sets (ShiBardeesy_CellLines_TMT1 to TMT12) using TMT11-barcoding. The samples were analyzed on an Orbitrap Lumos mass spectrometer using the SPS-MS3 method. Prior to analysis, samples were fractionated offline using high pH reversed chromatography (12 fractions per TMT set). Across all TMT sets, channel 131c was used as the bridge channel (pooled digests of all samples). Samples were labeled as follows (rep = replicate: (i) Cell lines samples with acquired resistance to YC-1 treatment: ShiBardeesy_CellLines_TMT1: RBE_rep_1 (126), RBE YC1 Resistant 6_rep_1 (129c). ShiBardeesy_CellLines_TMT2: RBE YC1 Resistant 3_rep_1 (129n), RBE YC1 Resistant 1_rep_1 (130n). ShiBardeesy_CellLines_TMT3: RBE YC1 Resistant 2_rep_1 (126), RBE YC1 Resistant 5_rep_1 (130c). ShiBardeesy_CellLines_TMT4: RBE YC1 Resistant 4_rep_1 (126). ShiBardeesy_CellLines_TMT5: RBE YC1 Resistant 1_rep_2 (127n), RBE YC1 Resistant 4_rep_2 (128c), RBE YC1 Resistant 3_rep_2 (130c). ShiBardeesy_CellLines_TMT6: RBE YC1 Resistant 2_rep_2 (126), RBE YC1 Resistant 6_rep_2 (127c). ShiBardeesy_CellLines_TMT7: RBE_rep_2 (128n), RBE YC1 Resistant 5_rep_2 (130n). (ii) Proteomes of untreated biliary cell lines (baseline): ShiBardeesy_CellLines_TMT1: RBE_rep_1 (126), GB2_rep_1 (127n), HuCCT1_rep_1 (127c), ECC3_rep_1 (128n), ICC10_rep_1 (128c), KMCH-1_rep_1 (129n), SNU-1196_rep_1 (130n). ShiBardeesy_CellLines_TMT2: ICC13-7_rep_1 (126), ICC8_rep_1 (127n), ICC9_rep_1 (127c), SNU-478_rep_1 (128n), CC-SW-1_rep_1 (128c), CC-LP-1_rep_1 (129c), SSP-25_rep_1 (130c), ICC10-8_rep_1 (131n) ShiBardeesy_CellLines_TMT3: SNU-1079_rep_1 (127n), ICC5_rep_1 (127c), ICC7_rep_1 (128c), COR-L105_rep_1 (129n), ICC17_rep_1 (129c), GBC1_rep_1 (131n). ShiBardeesy_CellLines_TMT4: ICC3_rep_1 (127n), ICC2_rep_1 (127c), ICC106_rep_1 (128n), ICC11_rep_1 (128c), HKGZ-CC_rep_1 (129n), SNU-869_rep_1 (129c), HuH28_rep_1 (130n), ICC12_rep_1 (130c), SNU-308_rep_1 (131n). ShiBardeesy_CellLines_TMT5: ICC2_rep_2 (126), ECC3_rep_2 (127c), GB2_rep_2 (128n), ICC11_rep_2 (129n), ICC7_rep_2 (129c), SNU-869_rep_2 (130n), SSP-25_rep_2 (131n). ShiBardeesy_CellLines_TMT6: CC-LP-1_rep_2 (127n), COR-L105_rep_2 (128n), HuCCT1_rep_2 (129n), ICC12_rep_2 (129c), ICC3_rep_2 (131n), ICC5_rep_2 (130n), SNU-478_rep_2 (130c). ShiBardeesy_CellLines_TMT7: ICC10_rep_2 (126), ICC10-6_rep_2 (127n), ICC10-8_rep_2 (127c), RBE_rep_2 (128n), ICC9_rep_2 (128c), ICC17_rep_2 (129n), ICC8_rep_2 (129c), CC-SW-1_rep_2 (130c), GBC1_rep_2 (131n). ShiBardeesy_CellLines_TMT8: ICC13-7_rep_2 (127c), HuH28_rep_2 (128n), HKGZ-CC_rep_2 (128c), SNU-1079_rep_2 (129n), KMCH-1_rep_2 (129c), SNU-1196_rep_2 (130n), SNU-308_rep_2 (131n). ShiBardeesy_CellLines_TMT9: SG231_rep_1 (126), KKU-100_rep_1 (127n), YSCCC_rep_1 (127c), ICC4_rep_1 (128n), TKKK_rep_1 (128c), ECC2_rep_1 (129n), KKU-M213/M214 (129c). ShiBardeesy_CellLines_TMT10: YSCCC_rep_2 (126), KKU-M213/M214_rep_2 (127n), SG231_rep_2 (127c), TKKK_rep_2 (129n), ECC2_rep_2 (129c), ICC4_rep_2 (130n), KKU-100_rep_2 (131n). ShiBardeesy_CellLines_TMT11: ICC13-7_rep_1 (129n). ShiBardeesy_CellLines_TMT12: ICC13-7_rep2 (131n)

Dataset Information

A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis.

Publications

A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis.

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