Regulation of breast cancer progression by FAK expression in tumor macrophages

描述（由申请人提供）：实体瘤的生长和转移扩散受肿瘤细胞、周围基质中的免疫细胞和成纤维细胞、细胞外基质成分、可溶性生长因子和细胞因子发出的信号控制。虽然这种复杂性为治疗干预带来了挑战，但它也提供了独特的机会，可以利用许多不同的细胞和分子靶点来控制肿瘤的生长和进展。本提案的重点是聚焦黏附激酶（FAK），一种蛋白酪氨酸激酶，其表达在许多晚期癌症中显著增加，包括乳腺癌。我们假设FAK在肿瘤微环境的两个组成部分，肿瘤细胞和肿瘤相关巨噬细胞（tam）中的表达在促进乳腺肿瘤的进展和转移中起关键作用。我们将使用乳腺癌小鼠模型来了解FAK在乳腺癌细胞和/或辅助肿瘤相关巨噬细胞中的表达如何控制原发性乳腺肿瘤的生长和转移扩散。通过将这些小鼠的基因操作与目前处于I期临床试验的FAK抑制剂相结合，我们提出：1)确定巨噬细胞中FAK表达的缺失如何改变或削弱驱动乳腺肿瘤生长/进展和转移的巨噬细胞功能（目的1）；2)评估乳腺肿瘤细胞和肿瘤相关巨噬细胞中FAK表达的双重调节如何改变乳腺肿瘤的生长和转移（Aim 2A）；3)评估FAK表达的系统性抑制如何改变乳腺肿瘤的生长和转移（Aim 2B）。这项研究的成功完成将为肿瘤的特征提供新的见解，这些特征可以预测目前正在临床试验中的fak靶向药物的临床反应，以及这些治疗的最佳时机。在更广泛的范围内，我们将了解肿瘤细胞和肿瘤微环境中的其他细胞通过交流促进乳腺肿瘤生长和转移的机制。我们预计这项工作将有助于将乳腺癌治疗模式从肿瘤细胞本身转向促进肿瘤生长和转移的所有因素。公共卫生相关性：通过关注FAK在巨噬细胞和肿瘤细胞中的作用，本工作将揭示巨噬细胞-肿瘤细胞协同作用的新特征，这些特征有助于乳腺癌肿瘤行为。除了提供FAK抑制剂如何用于治疗乳腺癌患者的关键信息外，这项工作还将潜在地确定针对肿瘤内不同细胞区室的新策略，这些策略可以用于治疗控制肿瘤的生长和进展。预计，通过从这些研究中获得的知识，将大大降低乳腺癌的死亡率。

DESCRIPTION (provided by applicant): The growth and metastatic spread of solid tumors is controlled by signals emanating from tumor cells as well as by immune cells and fibroblasts in the surrounding stroma, components of the extracellular matrix, and soluble growth factors and cytokines. While this complexity creates challenges for therapeutic intervention, it also provides unique opportunities by making available a number of distinct cellular and molecular targets that can be exploited to control tumor growth and progression. The focus of this proposal is on Focal Adhesion Kinase (FAK), a protein tyrosine kinase whose expression is significantly increased in many late-stage cancers, including breast cancer. We hypothesize that FAK expression in two components of the tumor microenvironment, the tumor cells and tumor-associated macrophages (TAMs), plays a critical role in promoting breast tumor progression and metastasis. We will use mouse models of breast cancer to gain an understanding of how FAK expression in breast carcinoma cells and/or the ancillary tumor-associated macrophages controls primary breast tumor growth and metastatic spread. By combining genetic manipulation of these mice with FAK inhibitors currently in Phase I clinical trials, we propose to 1) determine how the loss of FAK expression in macrophages alters or ablates macrophage functions that drive breast tumor growth/progression and metastasis (Aim 1); 2) assess how the dual modulation of FAK expression in breast tumor cells and in tumor-associated macrophages alters breast tumor growth and metastasis (Aim 2A); and 3) assess how systemic inhibition of FAK expression alters breast tumor growth and metastasis (Aim 2B). Successful completion of this study will provide new insights into features of the tumor that can predict a clinical response to the FAK-targeted drugs currently in clinical trials and the optimal timing for these treatments. More globally, we will learn about mechanisms through which tumor cells and other cells within the tumor microenvironment communicate to promote breast tumor growth and metastasis. We anticipate that this work will help to move the paradigm for breast cancer treatment away from the tumor cells per se and toward the full complement of factors that contribute to tumor growth and metastasis. PUBLIC HEALTH RELEVANCE: By focusing on the role of FAK in both macrophages and tumor cells, this work will uncover novel features of macrophage - tumor cell synergy that contribute to breast tumor behaviors. In addition to providing critical information about how FAK inhibitors should be used to treat breast cancer patients, this work will potentially identify new strategies for targeting distinct cellular compartments within the tumor that can be exploited therapeutically to control tumor growth and progression. It is anticipated that, through the knowledge gained from these studies, there will be a significant reduction in mortality from breast cancer.