MYC失调和PTEN缺失模型对侵袭性三阴性乳腺癌的肿瘤和基质异质性进行建模。
MYC Deregulation and PTEN Loss Model Tumor and Stromal Heterogeneity of Aggressive Triple-Negative Breast Cancer.
发表日期：2023 Sep 13
作者：
Zinab O Doha, Xiaoyan Wang, Nicholas L Calistri, Jennifer Eng, Colin J Daniel, Luke Ternes, Eun Na Kim, Carl Pelz, Michael Munks, Courtney Betts, Sunjong Kwon, Elmar Bucher, Xi Li, Trent Waugh, Zuzana Tatarova, Dylan Blumberg, Aaron Ko, Nell Kirchberger, Jennifer A Pietenpol, Melinda E Sanders, Ellen M Langer, Mu-Shui Dai, Gordon Mills, Koei Chin, Young Hwan Chang, Lisa M Coussens, Joe W Gray, Laura M Heiser, Rosalie C Sears
来源：
BIOMEDICINE & PHARMACOTHERAPY
摘要：
三阴性乳腺癌（TNBC）患者预后不良且治疗选择有限。TNBC的小鼠模型对于开发新的治疗方案非常重要，然而很少有小鼠模型能够代表TNBC的复杂性。在这里，我们通过模拟具有高共存率的两种常见TNBC突变：致癌基因MYC扩增和肿瘤抑制因子PTEN缺失，开发了一个雌性TNBC小鼠模型。这个Myc;Ptenfl模型形成了具有组织学和分子特征的多样性三阴性乳腺肿瘤，这些特征通常在人类TNBC中发现。我们的研究对Myc;Ptenfl肿瘤进行了深入的分子和空间分析，包括批量和单细胞RNA测序以及多重组织成像。通过与人类TNBC进行比较，我们证明了这个基因小鼠模型发展出的乳腺肿瘤具有与人类TNBC的肿瘤内和肿瘤间以及微环境异质性密切相似的不同存活和治疗反应，为评估患者TNBC生物学和药物反应的范围提供了一个临床前工具。© 2023. Springer Nature Limited.
Triple-negative breast cancer (TNBC) patients have a poor prognosis and few treatment options. Mouse models of TNBC are important for development of new therapies, however, few mouse models represent the complexity of TNBC. Here, we develop a female TNBC murine model by mimicking two common TNBC mutations with high co-occurrence: amplification of the oncogene MYC and deletion of the tumor suppressor PTEN. This Myc;Ptenfl model develops heterogeneous triple-negative mammary tumors that display histological and molecular features commonly found in human TNBC. Our research involves deep molecular and spatial analyses on Myc;Ptenfl tumors including bulk and single-cell RNA-sequencing, and multiplex tissue-imaging. Through comparison with human TNBC, we demonstrate that this genetic mouse model develops mammary tumors with differential survival and therapeutic responses that closely resemble the inter- and intra-tumoral and microenvironmental heterogeneity of human TNBC, providing a pre-clinical tool for assessing the spectrum of patient TNBC biology and drug response.© 2023. Springer Nature Limited.