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

 描述（由申请人提供）：三阴性乳腺癌（TNBC）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形式，大多数（约77%）在5年内死于转移。然而，转移如何依赖于来自肿瘤微环境的信号传导的性质还没有很好地理解。 巨噬细胞还与人乳腺癌侵袭和转移以及耐药性有关，最近已与TNBC有关。M1样促炎性巨噬细胞被认为抑制肿瘤生长和转移，而肿瘤相关巨噬细胞（TAM）被表征为M2样促转移性巨噬细胞。然而，最近的蛋白质组学和RNA研究表明，巨噬细胞群体是由更多的表型亚型比以前认识到的。因此，TNBC TAM的表型和它们与TNBC相互作用的机制尚未得到很好的理解，需要进一步表征。 在最近的研究中，我一直在测试TNBC通过CCL 5招募一种独特的TAM亚型的假设，这种亚型驱动侵袭和转移。使用基因匹配的转移性和非转移性TNBC肿瘤，不同的只是通过表达的转移抑制Raf激酶抑制蛋白（RKIP），我表明，RKIP不仅改变了招募的TAM的数量，但他们的表型。我进一步证明，由转移性肿瘤表达的CCL 5招募分泌促转移因子的TAM，促进TNBC细胞的侵袭，在人类TNBC患者中高度表达，并有助于患者生存的预后特征。总之，这些发现表明TNBC募集的TAM在表型和功能上均不同于其他TAM以及M1或M2巨噬细胞。 我现在建议测试的假设，这些TAM可以区分独特的表面受体，调节促转移因子的表达和分泌。我进一步提出，由CCL 5募集到转移性TNBC的TAM通过GRN沿着其他相关因子的表达来驱动转移。具体而言，我将：1）表征TNBC中促转移性TAM的表型;和2）确定TAM和TAM分泌因子在TNBC转移中的功能作用。这项研究是创新的，因为它试图了解TNBC中鉴定的新TAM亚型的表型，以及TNBC中TAM驱动侵袭的体内机制。总之，这些结果可以产生新的诊断标志物和预后特征，以及确定潜在的治疗靶点，以消除或重新编程TNBC患者中的促转移性TAM。这项工作也应该导致更好地理解TAM在TNBC患者不良结局中的作用。

 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.