Induced collagen type-I secretion by hepatocytes of the melanoma liver metastasis is associated with a reduction in tumour-infiltrating lymphocytes

IF 7.9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Clinical and Translational Medicine Pub Date : 2024-11-04 DOI:10.1002/ctm2.70067

Shodai Mizuno, Matias A. Bustos, Yoshinori Hayashi, Kodai Abe, Satoru Furuhashi, Yalda Naeini, Xiaowei Xu, Anton J Bilchik, Dave S. B. Hoon

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Abstract

Background

Overall patients with melanoma liver metastasis (MLiM) have a dismal prognosis and poor responses to the standard of care treatment. Understanding the role of the tumour microenvironment (TME) is critical for discovering better strategies to overcome intrinsic therapy resistance in MLiM. The aim was to understand the crosstalk signalling pathways between hepatocytes and metastatic melanoma cells in the TME of MLiM.

Methods

Hepatocytes and melanoma tumour cells of MLiM were assessed using transcriptomic NanoString GeoMx digital spatial profiling (NGDSP) assay. Functional assays were performed using normal hepatocytes and MLiM-derived cell lines. Validation was performed using multiplex immunofluorescence.

Results

In NGDSP analysis adjacent normal hepatocytes (ANH) had higher CXCR4 and COL1A1/2 levels than distant normal hepatocytes (DNH), while melanoma cells had higher TNF-α levels. In vitro, MLiM cell lines released TNF-α which upregulated CXCR4 and CXCL12 levels in ANH. CXCL12 activated CXCR4, which triggered AKT and NFκB signalling pathways. Consequently, AKT signalling induced the upregulation of collagen type I. MLiM were significantly encircled by a shield of collagen, whereas other liver metastases showed reduced levels of collagen. Of all the liver metastasis analyzed, the presence of collagen in melanoma liver metastasis was associated with a reduction in tumour-infiltrating lymphocytes.

Conclusions

MLiM modified ANH to increase collagen production and created a physical barrier. The collagen barrier was associated with a reduction of immune cell infiltration which could potentially deter MLiM immune surveillance and treatment responses.

Highlights

Spatial analyses of melanoma liver metastasis show that adjacent normal hepatocytes have increased collagen-type I levels.
Melanoma liver metastases tumour cells secrete enhanced levels of TNF-α to stimulate CXCR4/CXCL12 upregulation in adjacent normal hepatocytes.
Activation of CXCR4 promotes AKT and NF-κB signalling pathways to promote collagen-type I secretion in adjacent normal hepatocytes.
Elevated collagen levels were associated with reduced tumour-infiltrating lymphocytes

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黑色素瘤肝转移灶肝细胞分泌的诱导型 I 型胶原蛋白与肿瘤浸润淋巴细胞的减少有关。

背景：黑色素瘤肝转移（MLiM）患者的总体预后不佳，对标准疗法的反应也很差。了解肿瘤微环境（TME）的作用对于发现克服黑色素瘤内在耐药性的更好策略至关重要。方法：使用转录组NanoString GeoMx数字空间谱分析（NGDSP）对MLiM的肝细胞和黑色素瘤肿瘤细胞进行评估。使用正常肝细胞和 MLiM 衍生细胞系进行了功能测试。结果：结果：在 NGDSP 分析中，邻近正常肝细胞（ANH）的 CXCR4 和 COL1A1/2 水平高于远处正常肝细胞（DNH），而黑色素瘤细胞的 TNF-α 水平较高。在体外，MLiM 细胞系释放的 TNF-α 上调了 ANH 中的 CXCR4 和 CXCL12 水平。CXCL12 激活了 CXCR4，从而触发了 AKT 和 NFκB 信号通路。因此，AKT 信号诱导了 I 型胶原蛋白的上调。MLiM 明显被胶原蛋白盾包围，而其他肝转移灶的胶原蛋白水平则有所降低。在分析的所有肝转移瘤中，黑色素瘤肝转移瘤中胶原蛋白的存在与肿瘤浸润淋巴细胞的减少有关：结论：MLiM改变了ANH，增加了胶原蛋白的生成，形成了物理屏障。胶原屏障与免疫细胞浸润的减少有关，这有可能阻止 MLiM 的免疫监视和治疗反应：黑色素瘤肝转移瘤的空间分析表明，邻近的正常肝细胞的 I 型胶原蛋白水平升高。黑色素瘤肝转移灶肿瘤细胞分泌更高水平的 TNF-α，刺激邻近正常肝细胞的 CXCR4/CXCL12 上调。CXCR4 的激活会促进 AKT 和 NF-κB 信号通路，从而促进邻近正常肝细胞分泌 I 型胶原蛋白。胶原蛋白水平升高与肿瘤浸润淋巴细胞减少有关。

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.