Kinase signaling during mammary tumor initiation

项目摘要 临床和流行病学证据表明，约40%的导管原位癌（DCIS）患者 如果不治疗，将发展为浸润性乳腺癌。然而，由于我们无法区分病变， 从那些将无限期保持非侵入性的癌症进展到侵入性癌症，所有DCIS患者都接受治疗， 有没有放射治疗的手术这种过度治疗的困境需要个性化的病人 基于生物标志物的护理，预测哪些患者会进展。不幸的是，我们对 浸润前DCIS细胞如何获得侵袭邻近间质的能力，以及间质如何影响 尚未研究局部侵袭。拟议的研究旨在定义分子间的相互作用 之间的浸润巨噬细胞和前浸润上皮细胞，并揭示机制，促进 早期病变的肿瘤发展。使用独特的早期进展的临床前模型，我们表明， 巨噬细胞被募集到具有高肿瘤形成潜力的浸润前病变， 促肿瘤发生表型，并分泌细胞因子Gas 6。我们假设巨噬细胞募集到 侵入前损伤以Gas 6依赖性方式诱导细胞存活和局部侵入。这一假设 目的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性Axl信号转导在肿瘤细胞凋亡中的作用。 早期病变目的3：阐明Axl基因转录调控机制，并鉴定Gas 6- 依赖的肿瘤促进途径。我们的研究将利用几种小鼠模型，一种独特的异种移植物， DCIS进展模型，以及异型3-D培养系统，以解剖Gas 6介导的巨噬细胞- 上皮串扰意义：拟议的研究将确定DCIS细胞 增殖和/或侵入基底膜，并确定基质如何促进进展， 侵袭性癌症，解决了在癌前病变领域的主要知识差距。最近的研究表明， 癌细胞的扩散早在癌前阶段就发生了，这就需要 了解早期病变中细胞迁移和侵袭的机制。最后，Gas 6和Axl 在许多癌症中，它与总体生存率低和治疗耐药性相关。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.