Liver lineage confers sensitivity of cancer cells to sulfonation-dependent alkylators
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA714004 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13952500_1.fastq.gz | Fastqsanger.gz | |||
| SRR13952500_2.fastq.gz | Fastqsanger.gz | |||
| SRR13952501_1.fastq.gz | Fastqsanger.gz | |||
| SRR13952501_2.fastq.gz | Fastqsanger.gz | |||
| SRR13952502_1.fastq.gz | Fastqsanger.gz |
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Project description:Adult liver malignancies, including intrahepatic cholangiocarcinoma and hepatocellular carcinoma, are the 2nd leading cause of cancer related death worldwide. The majority of patients are currently treated with either combination chemotherapy or immunotherapy, respectively, without specific biomarkers for patient selection. Here, using high-throughput screens, proteomics, and in vitro resistance models, we identify the small molecule, YC-1, as selectively active against a defined subset of cell lines derived from both major liver cancer types. We demonstrate that selectivity in vitro and in vivo is determined by expression of a human cytosolic sulfotransferase – the liver resident enzyme SULT1A1, which sulfonates YC-1. Sulfonation stimulates covalent binding of YC-1 to lysine residues in protein targets, enriching for RNA binding factors. Using computational analysis as well as structural modeling, we also define a wider group of structurally related SULT1A1-activated small molecules with distinct target profiles, which together constitute an untapped small molecule class. These studies provide a foundation for pre-clinical development of these agents and point to the broader potential of exploiting the liver lineage enzyme SULT1A1 for selective targeting strategies.
2023-01-24 | GSE168791 | GEO
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)
2022-11-29 | MSV000090805 | MassIVE
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.
(iii) PDX samples were analyzed using TMT multiplexing on an Orbitrap Fusion mass spectrometer using the SPS-MS3 method. Prior to analysis, samples were fractionated offline using high pH reversed chromatography (12 fractions per TMT set). Three TMT sets were analyzed (ShiBardeesy_PDX_TMT1, ShiBardeesy_PDX_TMT2, and ShiBardeesy_PDX_TMT3), and samples were labeled as follows with channel (bridge channel, 130c):
ShiBardeesy_PDX_TMT1: SS101 (126), MG12 (127c), SS106 (127n), MG62 (128c), MG26 (128n), LCCH13 (129c), LCCH3 (129n), Q12050 (130n).
ShiBardeesy_PDX_TMT2: SS102 (126), SS110 (127n), MG34 (128c), MG17 (128n), LCCH4 (129c), MG68 (129n), HBT110 (130n).
ShiBardeesy_PDX_TMT3: SS103 (126), MG10 (127n), MG59 (128c), MG25 (128n), LCCH10 (129c), MG73 (129n), HBT211 (130n).
(iv) Samples from experiments using immobilized small molecules to determine direct interactors of YC-1 were performed using TMT10-barcoding and the SPS-MS3 method on an Orbitrap Lumos mass spectrometer. No off-line fraction was performed. Samples were grouped into two TMT sets (ShiBardeesy_ImmobilizedDrug_TMT1 and ShiBardeesy_ImmobilizedDrug_TMT2). Channel 131N was used as the bridge channel. Samples were labeled as follows:
ShiBardeesy_ImmobilizedDrug_TMT1: immobilized_inactiveYC-1_rep_1 (126), immobilized_inactiveYC-1_rep_2 (128n), immobilized_inactiveYC-1_rep_3 (128c), immobilized_YC-1_rep_1 (129n), immobilized_YC-1_plus_soluble_YC-1_competitor_rep_1 (130c).
ShiBardeesy_ImmobilizedDrug_TMT2: immobilized_YC-1_rep_2 (127n), immobilized_YC-1_plus_soluble_YC-1_competitor_rep_2 (128n), immobilized_YC-1_plus_soluble_YC-1_competitor_rep_3 (129c), immobilized_YC-1_rep_3 (130c).
2022-11-29 | MSV000090808 | MassIVE
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