Orchestrated desaturation reprogramming from stearoyl‐CoA desaturase to fatty acid desaturase 2 in cancer epithelial‐mesenchymal transition and metastasis
Abstract Background Adaptative desaturation in fatty acid (FA) is an emerging hallmark of cancer metabolic plasticity. Desaturases such as stearoyl‐CoA desaturase (SCD) and fatty acid desaturase 2 (FADS2) have been implicated in multiple cancers, and their dominant and compensatory effects have rece...
Saved in:
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-03-01
|
| Series: | Cancer Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/cac2.12644 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850067246386249728 |
|---|---|
| author | Zhicong Chen Yanqing Gong Fukai Chen Hyeon Jeong Lee Jinqin Qian Jing Zhao Wenpeng Zhang Yamin Li Yihui Zhou Qiaobing Xu Yu Xia Liqun Zhou Ji‐Xin Cheng |
| author_facet | Zhicong Chen Yanqing Gong Fukai Chen Hyeon Jeong Lee Jinqin Qian Jing Zhao Wenpeng Zhang Yamin Li Yihui Zhou Qiaobing Xu Yu Xia Liqun Zhou Ji‐Xin Cheng |
| author_sort | Zhicong Chen |
| collection | DOAJ |
| description | Abstract Background Adaptative desaturation in fatty acid (FA) is an emerging hallmark of cancer metabolic plasticity. Desaturases such as stearoyl‐CoA desaturase (SCD) and fatty acid desaturase 2 (FADS2) have been implicated in multiple cancers, and their dominant and compensatory effects have recently been highlighted. However, how tumors initiate and sustain their self‐sufficient FA desaturation to maintain phenotypic transition remains elusive. This study aimed to explore the molecular orchestration of SCD and FADS2 and their specific reprogramming mechanisms in response to cancer progression. Methods The potential interactions between SCD and FADS2 were explored by bioinformatics analyses across multiple cancer cohorts, which guided subsequent functional and mechanistic investigations. The expression levels of desaturases were investigated with online datasets and validated in both cancer tissues and cell lines. Specific desaturation activities were characterized through various isomer‐resolved lipidomics methods and sensitivity assays using desaturase inhibitors. In‐situ lipid profiling was conducted using multiplex stimulated Raman scattering imaging. Functional assays were performed both in vitro and in vivo, with RNA‐sequencing employed for the mechanism verification. Results After integration of the RNA‐protein‐metabolite levels, the data revealed that a reprogramming from SCD‐dependent to FADS2‐dependent desaturation was linked to cancer epithelial‐mesenchymal transition (EMT) and progression in both patients and cell lines. FADS2 overexpression and SCD suppression concurrently maintained EMT plasticity. A FADS2/β‐catenin self‐reinforcing feedback loop facilitated the degree of lipid unsaturation, membrane fluidity, metastatic potential and EMT signaling. Moreover, SCD inhibition triggered a lethal apoptosis but boosted survival plasticity by inducing EMT and enhancing FA uptake via adenosine monophosphate‐activated protein kinase activation. Notably, this desaturation reprogramming increased transforming growth factor‐β2, effectively sustaining aggressive phenotypes and metabolic plasticity during EMT. Conclusions These findings revealed a metabolic reprogramming from SCD‐dependent to FADS2‐dependent desaturation during cancer EMT and progression, which concurrently supports EMT plasticity. Targeting desaturation reprogramming represents a potential vulnerability for cancer metabolic therapy. |
| format | Article |
| id | doaj-art-e46d2a93ef81452d850337fc2339332f |
| institution | DOAJ |
| issn | 2523-3548 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Communications |
| spelling | doaj-art-e46d2a93ef81452d850337fc2339332f2025-08-20T02:48:24ZengWileyCancer Communications2523-35482025-03-0145324528010.1002/cac2.12644Orchestrated desaturation reprogramming from stearoyl‐CoA desaturase to fatty acid desaturase 2 in cancer epithelial‐mesenchymal transition and metastasisZhicong Chen0Yanqing Gong1Fukai Chen2Hyeon Jeong Lee3Jinqin Qian4Jing Zhao5Wenpeng Zhang6Yamin Li7Yihui Zhou8Qiaobing Xu9Yu Xia10Liqun Zhou11Ji‐Xin Cheng12Department of Obstetrics and Gynecology Center for Reproductive Medicine Guangdong Provincial Key Laboratory of Major Obstetric Diseases Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology Guangdong‐Hong Kong‐Macao Greater Bay Area Higher Education Joint Laboratory of Maternal‐Fetal Medicine The Third Affiliated Hospital Guangzhou Medical University Guangzhou Guangdong P. R. ChinaDepartment of Urology Peking University First Hospital Beijing P. R. ChinaDepartment of Biomedical Engineering Department of Electrical and Computer Engineering Photonics Center Boston University Boston Massachusetts USADepartment of Biomedical Engineering Department of Electrical and Computer Engineering Photonics Center Boston University Boston Massachusetts USADepartment of Urology Peking University First Hospital Beijing P. R. ChinaMOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology Department of Chemistry Tsinghua University Beijing P. R. ChinaState Key Laboratory of Precision Measurement Technology and Instruments Department of Precision Instrument Tsinghua University Beijing P. R. ChinaDepartment of Biomedical Engineering Tufts University Medford Massachusetts USACollege of Biomedical Engineering & Instrument Science Key Laboratory for Biomedical Engineering of Ministry of Education Zhejiang University Hangzhou Zhejiang P. R. ChinaDepartment of Biomedical Engineering Tufts University Medford Massachusetts USAMOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology Department of Chemistry Tsinghua University Beijing P. R. ChinaDepartment of Urology Peking University First Hospital Beijing P. R. ChinaDepartment of Biomedical Engineering Department of Electrical and Computer Engineering Photonics Center Boston University Boston Massachusetts USAAbstract Background Adaptative desaturation in fatty acid (FA) is an emerging hallmark of cancer metabolic plasticity. Desaturases such as stearoyl‐CoA desaturase (SCD) and fatty acid desaturase 2 (FADS2) have been implicated in multiple cancers, and their dominant and compensatory effects have recently been highlighted. However, how tumors initiate and sustain their self‐sufficient FA desaturation to maintain phenotypic transition remains elusive. This study aimed to explore the molecular orchestration of SCD and FADS2 and their specific reprogramming mechanisms in response to cancer progression. Methods The potential interactions between SCD and FADS2 were explored by bioinformatics analyses across multiple cancer cohorts, which guided subsequent functional and mechanistic investigations. The expression levels of desaturases were investigated with online datasets and validated in both cancer tissues and cell lines. Specific desaturation activities were characterized through various isomer‐resolved lipidomics methods and sensitivity assays using desaturase inhibitors. In‐situ lipid profiling was conducted using multiplex stimulated Raman scattering imaging. Functional assays were performed both in vitro and in vivo, with RNA‐sequencing employed for the mechanism verification. Results After integration of the RNA‐protein‐metabolite levels, the data revealed that a reprogramming from SCD‐dependent to FADS2‐dependent desaturation was linked to cancer epithelial‐mesenchymal transition (EMT) and progression in both patients and cell lines. FADS2 overexpression and SCD suppression concurrently maintained EMT plasticity. A FADS2/β‐catenin self‐reinforcing feedback loop facilitated the degree of lipid unsaturation, membrane fluidity, metastatic potential and EMT signaling. Moreover, SCD inhibition triggered a lethal apoptosis but boosted survival plasticity by inducing EMT and enhancing FA uptake via adenosine monophosphate‐activated protein kinase activation. Notably, this desaturation reprogramming increased transforming growth factor‐β2, effectively sustaining aggressive phenotypes and metabolic plasticity during EMT. Conclusions These findings revealed a metabolic reprogramming from SCD‐dependent to FADS2‐dependent desaturation during cancer EMT and progression, which concurrently supports EMT plasticity. Targeting desaturation reprogramming represents a potential vulnerability for cancer metabolic therapy.https://doi.org/10.1002/cac2.12644metabolic reprogrammingstearoyl‐CoA desaturasefatty acid desaturase 2epithelial‐mesenchymal transitioncancer metastasis |
| spellingShingle | Zhicong Chen Yanqing Gong Fukai Chen Hyeon Jeong Lee Jinqin Qian Jing Zhao Wenpeng Zhang Yamin Li Yihui Zhou Qiaobing Xu Yu Xia Liqun Zhou Ji‐Xin Cheng Orchestrated desaturation reprogramming from stearoyl‐CoA desaturase to fatty acid desaturase 2 in cancer epithelial‐mesenchymal transition and metastasis Cancer Communications metabolic reprogramming stearoyl‐CoA desaturase fatty acid desaturase 2 epithelial‐mesenchymal transition cancer metastasis |
| title | Orchestrated desaturation reprogramming from stearoyl‐CoA desaturase to fatty acid desaturase 2 in cancer epithelial‐mesenchymal transition and metastasis |
| title_full | Orchestrated desaturation reprogramming from stearoyl‐CoA desaturase to fatty acid desaturase 2 in cancer epithelial‐mesenchymal transition and metastasis |
| title_fullStr | Orchestrated desaturation reprogramming from stearoyl‐CoA desaturase to fatty acid desaturase 2 in cancer epithelial‐mesenchymal transition and metastasis |
| title_full_unstemmed | Orchestrated desaturation reprogramming from stearoyl‐CoA desaturase to fatty acid desaturase 2 in cancer epithelial‐mesenchymal transition and metastasis |
| title_short | Orchestrated desaturation reprogramming from stearoyl‐CoA desaturase to fatty acid desaturase 2 in cancer epithelial‐mesenchymal transition and metastasis |
| title_sort | orchestrated desaturation reprogramming from stearoyl coa desaturase to fatty acid desaturase 2 in cancer epithelial mesenchymal transition and metastasis |
| topic | metabolic reprogramming stearoyl‐CoA desaturase fatty acid desaturase 2 epithelial‐mesenchymal transition cancer metastasis |
| url | https://doi.org/10.1002/cac2.12644 |
| work_keys_str_mv | AT zhicongchen orchestrateddesaturationreprogrammingfromstearoylcoadesaturasetofattyaciddesaturase2incancerepithelialmesenchymaltransitionandmetastasis AT yanqinggong orchestrateddesaturationreprogrammingfromstearoylcoadesaturasetofattyaciddesaturase2incancerepithelialmesenchymaltransitionandmetastasis AT fukaichen orchestrateddesaturationreprogrammingfromstearoylcoadesaturasetofattyaciddesaturase2incancerepithelialmesenchymaltransitionandmetastasis AT hyeonjeonglee orchestrateddesaturationreprogrammingfromstearoylcoadesaturasetofattyaciddesaturase2incancerepithelialmesenchymaltransitionandmetastasis AT jinqinqian orchestrateddesaturationreprogrammingfromstearoylcoadesaturasetofattyaciddesaturase2incancerepithelialmesenchymaltransitionandmetastasis AT jingzhao orchestrateddesaturationreprogrammingfromstearoylcoadesaturasetofattyaciddesaturase2incancerepithelialmesenchymaltransitionandmetastasis AT wenpengzhang orchestrateddesaturationreprogrammingfromstearoylcoadesaturasetofattyaciddesaturase2incancerepithelialmesenchymaltransitionandmetastasis AT yaminli orchestrateddesaturationreprogrammingfromstearoylcoadesaturasetofattyaciddesaturase2incancerepithelialmesenchymaltransitionandmetastasis AT yihuizhou orchestrateddesaturationreprogrammingfromstearoylcoadesaturasetofattyaciddesaturase2incancerepithelialmesenchymaltransitionandmetastasis AT qiaobingxu orchestrateddesaturationreprogrammingfromstearoylcoadesaturasetofattyaciddesaturase2incancerepithelialmesenchymaltransitionandmetastasis AT yuxia orchestrateddesaturationreprogrammingfromstearoylcoadesaturasetofattyaciddesaturase2incancerepithelialmesenchymaltransitionandmetastasis AT liqunzhou orchestrateddesaturationreprogrammingfromstearoylcoadesaturasetofattyaciddesaturase2incancerepithelialmesenchymaltransitionandmetastasis AT jixincheng orchestrateddesaturationreprogrammingfromstearoylcoadesaturasetofattyaciddesaturase2incancerepithelialmesenchymaltransitionandmetastasis |