Kinase signaling during mammary tumor initiation

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。这种过度治疗的困境要求个性化患者的需求 基于预测哪些患者将进展的生物标志物的护理。不幸的是，人们对此知之甚少 侵袭前DCIS细胞如何获得侵袭邻近间质的能力，以及间质如何影响 局部侵袭还没有被研究过。拟议的研究旨在定义分子间的相互作用 在渗透的巨噬细胞和侵袭前的上皮细胞之间，并揭示促进 早期病变中的肿瘤发展。使用独特的临床前早期进展模型，我们表明 巨噬细胞被招募到具有高肿瘤形成潜力的侵袭前病变，极化为 促肿瘤表型，并分泌细胞因子Gas6。我们假设巨噬细胞招募到 侵袭前病变以依赖于Gas6的方式诱导细胞存活和局部侵袭。这一假设 将通过以下目标进行测试：目标1：确定Axl在乳腺肿瘤中的致癌潜力 入会仪式。目的2：阐明旁分泌、自分泌和配体非依赖的Axl信号在脑内的作用。 早期病变。目的3：破译Axl转录调控机制，鉴定Gas6- 依赖的促肿瘤途径。我们的研究将利用几种小鼠模型，一种独特的异种移植 DCIS进展模型和异型3-D培养系统解剖Gas6介导的巨噬细胞- 上皮性相声。意义：拟议的研究将确定DCIS细胞的一种机制 增殖和/或侵入基底膜，并确定基质如何促进进展到 侵袭性癌症，解决癌前领域的主要知识空白。最近的研究表明 癌细胞的扩散早在癌前阶段就发生了，这就要求有必要 了解早期病变中细胞迁移和侵袭的机制。最后，Gas6和Axl拥有 在一些癌症中与总体存活率和治疗抵抗力差有关。我们的发现将 显著推进DCIS生物学和早期乳腺癌进展领域。

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. This overtreatment dilemma demands the need for individualized patient care based on biomarkers that predict which patients will progress. 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. Using unique preclinical models of early progression, we show that macrophages are recruited to pre-invasive lesions that have a high tumor-forming potential, polarized toward a pro-tumorigenic phenotype, and secrete the cytokine Gas6. We hypothesize that macrophages recruited to pre-invasive lesions induce cell survival and localized invasion in a Gas6-dependent manner. This hypothesis will be tested by the following aims: Aim 1: To define the oncogenic potential of Axl during mammary tumor initiation. Aim 2: To delineate the contribution of paracrine, autocrine and ligand-independent Axl signaling in early stage lesions. Aim 3: To decipher Axl transcriptional regulatory mechanisms, and identify Gas6- dependent tumor-promoting pathways. Our studies will utilize several mouse models, a unique xenograft model of DCIS progression, and a heterotypic 3-D culture system to dissect Gas6-mediated macrophage- epithelial crosstalk. 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. Recent studies suggest that the dissemination of cancer cells occurs as early as the premalignant stage, which begs the need to understand the mechanisms of cell migration and invasion in early stage lesions. Finally, Gas6 and Axl have been correlated with poor overall survival and therapy resistance in a number of cancers. Our findings will significantly advance the fields of DCIS biology and early stage breast cancer progression.