A new Neu-a syngeneic model of spontaneously metastatic HER2-positive breast cancer.

IF 4.2 3区 医学 Q2 ONCOLOGY
Clinical & Experimental Metastasis Pub Date : 2024-10-01 Epub Date: 2024-05-08 DOI:10.1007/s10585-024-10289-z
Aaron G Baugh, Edgar Gonzalez, Valerie H Narumi, Jesse Kreger, Yingtong Liu, Christine Rafie, Sofi Castanon, Julie Jang, Luciane T Kagohara, Dimitra P Anastasiadou, James Leatherman, Todd Armstrong, Isaac Chan, George S Karagiannis, Elizabeth M Jaffee, Adam MacLean, Evanthia T Roussos Torres
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Abstract

Metastatic disease results from the dissemination of tumor cells beyond their organ of origin to grow in distant organs and is the primary cause of death in patients with advanced breast cancer. Preclinical murine models in which primary tumors spontaneously metastasize are valuable tools for studying metastatic progression and novel cancer treatment combinations. Here, we characterize a novel syngeneic murine breast tumor cell line that provides a model of spontaneously metastatic neu-expressing breast cancer with quicker onset of widespread metastases after orthotopic mammary implantation in immune-competent NeuN mice. The NT2.5-lung metastasis (-LM) cell line was derived from serial passaging of tumor cells that were macro-dissected from spontaneous lung metastases after orthotopic mammary implantation of parental NT2.5 cells. Within one week of NT2.5-LM implantation, metastases are observed in the lungs. Within four weeks, metastases are also observed in the bones, spleen, colon, and liver. We demonstrate that NT2.5-LM metastases are positive for NeuN-the murine equivalent of human epidermal growth factor 2 (HER2). We further demonstrate altered expression of markers of epithelial-to-mesenchymal transition (EMT), suggestive of their enhanced metastatic potential. Genomic analyses support these findings and reveal enrichment in EMT-regulating pathways. In addition, the metastases are rapidly growing, proliferative, and responsive to HER2-directed therapy. The new NT2.5-LM model provides certain advantages over the parental NT2/NT2.5 model, given its more rapid and spontaneous development of metastases. Besides investigating mechanisms of metastatic progression, this new model may be used for the rationalized development of novel therapeutic interventions and assessment of therapeutic responses.

Abstract Image

自发转移性 HER2 阳性乳腺癌的新型 Neu-a 合成模型。
转移性疾病是由于肿瘤细胞扩散到原发器官之外,在远处器官生长,是晚期乳腺癌患者死亡的主要原因。原发性肿瘤自发转移的临床前小鼠模型是研究转移进展和新型癌症治疗组合的宝贵工具。在这里,我们描述了一种新型合成小鼠乳腺肿瘤细胞系的特征,该细胞系提供了一种自发转移的神经表达乳腺癌模型,在免疫功能正常的 NeuN 小鼠乳腺正位植入后,可较快地发生广泛转移。NT2.5-肺转移(-LM)细胞系是在亲代NT2.5细胞乳腺正位植入后,从自发性肺转移瘤中宏切分的肿瘤细胞连续传代得到的。在 NT2.5-LM 植入一周内,肺部就会出现转移灶。四周内,骨骼、脾脏、结肠和肝脏也出现转移。我们证明,NT2.5-LM 转移瘤的 NeuN(相当于鼠类的人类表皮生长因子 2(HER2))呈阳性。我们进一步证明了上皮细胞向间质转化(EMT)标志物表达的改变,这表明它们的转移潜力增强了。基因组分析支持这些发现,并揭示了 EMT 调节通路的富集。此外,这些转移瘤生长迅速、增殖旺盛,并对 HER2 导向疗法有反应。与亲代NT2/NT2.5模型相比,新的NT2.5-LM模型具有一定的优势,因为它的转移灶发展更快、更自发。除了研究转移进展的机制外,这种新模型还可用于合理开发新型治疗干预措施和评估治疗反应。
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来源期刊
CiteScore
7.80
自引率
5.00%
发文量
55
审稿时长
12 months
期刊介绍: The Journal''s scope encompasses all aspects of metastasis research, whether laboratory-based, experimental or clinical and therapeutic. It covers such areas as molecular biology, pharmacology, tumor biology, and clinical cancer treatment (with all its subdivisions of surgery, chemotherapy and radio-therapy as well as pathology and epidemiology) insofar as these disciplines are concerned with the Journal''s core subject of metastasis formation, prevention and treatment.
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