The role of macrophages in triple-negative breast cancer invasion and metastasis

巨噬细胞在三阴性乳腺癌侵袭和转移中的作用

• 批准号: 8982958
• 负责人: Daniel Christopher Rabe
• 金额: $ 4.31万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-29 至 2017-09-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8982958
• 关键词: Biological Markers; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; Breast cancer metastasis; Cell membrane; Diagnosis; Diagnostic; Drug resistance; Equilibrium; Human; Inflammatory; Lead; Link; Metastatic to; Nature; Neoplasm Metastasis; Outcome; Patients; Phenotype; Population; Prognostic Marker; Progranulin; Proteins; Proteomics; RANTES; RNA; Recruitment Activity; Relapse; Risk Factors; Role; Signal Transduction; Surface; Testing; Therapeutic; Time; Tumor Subtype; Tumor-Derived; Woman; Work; Xenograft procedure; aggressive therapy; in vivo; innovation; macrophage; malignant breast neoplasm; neoplastic cell; novel; novel diagnostics; prognostic; public health relevance; raf Kinases; receptor; targeted treatment; therapeutic target; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment

 DESCRIPTION (provided by applicant): Women with triple-negative breast cancer (TNBC), the most aggressive subtype of breast cancer, have the shortest survival times and the highest rate of relapse. These patients have no currently available forms of targeted therapy and most (~77%) succumb to metastases within 5 years. However, the nature of how metastasis relies on signaling from the tumor microenvironment is not well understood. Macrophages have also been linked to human breast cancer invasion and metastasis as well as drug resistance, and recently have been implicated in TNBC. M1-like pro-inflammatory macrophages are thought suppress tumor growth and metastasis, whereas the tumor-associated macrophages (TAMs) are characterized as M2-like pro-metastatic macrophages. However, recent proteomic and RNA studies indicate that macrophage populations are composed of more phenotypic subtypes than previously recognized. Thus, the phenotype of TNBC TAMs and the mechanisms by which they interact with TNBCs are not well understood and require further characterization. In recent studies I have been testing the hypothesis that TNBC recruits a unique subtype of TAMs via CCL5 that drives invasion and metastasis. Using genetically matched metastatic and non-metastatic TNBC tumors that differ only by expression of the metastasis suppressor Raf Kinase Inhibitory Protein (RKIP), I show that RKIP alters not only the number of recruited TAMs but also their phenotype. I further demonstrate that CCL5 expressed by metastatic tumors recruits TAMs that secrete pro-metastatic factors, promote invasion of TNBC cells, are highly expressed in human TNBC patients, and contribute to a prognostic signature for patient survival. Taken together, these findings suggest that TNBC recruited TAMs are both phenotypically and functionally distinct from other TAMs, and M1 or M2 macrophages. I now propose to test the hypothesis that these TAMs can be distinguished by unique surface receptors that regulate expression and secretion of pro-metastatic factors. I further propose that TAMs recruited by CCL5 to metastatic TNBCs drive metastasis through expression of GRN along with other associated factors. Specifically, I will: 1) Characterize the phenotype of pro-metastatic TAMs in TNBC; and 2) Determine the functional role of TAMs & TAM secreted factors in TNBC metastasis. This study is innovative because it seeks to understand the phenotype of a novel TAM subtype identified in TNBC, as well as the in vivo mechanism of TAM driven invasion in TNBC. Together, these results could generate new diagnostic markers and prognostic signatures as well as identify potential therapeutic targets to deplete or reprogram pro-metastatic TAMs in TNBC patients. This work should also lead to a better understanding of the role of TAMs in the poor outcomes of TNBC patients.

 描述（由申请人提供）：患有三阴性乳腺癌（TNBC）的女性是乳腺癌中最具侵袭性的亚型，其生存时间最短，复发率最高。这些患者目前没有可用的靶向治疗，大多数（约 77%）在 5 年内死于转移。然而，转移如何依赖于肿瘤微环境信号传导的本质尚不清楚。 巨噬细胞还与人类乳腺癌的侵袭和转移以及耐药性有关，最近还与 TNBC 有关。 M1 样促炎巨噬细胞被认为可抑制肿瘤生长和转移，而肿瘤相关巨噬细胞 (TAM) 则被认为是 M2 样促转移巨噬细胞。然而，最近的蛋白质组学和 RNA 研究表明，巨噬细胞群由比之前认识到的更多的表型亚型组成。因此，TNBC TAM 的表型及其与 TNBC 相互作用的机制尚不清楚，需要进一步表征。 在最近的研究中，我一直在检验这样的假设：TNBC 通过 CCL5 招募一种独特的 TAM 亚型来驱动侵袭和转移。使用基因匹配的转移性和非转移性 TNBC 肿瘤（其差异仅在于转移抑制因子 Raf 激酶抑制蛋白 (RKIP) 的表达），我发现 RKIP 不仅改变了招募的 TAM 的数量，还改变了它们的表型。我进一步证明，转移性肿瘤表达的 CCL5 会招募 TAM，分泌促转移因子，促进 TNBC 细胞的侵袭，在人类 TNBC 患者中高表达，并有助于患者生存的预后特征。总而言之，这些发现表明 TNBC 招募的 TAM 在表型和功能上都与其他 TAM 以及 M1 或 M2 巨噬细胞不同。 我现在提议检验以下假设：这些 TAM 可以通过调节促转移因子表达和分泌的独特表面受体来区分。我进一步提出，CCL5 将 TAM 招募到转移性 TNBC 中，通过 GRN 以及其他相关因子的表达来驱动转移。具体来说，我将： 1）表征 TNBC 中促转移 TAM 的表型； 2) 确定 TAM 和 TAM 分泌因子在 TNBC 转移中的功能作用。这项研究具有创新性，因为它旨在了解 TNBC 中发现的新型 TAM 亚型的表型，以及 TAM 驱动 TNBC 侵袭的体内机制。总之，这些结果可以产生新的诊断标志物和预后特征，并确定潜在的治疗靶点，以消除或重新编程 TNBC 患者的促转移 TAM。这项工作还应该有助于更好地理解 TAM 在 TNBC 患者不良预后中的作用。