Mechanisms promoting the transition to invasive cancer

项目总结 临床和流行病学证据表明，约40%的导管原位癌(DCIS)患者 如果不进行治疗，将发展为浸润性乳腺癌。然而，由于我们无法区分将 从那些将无限期保持非侵袭性的癌症进展到浸润性癌症，所有DCIS患者都得到了治疗 手术加或不加放射治疗。不幸的是，人们对入侵前DCIS细胞是如何 获得入侵邻近基质的能力，而基质如何影响局部入侵还没有 已经研究过了。拟议的研究旨在确定浸润性巨噬细胞之间的分子相互作用。 和侵袭前上皮细胞，并揭示在早期促进肿瘤发展的机制 损伤。中心假设是不同的巨噬细胞群促进向侵袭性转化 肿瘤和Ax1介导的侵袭依赖于转录因子C/EBPβ。这一假设将是 通过以下目标进行测试：目标1：在体内跟踪巨噬细胞从侵袭前到 浸润性癌症。目的2：研究早期病变中巨噬细胞的异质性。目标3：确定 C/EBPβ诱导的侵袭前细胞中的AxL是否需要在早期病变中进行局部侵袭。我们的 研究将利用几种小鼠模型和双光子显微镜来揭示局限化的机制 入侵。意义：拟议的研究将确定DCIS细胞增殖和/或 侵袭基底膜，并定义间质如何促进侵袭性癌症的进展， 解决癌前疾病领域的主要知识空白。

PROJECT SUMMARY Clinical and epidemiological evidence suggests that ~40% of patients with ductal carcinoma in situ (DCIS) left untreated will progress to invasive breast cancer. However, due to our inability to distinguish lesions that will progress to invasive cancer from those that will remain non-invasive indefinitely, all DCIS patients are treated with surgery with or without radiation. Unfortunately, very little is known about how pre-invasive DCIS cells acquire the ability to invade the adjacent stroma, and how the stroma influences localized invasion has not been studied. The proposed studies aim to define the molecular interactions between infiltrating macrophages and pre-invasive epithelial cells, and uncover the mechanisms that promote tumor development in early stage lesions. The central hypothesis is that distinct macrophage populations promote the transition to invasive cancer and that Axl-mediated invasion is dependent on the transcription factor C/EBPβ. This hypothesis will be tested by the following aims: Aim 1: To track macrophages in vivo during the transition from pre-invasive to invasive cancer. Aim 2: To characterize macrophage heterogeneity in early stage lesions. Aim 3: To determine whether C/EBPβ-induced Axl in pre-invasive cells is required for localized invasion in early stage lesions. Our studies will utilize several mouse models and 2-photon microscopy to uncover the mechanism of localized invasion. Significance: The proposed studies will identify a mechanism by which DCIS cells proliferate and/or invade the basement membrane, and define how the stroma promotes progression to invasive cancer, addressing major knowledge gaps in the field of premalignancy.