The MMTV-Wnt1 murine model produces two phenotypically distinct subtypes of mammary tumors with unique therapeutic responses to an EGFR inhibitor
The MMTV-Wnt1 murine model produces two phenotypically distinct subtypes of mammary tumors with unique therapeutic responses to an EGFR inhibitor
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DOI：
10.1242/dmm.037192
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发表时间：
2019-07-01
影响因子：
4.3
通讯作者：
Perout, Charles M.
中科院分区：
文献类型：
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作者：
Pfefferle, Adam D.;Darr, David B.;Perout, Charles M.
Wnt基因家族编码调节细胞生长、分化和干细胞自我更新的进化上保守的蛋白质组。人类乳腺肿瘤中的异常Wnt信号传导已被认为是肿瘤发生的驱动因素，特别是在基底样肿瘤亚型中，其中经典Wnt信号传导既富集又预测不良临床结果。然而，由于对这些畸变影响乳腺肿瘤发生的背景依赖性的理解有限，有效的基于Wnt的治疗方法的开发已经放缓。我们以前报道过，MMTV-Wnt 1小鼠，一种研究乳腺肿瘤中Wnt信号传导的既定模型，通过基因表达分类发展了两种肿瘤亚型：Wnt 1-早期（Ex）和Wnt 1-晚期（Ex）。在这里，我们扩展了这一初步观察，并表明Wnt 1-早期（Ex）肿瘤表现出典型Wnt，非典型Wnt和EGFR信号通路签名的高表达。在治疗上，当用EGFR抑制剂治疗时，Wnt 1-早期（Ex）肿瘤显示肿瘤体积的动态减小。Wnt 1-早期（Ex）肿瘤主要具有Cd 49 f（pos）/Epcam（neg）FACS特征，但不可能将这些肿瘤连续移植到野生型FVB雌性小鼠中。相反，Wnt 1-晚期（Ex）肿瘤具有血性大体病理学，其通过H&E染色鉴定的“血湖”的存在而突出显示。这些肿瘤主要具有Cd 49 f（pos）/Epcam（pos）FACS特征，但也含有次要Cd 49 f（pos）/Epcam（neg）亚群。Wnt 1-晚期（Ex）肿瘤富含激活Hras 1突变，并且当连续移植到野生型FVB雌性小鼠中时能够复制肿瘤。这项研究明确表明，MMTV-Wnt 1小鼠模型产生了两种表型不同的乳腺肿瘤亚型，它们在多个生物学方面存在差异，包括对EGFR抑制剂的敏感性。
The Wnt gene family encodes an evolutionarily conserved group of proteins that regulate cell growth, differentiation and stem cell self-renewal. Aberrant Wnt signaling in human breast tumors has been proposed as a driver of tumorigenesis, especially in the basal-like tumor subtype where canonical Wnt signaling is both enriched and predictive of poor clinical outcomes. The development of effective Wnt-based therapeutics, however, has been slowed in part by a limited understanding of the context-dependent nature with which these aberrations influence breast tumorigenesis. We previously reported that MMTV-Wnt1 mice, an established model for studying Wnt signaling in breast tumors, develop two subtypes of tumors by gene expression classification: Wnt1-Early(Ex) and Wnt1-Late(Ex). Here, we extend this initial observation and show that Wnt1-Early(Ex) tumors exhibit high expression of canonical Wnt, non-canonical Wnt, and EGFR signaling pathway signatures. Therapeutically, Wnt1-Early(Ex) tumors showed a dynamic reduction in tumor volume when treated with an EGFR inhibitor. Wnt1-Early(Ex) tumors had primarily Cd49f(pos)/Epcam(neg) FACS profiles, but it was not possible to serially transplant these tumors into wild-type FVB female mice. Conversely, Wnt1-Late(Ex) tumors had a bloody gross pathology, which was highlighted by the presence of 'blood lakes' identified by H&E staining. These tumors had primarily Cd49f(pos)/Epcam(pos) FACS profiles, but also contained a secondary Cd49f(pos)/Epcam(neg) subpopulation. Wnt1-Late(Ex) tumors were enriched for activating Hras1 mutations and were capable of reproducing tumors when serially transplanted into wild-type FVB female mice. This study definitively shows that the MMTV-Wnt1 mouse model produces two phenotypically distinct subtypes of mammary tumors that differ in multiple biological aspects including sensitivity to an EGFR inhibitor.