An engineered niche delineates metastatic potential of breast cancer.
An engineered niche delineates metastatic potential of breast cancer.
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DOI：
10.1002/btm2.10606
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发表时间：
2024-01
影响因子：
7.4
通讯作者：
中科院分区：
文献类型：
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转移性乳腺癌通常在继发性肿瘤变得肉眼可见并且数百万肿瘤细胞侵入远处组织之前无法诊断。然而，转移是由一系列导致转移前小生境形成的事件引发的，这可能先于肿瘤形成数年。我们旨在使用姐妹细胞系4T1（转移性）、4T07（侵袭性，非转移性）和67 NR（非转移性）在早期区分三阴性乳腺癌的转移性疾病和非转移性疾病的可能性。我们使用了一种多孔的聚己内酯支架，作为一个工程转移小生境，通过微环境的特征来识别转移性疾病。对支架上免疫细胞组成的分析能够区分非侵袭性67NR荷瘤小鼠与4T07和4T1荷瘤小鼠，但无法描述两种侵袭性细胞系之间的转移潜力。支架中的基因表达与癌症标志物的上调相关（例如，血管生成、缺氧）。我们开发了一种9基因签名（Dhx9，Dusp12，Fth1，Ifitm1，Ndufs1，Pja 2，Slc1a3，Soga 1，Spon2），成功区分了4T1疾病与67 NR或4T07疾病的转移进展。此外，该特征被证明在转移性乳腺癌的小鼠模型和肺癌的人类模型的公开可用数据集中区分患病肺是非常有效的。早期和准确地检测转移性疾病，可能导致早期治疗，有可能改善患者的预后和生活质量。
Metastatic breast cancer is often not diagnosed until secondary tumors have become macroscopically visible and millions of tumor cells have invaded distant tissues. Yet, metastasis is initiated by a cascade of events leading to formation of the pre‐metastatic niche, which can precede tumor formation by a matter of years. We aimed to distinguish the potential for metastatic disease from nonmetastatic disease at early times in triple‐negative breast cancer using sister cell lines 4T1 (metastatic), 4T07 (invasive, nonmetastatic), and 67NR (nonmetastatic). We used a porous, polycaprolactone scaffold, that serves as an engineered metastatic niche, to identify metastatic disease through the characteristics of the microenvironment. Analysis of the immune cell composition at the scaffold was able to distinguish noninvasive 67NR tumor‐bearing mice from 4T07 and 4T1 tumor‐bearing mice but could not delineate metastatic potential between the two invasive cell lines. Gene expression in the scaffolds correlated with the up‐regulation of cancer hallmarks (e.g., angiogenesis, hypoxia) in the 4T1 mice relative to 4T07 mice. We developed a 9‐gene signature (Dhx9, Dusp12, Fth1, Ifitm1, Ndufs1, Pja2, Slc1a3, Soga1, Spon2) that successfully distinguished 4T1 disease from 67NR or 4T07 disease throughout metastatic progression. Furthermore, this signature proved highly effective at distinguishing diseased lungs in publicly available datasets of mouse models of metastatic breast cancer and in human models of lung cancer. The early and accurate detection of metastatic disease that could lead to early treatment has the potential to improve patient outcomes and quality of life.
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