Multi-targeted therapy resistance via drug-induced secretome fucosylation

Cancer secretome is a reservoir for aberrant glycosylation. How therapies alter this post- translational cancer hallmark and the consequences thereof remain elusive. Here, we show that an elevated secretome fucosylation is a pan-cancer signature of both response and resistance to multiple targeted t...
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Autor*in:	Mark Borris D Aldonza [verfasserIn] Junghwa Cha [verfasserIn] Insung Yong [verfasserIn] Jayoung Ku [verfasserIn] Pavel Sinitcyn [verfasserIn] Dabin Lee [verfasserIn] Ryeong-Eun Cho [verfasserIn] Roben D Delos Reyes [verfasserIn] Dongwook Kim [verfasserIn] Soyeon Kim [verfasserIn] Minjeong Kang [verfasserIn] Yongsuk Ku [verfasserIn] Geonho Park [verfasserIn] Hye-Jin Sung [verfasserIn] Han Suk Ryu [verfasserIn] Sukki Cho [verfasserIn] Tae Min Kim [verfasserIn] Pilnam Kim [verfasserIn] Je-Yoel Cho [verfasserIn] Yoosik Kim [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2023

Schlagwörter:	fucosylation n-linked glycosylation targeted therapy secretome drug resistance cancer

Übergeordnetes Werk:	In: eLife - eLife Sciences Publications Ltd, 2013, 12(2023)
Übergeordnetes Werk:	volume:12 ; year:2023

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.7554/eLife.75191

Katalog-ID:	DOAJ088962679

Internformat


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allfields	10.7554/eLife.75191 doi (DE-627)DOAJ088962679 (DE-599)DOAJ04cffef7074f4c568c8aa2b97115d57f DE-627 ger DE-627 rakwb eng QH301-705.5 Mark Borris D Aldonza verfasserin aut Multi-targeted therapy resistance via drug-induced secretome fucosylation 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Cancer secretome is a reservoir for aberrant glycosylation. How therapies alter this post- translational cancer hallmark and the consequences thereof remain elusive. Here, we show that an elevated secretome fucosylation is a pan-cancer signature of both response and resistance to multiple targeted therapies. Large-scale pharmacogenomics revealed that fucosylation genes display widespread association with resistance to these therapies. In cancer cell cultures, xenograft mouse models, and patients, targeted kinase inhibitors distinctively induced core fucosylation of secreted proteins less than 60 kDa. Label-free proteomics of N-glycoproteomes identified fucosylation of the antioxidant PON1 as a critical component of the therapy-induced secretome (TIS). N-glycosylation of TIS and target core fucosylation of PON1 are mediated by the fucose salvage-FUT8-SLC35C1 axis with PON3 directly modulating GDP-Fuc transfer on PON1 scaffolds. Core fucosylation in the Golgi impacts PON1 stability and folding prior to secretion, promoting a more degradation-resistant PON1. Global and PON1-specific secretome de-N-glycosylation both limited the expansion of resistant clones in a tumor regression model. We defined the resistance-associated transcription factors (TFs) and genes modulated by the N-glycosylated TIS via a focused and transcriptome-wide analyses. These genes characterize the oxidative stress, inflammatory niche, and unfolded protein response as important factors for this modulation. Our findings demonstrate that core fucosylation is a common modification indirectly induced by targeted therapies that paradoxically promotes resistance. fucosylation n-linked glycosylation targeted therapy secretome drug resistance cancer Medicine R Science Q Biology (General) Junghwa Cha verfasserin aut Insung Yong verfasserin aut Jayoung Ku verfasserin aut Pavel Sinitcyn verfasserin aut Dabin Lee verfasserin aut Ryeong-Eun Cho verfasserin aut Roben D Delos Reyes verfasserin aut Dongwook Kim verfasserin aut Soyeon Kim verfasserin aut Minjeong Kang verfasserin aut Yongsuk Ku verfasserin aut Geonho Park verfasserin aut Hye-Jin Sung verfasserin aut Han Suk Ryu verfasserin aut Sukki Cho verfasserin aut Tae Min Kim verfasserin aut Pilnam Kim verfasserin aut Je-Yoel Cho verfasserin aut Yoosik Kim verfasserin aut In eLife eLife Sciences Publications Ltd, 2013 12(2023) (DE-627)728518384 (DE-600)2687154-3 2050084X nnns volume:12 year:2023 https://doi.org/10.7554/eLife.75191 kostenfrei https://doaj.org/article/04cffef7074f4c568c8aa2b97115d57f kostenfrei https://elifesciences.org/articles/75191 kostenfrei https://doaj.org/toc/2050-084X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2023
spelling	10.7554/eLife.75191 doi (DE-627)DOAJ088962679 (DE-599)DOAJ04cffef7074f4c568c8aa2b97115d57f DE-627 ger DE-627 rakwb eng QH301-705.5 Mark Borris D Aldonza verfasserin aut Multi-targeted therapy resistance via drug-induced secretome fucosylation 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Cancer secretome is a reservoir for aberrant glycosylation. How therapies alter this post- translational cancer hallmark and the consequences thereof remain elusive. Here, we show that an elevated secretome fucosylation is a pan-cancer signature of both response and resistance to multiple targeted therapies. Large-scale pharmacogenomics revealed that fucosylation genes display widespread association with resistance to these therapies. In cancer cell cultures, xenograft mouse models, and patients, targeted kinase inhibitors distinctively induced core fucosylation of secreted proteins less than 60 kDa. Label-free proteomics of N-glycoproteomes identified fucosylation of the antioxidant PON1 as a critical component of the therapy-induced secretome (TIS). N-glycosylation of TIS and target core fucosylation of PON1 are mediated by the fucose salvage-FUT8-SLC35C1 axis with PON3 directly modulating GDP-Fuc transfer on PON1 scaffolds. Core fucosylation in the Golgi impacts PON1 stability and folding prior to secretion, promoting a more degradation-resistant PON1. Global and PON1-specific secretome de-N-glycosylation both limited the expansion of resistant clones in a tumor regression model. We defined the resistance-associated transcription factors (TFs) and genes modulated by the N-glycosylated TIS via a focused and transcriptome-wide analyses. These genes characterize the oxidative stress, inflammatory niche, and unfolded protein response as important factors for this modulation. Our findings demonstrate that core fucosylation is a common modification indirectly induced by targeted therapies that paradoxically promotes resistance. fucosylation n-linked glycosylation targeted therapy secretome drug resistance cancer Medicine R Science Q Biology (General) Junghwa Cha verfasserin aut Insung Yong verfasserin aut Jayoung Ku verfasserin aut Pavel Sinitcyn verfasserin aut Dabin Lee verfasserin aut Ryeong-Eun Cho verfasserin aut Roben D Delos Reyes verfasserin aut Dongwook Kim verfasserin aut Soyeon Kim verfasserin aut Minjeong Kang verfasserin aut Yongsuk Ku verfasserin aut Geonho Park verfasserin aut Hye-Jin Sung verfasserin aut Han Suk Ryu verfasserin aut Sukki Cho verfasserin aut Tae Min Kim verfasserin aut Pilnam Kim verfasserin aut Je-Yoel Cho verfasserin aut Yoosik Kim verfasserin aut In eLife eLife Sciences Publications Ltd, 2013 12(2023) (DE-627)728518384 (DE-600)2687154-3 2050084X nnns volume:12 year:2023 https://doi.org/10.7554/eLife.75191 kostenfrei https://doaj.org/article/04cffef7074f4c568c8aa2b97115d57f kostenfrei https://elifesciences.org/articles/75191 kostenfrei https://doaj.org/toc/2050-084X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2023
allfields_unstemmed	10.7554/eLife.75191 doi (DE-627)DOAJ088962679 (DE-599)DOAJ04cffef7074f4c568c8aa2b97115d57f DE-627 ger DE-627 rakwb eng QH301-705.5 Mark Borris D Aldonza verfasserin aut Multi-targeted therapy resistance via drug-induced secretome fucosylation 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Cancer secretome is a reservoir for aberrant glycosylation. How therapies alter this post- translational cancer hallmark and the consequences thereof remain elusive. Here, we show that an elevated secretome fucosylation is a pan-cancer signature of both response and resistance to multiple targeted therapies. Large-scale pharmacogenomics revealed that fucosylation genes display widespread association with resistance to these therapies. In cancer cell cultures, xenograft mouse models, and patients, targeted kinase inhibitors distinctively induced core fucosylation of secreted proteins less than 60 kDa. Label-free proteomics of N-glycoproteomes identified fucosylation of the antioxidant PON1 as a critical component of the therapy-induced secretome (TIS). N-glycosylation of TIS and target core fucosylation of PON1 are mediated by the fucose salvage-FUT8-SLC35C1 axis with PON3 directly modulating GDP-Fuc transfer on PON1 scaffolds. Core fucosylation in the Golgi impacts PON1 stability and folding prior to secretion, promoting a more degradation-resistant PON1. Global and PON1-specific secretome de-N-glycosylation both limited the expansion of resistant clones in a tumor regression model. We defined the resistance-associated transcription factors (TFs) and genes modulated by the N-glycosylated TIS via a focused and transcriptome-wide analyses. These genes characterize the oxidative stress, inflammatory niche, and unfolded protein response as important factors for this modulation. Our findings demonstrate that core fucosylation is a common modification indirectly induced by targeted therapies that paradoxically promotes resistance. fucosylation n-linked glycosylation targeted therapy secretome drug resistance cancer Medicine R Science Q Biology (General) Junghwa Cha verfasserin aut Insung Yong verfasserin aut Jayoung Ku verfasserin aut Pavel Sinitcyn verfasserin aut Dabin Lee verfasserin aut Ryeong-Eun Cho verfasserin aut Roben D Delos Reyes verfasserin aut Dongwook Kim verfasserin aut Soyeon Kim verfasserin aut Minjeong Kang verfasserin aut Yongsuk Ku verfasserin aut Geonho Park verfasserin aut Hye-Jin Sung verfasserin aut Han Suk Ryu verfasserin aut Sukki Cho verfasserin aut Tae Min Kim verfasserin aut Pilnam Kim verfasserin aut Je-Yoel Cho verfasserin aut Yoosik Kim verfasserin aut In eLife eLife Sciences Publications Ltd, 2013 12(2023) (DE-627)728518384 (DE-600)2687154-3 2050084X nnns volume:12 year:2023 https://doi.org/10.7554/eLife.75191 kostenfrei https://doaj.org/article/04cffef7074f4c568c8aa2b97115d57f kostenfrei https://elifesciences.org/articles/75191 kostenfrei https://doaj.org/toc/2050-084X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2023
allfieldsGer	10.7554/eLife.75191 doi (DE-627)DOAJ088962679 (DE-599)DOAJ04cffef7074f4c568c8aa2b97115d57f DE-627 ger DE-627 rakwb eng QH301-705.5 Mark Borris D Aldonza verfasserin aut Multi-targeted therapy resistance via drug-induced secretome fucosylation 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Cancer secretome is a reservoir for aberrant glycosylation. How therapies alter this post- translational cancer hallmark and the consequences thereof remain elusive. Here, we show that an elevated secretome fucosylation is a pan-cancer signature of both response and resistance to multiple targeted therapies. Large-scale pharmacogenomics revealed that fucosylation genes display widespread association with resistance to these therapies. In cancer cell cultures, xenograft mouse models, and patients, targeted kinase inhibitors distinctively induced core fucosylation of secreted proteins less than 60 kDa. Label-free proteomics of N-glycoproteomes identified fucosylation of the antioxidant PON1 as a critical component of the therapy-induced secretome (TIS). N-glycosylation of TIS and target core fucosylation of PON1 are mediated by the fucose salvage-FUT8-SLC35C1 axis with PON3 directly modulating GDP-Fuc transfer on PON1 scaffolds. Core fucosylation in the Golgi impacts PON1 stability and folding prior to secretion, promoting a more degradation-resistant PON1. Global and PON1-specific secretome de-N-glycosylation both limited the expansion of resistant clones in a tumor regression model. We defined the resistance-associated transcription factors (TFs) and genes modulated by the N-glycosylated TIS via a focused and transcriptome-wide analyses. These genes characterize the oxidative stress, inflammatory niche, and unfolded protein response as important factors for this modulation. Our findings demonstrate that core fucosylation is a common modification indirectly induced by targeted therapies that paradoxically promotes resistance. fucosylation n-linked glycosylation targeted therapy secretome drug resistance cancer Medicine R Science Q Biology (General) Junghwa Cha verfasserin aut Insung Yong verfasserin aut Jayoung Ku verfasserin aut Pavel Sinitcyn verfasserin aut Dabin Lee verfasserin aut Ryeong-Eun Cho verfasserin aut Roben D Delos Reyes verfasserin aut Dongwook Kim verfasserin aut Soyeon Kim verfasserin aut Minjeong Kang verfasserin aut Yongsuk Ku verfasserin aut Geonho Park verfasserin aut Hye-Jin Sung verfasserin aut Han Suk Ryu verfasserin aut Sukki Cho verfasserin aut Tae Min Kim verfasserin aut Pilnam Kim verfasserin aut Je-Yoel Cho verfasserin aut Yoosik Kim verfasserin aut In eLife eLife Sciences Publications Ltd, 2013 12(2023) (DE-627)728518384 (DE-600)2687154-3 2050084X nnns volume:12 year:2023 https://doi.org/10.7554/eLife.75191 kostenfrei https://doaj.org/article/04cffef7074f4c568c8aa2b97115d57f kostenfrei https://elifesciences.org/articles/75191 kostenfrei https://doaj.org/toc/2050-084X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2023
allfieldsSound	10.7554/eLife.75191 doi (DE-627)DOAJ088962679 (DE-599)DOAJ04cffef7074f4c568c8aa2b97115d57f DE-627 ger DE-627 rakwb eng QH301-705.5 Mark Borris D Aldonza verfasserin aut Multi-targeted therapy resistance via drug-induced secretome fucosylation 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Cancer secretome is a reservoir for aberrant glycosylation. How therapies alter this post- translational cancer hallmark and the consequences thereof remain elusive. Here, we show that an elevated secretome fucosylation is a pan-cancer signature of both response and resistance to multiple targeted therapies. Large-scale pharmacogenomics revealed that fucosylation genes display widespread association with resistance to these therapies. In cancer cell cultures, xenograft mouse models, and patients, targeted kinase inhibitors distinctively induced core fucosylation of secreted proteins less than 60 kDa. Label-free proteomics of N-glycoproteomes identified fucosylation of the antioxidant PON1 as a critical component of the therapy-induced secretome (TIS). N-glycosylation of TIS and target core fucosylation of PON1 are mediated by the fucose salvage-FUT8-SLC35C1 axis with PON3 directly modulating GDP-Fuc transfer on PON1 scaffolds. Core fucosylation in the Golgi impacts PON1 stability and folding prior to secretion, promoting a more degradation-resistant PON1. Global and PON1-specific secretome de-N-glycosylation both limited the expansion of resistant clones in a tumor regression model. We defined the resistance-associated transcription factors (TFs) and genes modulated by the N-glycosylated TIS via a focused and transcriptome-wide analyses. These genes characterize the oxidative stress, inflammatory niche, and unfolded protein response as important factors for this modulation. Our findings demonstrate that core fucosylation is a common modification indirectly induced by targeted therapies that paradoxically promotes resistance. fucosylation n-linked glycosylation targeted therapy secretome drug resistance cancer Medicine R Science Q Biology (General) Junghwa Cha verfasserin aut Insung Yong verfasserin aut Jayoung Ku verfasserin aut Pavel Sinitcyn verfasserin aut Dabin Lee verfasserin aut Ryeong-Eun Cho verfasserin aut Roben D Delos Reyes verfasserin aut Dongwook Kim verfasserin aut Soyeon Kim verfasserin aut Minjeong Kang verfasserin aut Yongsuk Ku verfasserin aut Geonho Park verfasserin aut Hye-Jin Sung verfasserin aut Han Suk Ryu verfasserin aut Sukki Cho verfasserin aut Tae Min Kim verfasserin aut Pilnam Kim verfasserin aut Je-Yoel Cho verfasserin aut Yoosik Kim verfasserin aut In eLife eLife Sciences Publications Ltd, 2013 12(2023) (DE-627)728518384 (DE-600)2687154-3 2050084X nnns volume:12 year:2023 https://doi.org/10.7554/eLife.75191 kostenfrei https://doaj.org/article/04cffef7074f4c568c8aa2b97115d57f kostenfrei https://elifesciences.org/articles/75191 kostenfrei https://doaj.org/toc/2050-084X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2023
language	English
source	In eLife 12(2023) volume:12 year:2023
sourceStr	In eLife 12(2023) volume:12 year:2023
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	fucosylation n-linked glycosylation targeted therapy secretome drug resistance cancer Medicine R Science Q Biology (General)
isfreeaccess_bool	true
container_title	eLife
authorswithroles_txt_mv	Mark Borris D Aldonza @@aut@@ Junghwa Cha @@aut@@ Insung Yong @@aut@@ Jayoung Ku @@aut@@ Pavel Sinitcyn @@aut@@ Dabin Lee @@aut@@ Ryeong-Eun Cho @@aut@@ Roben D Delos Reyes @@aut@@ Dongwook Kim @@aut@@ Soyeon Kim @@aut@@ Minjeong Kang @@aut@@ Yongsuk Ku @@aut@@ Geonho Park @@aut@@ Hye-Jin Sung @@aut@@ Han Suk Ryu @@aut@@ Sukki Cho @@aut@@ Tae Min Kim @@aut@@ Pilnam Kim @@aut@@ Je-Yoel Cho @@aut@@ Yoosik Kim @@aut@@
publishDateDaySort_date	2023-01-01T00:00:00Z
hierarchy_top_id	728518384
id	DOAJ088962679
language_de	englisch
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callnumber-first	Q - Science
author	Mark Borris D Aldonza
spellingShingle	Mark Borris D Aldonza misc QH301-705.5 misc fucosylation misc n-linked glycosylation misc targeted therapy misc secretome misc drug resistance misc cancer misc Medicine misc R misc Science misc Q misc Biology (General) Multi-targeted therapy resistance via drug-induced secretome fucosylation
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topic_title	QH301-705.5 Multi-targeted therapy resistance via drug-induced secretome fucosylation fucosylation n-linked glycosylation targeted therapy secretome drug resistance cancer
topic	misc QH301-705.5 misc fucosylation misc n-linked glycosylation misc targeted therapy misc secretome misc drug resistance misc cancer misc Medicine misc R misc Science misc Q misc Biology (General)
topic_unstemmed	misc QH301-705.5 misc fucosylation misc n-linked glycosylation misc targeted therapy misc secretome misc drug resistance misc cancer misc Medicine misc R misc Science misc Q misc Biology (General)
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title	Multi-targeted therapy resistance via drug-induced secretome fucosylation
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title_full	Multi-targeted therapy resistance via drug-induced secretome fucosylation
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author_browse	Mark Borris D Aldonza Junghwa Cha Insung Yong Jayoung Ku Pavel Sinitcyn Dabin Lee Ryeong-Eun Cho Roben D Delos Reyes Dongwook Kim Soyeon Kim Minjeong Kang Yongsuk Ku Geonho Park Hye-Jin Sung Han Suk Ryu Sukki Cho Tae Min Kim Pilnam Kim Je-Yoel Cho Yoosik Kim
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title_sort	multi-targeted therapy resistance via drug-induced secretome fucosylation
callnumber	QH301-705.5
title_auth	Multi-targeted therapy resistance via drug-induced secretome fucosylation
abstract	Cancer secretome is a reservoir for aberrant glycosylation. How therapies alter this post- translational cancer hallmark and the consequences thereof remain elusive. Here, we show that an elevated secretome fucosylation is a pan-cancer signature of both response and resistance to multiple targeted therapies. Large-scale pharmacogenomics revealed that fucosylation genes display widespread association with resistance to these therapies. In cancer cell cultures, xenograft mouse models, and patients, targeted kinase inhibitors distinctively induced core fucosylation of secreted proteins less than 60 kDa. Label-free proteomics of N-glycoproteomes identified fucosylation of the antioxidant PON1 as a critical component of the therapy-induced secretome (TIS). N-glycosylation of TIS and target core fucosylation of PON1 are mediated by the fucose salvage-FUT8-SLC35C1 axis with PON3 directly modulating GDP-Fuc transfer on PON1 scaffolds. Core fucosylation in the Golgi impacts PON1 stability and folding prior to secretion, promoting a more degradation-resistant PON1. Global and PON1-specific secretome de-N-glycosylation both limited the expansion of resistant clones in a tumor regression model. We defined the resistance-associated transcription factors (TFs) and genes modulated by the N-glycosylated TIS via a focused and transcriptome-wide analyses. These genes characterize the oxidative stress, inflammatory niche, and unfolded protein response as important factors for this modulation. Our findings demonstrate that core fucosylation is a common modification indirectly induced by targeted therapies that paradoxically promotes resistance.
abstractGer	Cancer secretome is a reservoir for aberrant glycosylation. How therapies alter this post- translational cancer hallmark and the consequences thereof remain elusive. Here, we show that an elevated secretome fucosylation is a pan-cancer signature of both response and resistance to multiple targeted therapies. Large-scale pharmacogenomics revealed that fucosylation genes display widespread association with resistance to these therapies. In cancer cell cultures, xenograft mouse models, and patients, targeted kinase inhibitors distinctively induced core fucosylation of secreted proteins less than 60 kDa. Label-free proteomics of N-glycoproteomes identified fucosylation of the antioxidant PON1 as a critical component of the therapy-induced secretome (TIS). N-glycosylation of TIS and target core fucosylation of PON1 are mediated by the fucose salvage-FUT8-SLC35C1 axis with PON3 directly modulating GDP-Fuc transfer on PON1 scaffolds. Core fucosylation in the Golgi impacts PON1 stability and folding prior to secretion, promoting a more degradation-resistant PON1. Global and PON1-specific secretome de-N-glycosylation both limited the expansion of resistant clones in a tumor regression model. We defined the resistance-associated transcription factors (TFs) and genes modulated by the N-glycosylated TIS via a focused and transcriptome-wide analyses. These genes characterize the oxidative stress, inflammatory niche, and unfolded protein response as important factors for this modulation. Our findings demonstrate that core fucosylation is a common modification indirectly induced by targeted therapies that paradoxically promotes resistance.
abstract_unstemmed	Cancer secretome is a reservoir for aberrant glycosylation. How therapies alter this post- translational cancer hallmark and the consequences thereof remain elusive. Here, we show that an elevated secretome fucosylation is a pan-cancer signature of both response and resistance to multiple targeted therapies. Large-scale pharmacogenomics revealed that fucosylation genes display widespread association with resistance to these therapies. In cancer cell cultures, xenograft mouse models, and patients, targeted kinase inhibitors distinctively induced core fucosylation of secreted proteins less than 60 kDa. Label-free proteomics of N-glycoproteomes identified fucosylation of the antioxidant PON1 as a critical component of the therapy-induced secretome (TIS). N-glycosylation of TIS and target core fucosylation of PON1 are mediated by the fucose salvage-FUT8-SLC35C1 axis with PON3 directly modulating GDP-Fuc transfer on PON1 scaffolds. Core fucosylation in the Golgi impacts PON1 stability and folding prior to secretion, promoting a more degradation-resistant PON1. Global and PON1-specific secretome de-N-glycosylation both limited the expansion of resistant clones in a tumor regression model. We defined the resistance-associated transcription factors (TFs) and genes modulated by the N-glycosylated TIS via a focused and transcriptome-wide analyses. These genes characterize the oxidative stress, inflammatory niche, and unfolded protein response as important factors for this modulation. Our findings demonstrate that core fucosylation is a common modification indirectly induced by targeted therapies that paradoxically promotes resistance.
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title_short	Multi-targeted therapy resistance via drug-induced secretome fucosylation
url	https://doi.org/10.7554/eLife.75191 https://doaj.org/article/04cffef7074f4c568c8aa2b97115d57f https://elifesciences.org/articles/75191 https://doaj.org/toc/2050-084X
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author2	Junghwa Cha Insung Yong Jayoung Ku Pavel Sinitcyn Dabin Lee Ryeong-Eun Cho Roben D Delos Reyes Dongwook Kim Soyeon Kim Minjeong Kang Yongsuk Ku Geonho Park Hye-Jin Sung Han Suk Ryu Sukki Cho Tae Min Kim Pilnam Kim Je-Yoel Cho Yoosik Kim
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Multi-targeted therapy resistance via drug-induced secretome fucosylation

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