Helicase-like转录因子(HLTF)，也被称为SMARCA3，保护基因组完整性。HLTF是一种肿瘤抑制因子，在早期结直肠癌(CRC)中，它在肿瘤细胞中表达，但不在肿瘤微环境(TME)中表达。随着疾病的发展，HLTF在CRC细胞中被表观遗传沉默，而在TME中HLTF的表达几乎不可忽略。我们开发了一种细胞系衍生的异种移植模型(CDX)，并首次显示出在癌细胞和TME中删除HLTF会导致代谢重编程，以缓解淋巴内血管转移座位的氧化应激。两个从葡萄糖-糖酵解和氧化磷酸化(OXPHOS)中获取能量的代谢途径，会根据TME的不同而被癌细胞各不相同地利用。通过RNA测序和空间转录组学研究，我们排除了HIF-1α这个糖酵解的主要调节因子在重编程代谢以满足CDX的能量需求中的作用。还排除了肠道微生物群的可变性对代谢变化的作用。HLTF被删除的癌细胞在转录组水平上恢复了DNA损伤，与肿瘤边界的变形虫相关表型的调节DNA修复和OXPHOS基因 (共聚焦显微镜)。HLTF被删除的癌细胞和TME中的淋巴内血管内皮细胞(PDPN)共享特定位点的蛋白质S-谷胱甘肽化标记 (2D DIGE, MALDI-TOF/TOF质谱)表现为三个糖酵解酶 (PGK1 Cys379/380, PGAM1 Cys55, ENOA1 Cys119) 改变了糖酵解以支持持续的谷胱甘肽生物合成。通过HLTF / Hltf的集体缺失促进了CDX中的氧化还原稳态，并促进了转移。版权所有：© 2023年Martinez-Marin等人。这是一篇以合作方式发布的开源文章，依据创作共用许可证条款，允许在任何媒介中进行不受限制的使用、传播和复制，只要原始作者和来源被标明。

Helicase-like transcription factor (HLTF) also known as SMARCA3, protects genome integrity. A tumor suppressor, HLTF is expressed in tumor cells but not in the tumor microenvironment (TME) in early-stage colorectal cancer (CRC). With disease progression, there is high concordance between epigenetic silencing of HLTF in CRC cells and negligible HLTF expression in the TME. We developed a cell line-derived xenograft (CDX) model and show for the first time that HLTF-deletion in cancer cells and the TME results in metabolic reprogramming that mitigates oxidative stress in lymphatic intravascular metastatic niches. The two metabolic pathways that derive energy from glucose-glycolysis and oxidative phosphorylation (OXPHOS)-are variously utilized by cancer cells depending upon the TME. HIF-1α, a master regulator of glycolysis, was eliminated from a role in reprogramming metabolism to satisfy CDX energetic requirements by RNAseq and spatial transcriptomics. Variability in the gut microbiome, with a putative role in altered metabolism, was also eliminated. HLTF-deleted cancer cells recovered from DNA damage at a transcriptomic level induction of DNA repair and OXPHOS genes linked to an amoeboid-associated phenotype at the tumor border (confocal microscopy). HLTF-deleted cancer and endothelial cells of lymphatic (PDPN) intravascular niches in the TME shared a site-specific protein S-glutathionylation signature (2D DIGE, MALDI-TOF/TOF mass spectrometry) for three glycolytic enzymes (PGK1 Cys379/380, PGAM1 Cys55, ENOA1 Cys119) that diverted glycolysis in support of continued glutathione biosynthesis. The collective absence of HLTF/Hltf from tumor and TME achieved redox homeostasis throughout the CDX and promoted metastasis.Copyright: © 2023 Martinez-Marin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.