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FOXD1-dependent RalA-ANXA2-Src complex promotes CTC formation in breast cancer

BACKGROUND: Early metastasis is a key factor contributing to poor breast cancer (BC) prognosis. Circulating tumor cells (CTCs) are regarded as the precursor cells of metastasis, which are ultimately responsible for the main cause of death in BC. However, to date molecular mechanisms underlying CTC f...

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Autores principales: Long, Yufei, Chong, Tuotuo, Lyu, Xiaoming, Chen, Lujia, Luo, Xiaomin, Faleti, Oluwasijibomi Damola, Deng, Simin, Wang, Fei, He, Mingliang, Qian, Zhipeng, Zhao, Hongli, Zhou, Wenyan, Guo, Xia, Chen, Ceshi, Li, Xin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9558416/
https://www.ncbi.nlm.nih.gov/pubmed/36229838
http://dx.doi.org/10.1186/s13046-022-02504-0
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author Long, Yufei
Chong, Tuotuo
Lyu, Xiaoming
Chen, Lujia
Luo, Xiaomin
Faleti, Oluwasijibomi Damola
Deng, Simin
Wang, Fei
He, Mingliang
Qian, Zhipeng
Zhao, Hongli
Zhou, Wenyan
Guo, Xia
Chen, Ceshi
Li, Xin
author_facet Long, Yufei
Chong, Tuotuo
Lyu, Xiaoming
Chen, Lujia
Luo, Xiaomin
Faleti, Oluwasijibomi Damola
Deng, Simin
Wang, Fei
He, Mingliang
Qian, Zhipeng
Zhao, Hongli
Zhou, Wenyan
Guo, Xia
Chen, Ceshi
Li, Xin
author_sort Long, Yufei
collection PubMed
description BACKGROUND: Early metastasis is a key factor contributing to poor breast cancer (BC) prognosis. Circulating tumor cells (CTCs) are regarded as the precursor cells of metastasis, which are ultimately responsible for the main cause of death in BC. However, to date molecular mechanisms underlying CTC formation in BC have been insufficiently defined. METHODS: RNA-seq was carried out in primary tissues from early-stage BC patients (with CTCs≥5 and CTCs = 0, respectively) and the validation study was conducted in untreated 80 BC patients. Multiple in vitro and in vivo models were used in functional studies. Luciferase reporter, ChIP-seq, CUT&Tag-seq, and GST-pulldown, etc. were utilized in mechanistic studies. CTCs were counted by the CanPatrol™ CTC classification system or LiquidBiospy™ microfluidic chips. ERK1/2 inhibitor SCH772984 was applied to in vivo treatment. RESULTS: Highly expressed FOXD1 of primary BC tissues was observed to be significantly associated with increased CTCs in BC patients, particularly in early BC patients. Overexpressing FOXD1 enhanced the migration capability of BC cells, CTC formation and BC metastasis, via facilitating epithelial-mesenchymal transition of tumor cells. Mechanistically, FOXD1 was discovered to induce RalA expression by directly bound to RalA promotor. Then, RalA formed a complex with ANXA2 and Src, promoting the interaction between ANXA2 and Src, thus increasing the phosphorylation (Tyr23) of ANXA2. Inhibiting RalA-GTP form attenuated the interaction between ANXA2 and Src. This cascade culminated in the activation of ERK1/2 signal that enhanced metastatic ability of BC cells. In addition, in vivo treatment with SCH772984, a specific inhibitor of ERK1/2, was used to dramatically inhibit the CTC formation and BC metastasis. CONCLUSION: Here, we report a FOXD1-dependent RalA-ANXA2-Src complex that promotes CTC formation via activating ERK1/2 signal in BC. FOXD1 may serve as a prognostic factor in evaluation of BC metastasis risks. This signaling cascade is druggable and effective for overcoming CTC formation from the early stages of BC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-022-02504-0.
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spelling pubmed-95584162022-10-14 FOXD1-dependent RalA-ANXA2-Src complex promotes CTC formation in breast cancer Long, Yufei Chong, Tuotuo Lyu, Xiaoming Chen, Lujia Luo, Xiaomin Faleti, Oluwasijibomi Damola Deng, Simin Wang, Fei He, Mingliang Qian, Zhipeng Zhao, Hongli Zhou, Wenyan Guo, Xia Chen, Ceshi Li, Xin J Exp Clin Cancer Res Research BACKGROUND: Early metastasis is a key factor contributing to poor breast cancer (BC) prognosis. Circulating tumor cells (CTCs) are regarded as the precursor cells of metastasis, which are ultimately responsible for the main cause of death in BC. However, to date molecular mechanisms underlying CTC formation in BC have been insufficiently defined. METHODS: RNA-seq was carried out in primary tissues from early-stage BC patients (with CTCs≥5 and CTCs = 0, respectively) and the validation study was conducted in untreated 80 BC patients. Multiple in vitro and in vivo models were used in functional studies. Luciferase reporter, ChIP-seq, CUT&Tag-seq, and GST-pulldown, etc. were utilized in mechanistic studies. CTCs were counted by the CanPatrol™ CTC classification system or LiquidBiospy™ microfluidic chips. ERK1/2 inhibitor SCH772984 was applied to in vivo treatment. RESULTS: Highly expressed FOXD1 of primary BC tissues was observed to be significantly associated with increased CTCs in BC patients, particularly in early BC patients. Overexpressing FOXD1 enhanced the migration capability of BC cells, CTC formation and BC metastasis, via facilitating epithelial-mesenchymal transition of tumor cells. Mechanistically, FOXD1 was discovered to induce RalA expression by directly bound to RalA promotor. Then, RalA formed a complex with ANXA2 and Src, promoting the interaction between ANXA2 and Src, thus increasing the phosphorylation (Tyr23) of ANXA2. Inhibiting RalA-GTP form attenuated the interaction between ANXA2 and Src. This cascade culminated in the activation of ERK1/2 signal that enhanced metastatic ability of BC cells. In addition, in vivo treatment with SCH772984, a specific inhibitor of ERK1/2, was used to dramatically inhibit the CTC formation and BC metastasis. CONCLUSION: Here, we report a FOXD1-dependent RalA-ANXA2-Src complex that promotes CTC formation via activating ERK1/2 signal in BC. FOXD1 may serve as a prognostic factor in evaluation of BC metastasis risks. This signaling cascade is druggable and effective for overcoming CTC formation from the early stages of BC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-022-02504-0. BioMed Central 2022-10-13 /pmc/articles/PMC9558416/ /pubmed/36229838 http://dx.doi.org/10.1186/s13046-022-02504-0 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Long, Yufei
Chong, Tuotuo
Lyu, Xiaoming
Chen, Lujia
Luo, Xiaomin
Faleti, Oluwasijibomi Damola
Deng, Simin
Wang, Fei
He, Mingliang
Qian, Zhipeng
Zhao, Hongli
Zhou, Wenyan
Guo, Xia
Chen, Ceshi
Li, Xin
FOXD1-dependent RalA-ANXA2-Src complex promotes CTC formation in breast cancer
title FOXD1-dependent RalA-ANXA2-Src complex promotes CTC formation in breast cancer
title_full FOXD1-dependent RalA-ANXA2-Src complex promotes CTC formation in breast cancer
title_fullStr FOXD1-dependent RalA-ANXA2-Src complex promotes CTC formation in breast cancer
title_full_unstemmed FOXD1-dependent RalA-ANXA2-Src complex promotes CTC formation in breast cancer
title_short FOXD1-dependent RalA-ANXA2-Src complex promotes CTC formation in breast cancer
title_sort foxd1-dependent rala-anxa2-src complex promotes ctc formation in breast cancer
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9558416/
https://www.ncbi.nlm.nih.gov/pubmed/36229838
http://dx.doi.org/10.1186/s13046-022-02504-0
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