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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2023-03-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/75191 |
| _version_ | 1797848763023228928 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Mark Borris D Aldonza |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T18:33:39Z |
| format | Article |
| id | doaj.art-04cffef7074f4c568c8aa2b97115d57f |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-09T18:33:39Z |
| publishDate | 2023-03-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-04cffef7074f4c568c8aa2b97115d57f2023-04-11T15:37:29ZengeLife Sciences Publications LtdeLife2050-084X2023-03-011210.7554/eLife.75191Multi-targeted therapy resistance via drug-induced secretome fucosylationMark Borris D Aldonza0https://orcid.org/0000-0002-0771-129XJunghwa Cha1Insung Yong2https://orcid.org/0000-0002-7828-4264Jayoung Ku3https://orcid.org/0000-0002-4112-4582Pavel Sinitcyn4https://orcid.org/0000-0002-2653-1702Dabin Lee5Ryeong-Eun Cho6Roben D Delos Reyes7https://orcid.org/0000-0003-1368-6817Dongwook Kim8Soyeon Kim9Minjeong Kang10Yongsuk Ku11Geonho Park12Hye-Jin Sung13Han Suk Ryu14Sukki Cho15Tae Min Kim16Pilnam Kim17https://orcid.org/0000-0002-5592-4599Je-Yoel Cho18Yoosik Kim19https://orcid.org/0000-0003-3064-4643Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea; Department of Biological Sciences, KAIST, Daejeon, Republic of Korea; Department of Biochemistry, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea; Comparative Medicine Disease Research Center (CDRC), Seoul National University, Seoul, Republic of Korea; BK21 PLUS Program for Creative Veterinary Science Research and Research Institute for Veterinary Science, Seoul National University, Seoul, Republic of KoreaDepartment of Bio and Brain Engineering, KAIST, Daejeon, Republic of KoreaDepartment of Bio and Brain Engineering, KAIST, Daejeon, Republic of KoreaDepartment of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of KoreaComputational Systems Biochemistry Research Group, Max Planck Institute of Biochemistry, Martinsried, GermanyComparative Medicine Disease Research Center (CDRC), Seoul National University, Seoul, Republic of Korea; BK21 PLUS Program for Creative Veterinary Science Research and Research Institute for Veterinary Science, Seoul National University, Seoul, Republic of KoreaDepartment of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of KoreaDepartment of Electrical Engineering, KAIST, Daejeon, Republic of KoreaDepartment of Biochemistry, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea; BK21 PLUS Program for Creative Veterinary Science Research and Research Institute for Veterinary Science, Seoul National University, Seoul, Republic of KoreaDepartment of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of KoreaDepartment of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of KoreaDepartment of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of KoreaDepartment of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of KoreaDepartment of Biochemistry, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea; BK21 PLUS Program for Creative Veterinary Science Research and Research Institute for Veterinary Science, Seoul National University, Seoul, Republic of KoreaDepartment of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of KoreaDepartment of Thoracic and Cardiovascular Surgery, Seoul National University Bundang Hospital, Seongnam, Republic of KoreaDepartment of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of KoreaDepartment of Bio and Brain Engineering, KAIST, Daejeon, Republic of Korea; KAIST Institute for Health Science and Technology (KIHST), KAIST, Daejeon, Republic of KoreaDepartment of Biochemistry, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea; Comparative Medicine Disease Research Center (CDRC), Seoul National University, Seoul, Republic of Korea; BK21 PLUS Program for Creative Veterinary Science Research and Research Institute for Veterinary Science, Seoul National University, Seoul, Republic of KoreaDepartment of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea; KAIST Institute for Health Science and Technology (KIHST), KAIST, Daejeon, Republic of Korea; KAIST Institute for BioCentury (KIB), KAIST, Daejeon, Republic of Korea; BioProcess Engineering Research Center and Bioinformatics Research Center, KAIST, Daejeon, Republic of KoreaCancer 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.https://elifesciences.org/articles/75191fucosylationn-linked glycosylationtargeted therapysecretomedrug resistancecancer |
| spellingShingle | 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 Multi-targeted therapy resistance via drug-induced secretome fucosylation eLife fucosylation n-linked glycosylation targeted therapy secretome drug resistance cancer |
| title | Multi-targeted therapy resistance via drug-induced secretome fucosylation |
| title_full | Multi-targeted therapy resistance via drug-induced secretome fucosylation |
| title_fullStr | Multi-targeted therapy resistance via drug-induced secretome fucosylation |
| title_full_unstemmed | Multi-targeted therapy resistance via drug-induced secretome fucosylation |
| title_short | Multi-targeted therapy resistance via drug-induced secretome fucosylation |
| title_sort | multi targeted therapy resistance via drug induced secretome fucosylation |
| topic | fucosylation n-linked glycosylation targeted therapy secretome drug resistance cancer |
| url | https://elifesciences.org/articles/75191 |
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