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TWEAK/Fn14 信号驱动的超级增强子重编程促进三阴性乳腺癌的促转移代谢重排。

TWEAK/Fn14 signalling driven super-enhancer reprogramming promotes pro-metastatic metabolic rewiring in triple-negative breast cancer.

机构信息

School of Biological Sciences (SBS), Nanyang Technological University (NTU), 60 Nanyang Drive, Singapore, 637551, Singapore.

Division of Surgery and Surgical Oncology, Department of Breast Surgery, National Cancer Centre Singapore, 30 Hospital Blvd, Singapore, 168583, Singapore.

出版信息

Nat Commun. 2024 Jul 5;15(1):5638. doi: 10.1038/s41467-024-50071-z.

DOI:10.1038/s41467-024-50071-z
PMID:38965263
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11224303/
Abstract

Triple Negative Breast Cancer (TNBC) is the most aggressive breast cancer subtype suffering from limited targeted treatment options. Following recent reports correlating Fibroblast growth factor-inducible 14 (Fn14) receptor overexpression in Estrogen Receptor (ER)-negative breast cancers with metastatic events, we show that Fn14 is specifically overexpressed in TNBC patients and associated with poor survival. We demonstrate that constitutive Fn14 signalling rewires the transcriptomic and epigenomic landscape of TNBC, leading to enhanced tumour growth and metastasis. We further illustrate that such mechanisms activate TNBC-specific super enhancers (SE) to drive the transcriptional activation of cancer dependency genes via chromatin looping. In particular, we uncover the SE-driven upregulation of Nicotinamide phosphoribosyltransferase (NAMPT), which promotes NAD+ and ATP metabolic reprogramming critical for filopodia formation and metastasis. Collectively, our study details the complex mechanistic link between TWEAK/Fn14 signalling and TNBC metastasis, which reveals several vulnerabilities which could be pursued for the targeted treatment of TNBC patients.

摘要

三阴性乳腺癌（TNBC）是侵袭性最强的乳腺癌亚型，其靶向治疗选择有限。最近有报道称，成纤维细胞生长因子诱导因子 14（Fn14）受体在雌激素受体（ER）阴性乳腺癌中的过表达与转移事件相关，我们发现 Fn14 在 TNBC 患者中特异性过表达，并与不良预后相关。我们证明，组成型 Fn14 信号转导重编程了 TNBC 的转录组和表观基因组景观，导致肿瘤生长和转移增强。我们进一步说明，这种机制激活了 TNBC 特异性超级增强子（SE），通过染色质环化驱动癌症依赖性基因的转录激活。特别是，我们揭示了 SE 驱动的烟酰胺磷酸核糖转移酶（NAMPT）的上调，其促进 NAD+和 ATP 代谢重编程，这对丝状伪足的形成和转移至关重要。总之，我们的研究详细阐述了 TWEAK/Fn14 信号与 TNBC 转移之间的复杂机制联系，揭示了几种可能成为 TNBC 患者靶向治疗的靶点的脆弱性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bc1/11224303/504c09b9e9e6/41467_2024_50071_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bc1/11224303/d8f0cab05930/41467_2024_50071_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bc1/11224303/f50c80e5a05e/41467_2024_50071_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bc1/11224303/378c704a76e2/41467_2024_50071_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bc1/11224303/5bfe32f87be4/41467_2024_50071_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bc1/11224303/1442e5688e76/41467_2024_50071_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bc1/11224303/a133b58a53b6/41467_2024_50071_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bc1/11224303/5d8ced582daf/41467_2024_50071_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bc1/11224303/504c09b9e9e6/41467_2024_50071_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bc1/11224303/d8f0cab05930/41467_2024_50071_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bc1/11224303/f50c80e5a05e/41467_2024_50071_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bc1/11224303/378c704a76e2/41467_2024_50071_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bc1/11224303/5bfe32f87be4/41467_2024_50071_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bc1/11224303/1442e5688e76/41467_2024_50071_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bc1/11224303/a133b58a53b6/41467_2024_50071_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bc1/11224303/5d8ced582daf/41467_2024_50071_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bc1/11224303/504c09b9e9e6/41467_2024_50071_Fig8_HTML.jpg

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2
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Nat Biotechnol. 2024 Feb;42(2):293-304. doi: 10.1038/s41587-023-01767-y. Epub 2023 May 25.
3
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烟酰胺磷酸核糖转移酶在NAD代谢中的作用：生理及病理生理意义
Cell Death Discov. 2025 Aug 8;11(1):371. doi: 10.1038/s41420-025-02672-w.
4
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iScience. 2025 May 30;28(7):112714. doi: 10.1016/j.isci.2025.112714. eCollection 2025 Jul 18.
5
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Commun Biol. 2025 Jun 23;8(1):951. doi: 10.1038/s42003-025-08338-8.
6
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Cancer Cell Int. 2025 Apr 10;25(1):139. doi: 10.1186/s12935-025-03769-z.
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4
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5
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6
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7
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8
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9
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10
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