C/EBPb Modulates Macrophages and Tumor-Initiating Cells During Preneoplastic Prog

描述(申请人提供)：炎症已经成为肿瘤微环境的一个重要组成部分，这是肿瘤进展所必需的。浸润性炎症细胞，包括肿瘤相关巨噬细胞(TAMs)，已被证明促进乳腺癌细胞的侵袭，并与转移和不良预后相关。然而，由于缺乏合适的模型来研究癌前进展，对巨噬细胞向肿瘤微环境募集的调节机制及其在肿瘤启动中的作用知之甚少。对癌前病变(导管原位癌)和浸润性乳腺癌的基因图谱研究都导致了不同亚型的分类，这在很大程度上决定了患者的预后。有人提出，不同的乳腺癌亚型包含不同的癌症干细胞群(肿瘤启动细胞，TICS)，它们在利基环境中相互作用，促进恶性进展。这些抽搐已经被证明是耐辐射和耐化疗的，并被认为有助于疾病的复发。拟议研究的长期研究目标是阐明启动致癌事件，诱导促炎环境，从而有利于癌前病变进展为浸润性癌症。这项建议的直接目标是描述TICS和TAM之间促进肿瘤发生和发展的相互作用，以及C/EBP2如何介导这些相互作用。本文验证的具体假设是，C/EBP2诱导关键的炎性细胞因子和趋化因子，这些细胞因子和趋化因子介导了抽动，并在癌前进展过程中对TAMs的招募至关重要。拟议的研究将利用两种不同的新的癌前小鼠模型来剖析这些复杂的相互作用。据此，提出了以下目标： 具体目标1：确定C/EBP2-LIP是否是癌前进展和肿瘤发生所必需的。 特定目的2：通过CCl_2的诱导，确定C/EBP_2-LIP是否对在癌前病变中的招募是必需的。 具体目的3：确定C/EBP2-LIP是否通过IL-6信号调节TIC的自我更新，以及TAMs是否是TIC活动所必需的。 本研究将利用小鼠和人类可诱导的癌前病变模型，研究C/EBP2-LIP在癌前病变进展过程中的作用，并研究癌前微环境中TAMS和TICS之间的相互作用。完成这些目标将增强我们对肿瘤前进展过程中利基微环境中调节抽搐的分子机制的理解，这将是设计选择性靶向治疗耐药抽搐的新疗法的关键。

DESCRIPTION (provided by applicant): Inflammation has emerged as a critical component of the tumor microenvironment that is required for tumor progression. Infiltrating inflammatory cells, including tumor-associated macrophages (TAMs), have been shown to promote breast cancer cell invasion and have been correlated with metastasis and poor prognosis. However, very little is known about the mechanisms regulating macrophage recruitment to the tumor microenvironment, and their role in tumor initiation due to a lack of suitable models to study preneoplastic progression. Gene profiling studies of both pre-malignant DCIS (ductal carcinoma in situ) and invasive breast cancer have resulted in the classification of various subtypes, which largely dictate patient outcome. It has been proposed that different breast cancer subtypes contain distinct cancer stem cell populations (tumor- initiating cells, TICs), which interact within a niche environment to enhance malignant progression. These TICs have been shown to be radio- and chemo-resistant, and are postulated to contribute to disease recurrence. The long-term research goal of the proposed studies is to elucidate the initiating oncogenic events that induce a pro-inflammatory environment, which is conducive for preneoplastic progression to invasive cancer. The immediate objective of this proposal is to delineate the interactions between TICs and TAMs that promote tumor initiation and progression, and how C/EBP2 mediates these interactions. The specific hypothesis tested herein is that C/EBP2 induces key inflammatory cytokines and chemokines that mediate TICs and are critical for the recruitment of TAMs during preneoplastic progression. The proposed studies will utilize two different novel preneoplastic mouse models to dissect these complex interactions. Accordingly, the following aims are proposed: Specific Aim 1: To determine whether C/EBP2-LIP is required for preneoplastic progression and tumorigenesis. Specific Aim 2: To determine whether C/EBP2-LIP is essential for TAM recruitment to preneoplastic lesions through the induction of CCL2. Specific Aim 3: To determine whether C/EBP2-LIP regulates TIC self-renewal through IL-6 signaling, and whether TAMs are required for TIC activity. The proposed studies will utilize both mouse and human inducible preneoplastic models to study the role of C/EBP2-LIP in TAM recruitment during preneoplastic progression, and to characterize the interactions between TAMs and TICs in the premalignant microenvironment. Completing these goals will enhance our understanding of the molecular mechanisms that regulate TICs in the niche microenvironment during preneoplastic progression, which will be critical for devising new treatments that selectively target therapy-resistant TICs.