Roles of neutrophils in c-Met mediated breast cancer brain metastases

大多数癌症死亡归因于转移性疾病，并且脑是转移性疾病的主要部位之一。 乳腺肿瘤转移即使采用立体定向放射外科（SRS）等先进治疗， 发生脑转移的乳腺癌患者的中位生存期不到一年。无论 尽管脑转移瘤具有高度的临床意义，但其病理机制仍不清楚。我们 最近发现（i）c-Met信号能够诱导一组炎性基因的表达， 在脑转移病灶中N2中性粒细胞的产生中起关键作用，（ii）N2中性粒细胞促进 癌症干细胞样细胞的自我更新和抑制T细胞介导的免疫监视和（iii）BBB 渗透性天然化合物PTER通过选择性靶向c-Met抑制脑转移。这些 新的发现使我们假设（i）c-Met促进脑转移和对肿瘤细胞的耐药性。 通过产生N2中性粒细胞的放射治疗，和（ii）N2中性粒细胞反过来增强癌症的自我更新 干细胞样细胞和促进局部免疫抑制。我们还假设，蝶芪（PTER），一个血脑屏障， 渗透性天然化合物通过抑制c-抑制放射治疗后的脑转移和复发 Met信号传导，从而减少N2中性粒细胞的量。为了验证这些假设，我们将（i） 研究c-Met诱导的中性粒细胞调节因子（NRFs）如何调节脑中的中性粒细胞活性 转移病灶（Aim 1），（ii）破译N2中性粒细胞促进肿瘤进展的机制 和放射抗性（目标2），和（iii）测试PTER在抑制BrM和SRS后复发中的功效 在体内（目标3）。该项目具有很强的创新性。首先，我们建立了最先进的系统生物学 筛选方法，并发现c-Met的过度表达与患者发生 脑转移，并与诱导NRFs，促进表型变化， 转移部位的中性粒细胞。因此，该项目的结果将揭示新的病理学 癌症分泌因子调节中性粒细胞如何促进脑转移的机制。 其次，N2中性粒细胞促进肿瘤进展和放射性的确切反馈机制， 对抵抗的了解很少。我们建议破译肿瘤之间相互作用的途径， 细胞，N2中性粒细胞和T细胞在大脑微环境中，我们相信这将导致一个发现， 靶向N2中性粒细胞的新治疗方法。最后，我们将研究BBB的潜在效用- 作为治疗剂和放射增敏剂用于治疗脑的渗透性天然化合物PTER 转移如果我们的假设得到证实，这项工作有可能成为一种新的范式， 显著改善乳腺癌的治疗和预防。

The majority of cancer death is attributed to metastatic disease, and the brain is one of the major sites of breast tumor metastasis. Even with the advanced treatment such as stereotactic radiosurgery (SRS), the median survival of breast cancer patients who developed brain metastases is less than a year. Regardless of high clinical significance, the pathological mechanism of brain metastasis is still poorly understood. We recently found that (i) c-Met signaling is able to induce the expression of a group of inflammatory genes which play critical roles in the generation of N2 neutrophils in the brain metastatic lesions, (ii) N2 neutrophils promote the self-renewal of cancer stem-like cells and suppress T cell mediated immune surveillance and (iii) the BBB permeable natural compound, PTER, suppresses brain metastasis by selectively targeting the c-Met. These novel and discoveries led us to hypothesize that (i) c-Met promotes brain metastasis and resistance to the radiation therapy by generating N2 neutrophils, and (ii) N2 neutrophils in turn enhance self-renewal of cancer stem-like cells and promote local immune suppression. We also hypothesize that pterostilbene (PTER), a BBB permeable natural compound suppresses brain metastasis and relapse after radio-therapy by suppressing c- Met signaling and thereby reducing the amount of N2 neutrophils. To test these hypotheses, we will (i) investigate how c-Met-induced neutrophil regulatory factors (NRFs) modulate neutrophil activities in the brain metastatic lesions (Aim1), (ii) decipher the mechanisms by which N2 neutrophils promote tumor progression and radio-resistance (Aim 2), and (iii) test the efficacy of PTER in suppressing BrM and post-SRS recurrence in vivo (Aim 3). The project is highly innovative. First, we have established a state-of-the-art system biology screening approach and found that overexpression of c-Met is strongly correlated with patients who developed brain metastasis and it is associated with an induction of NRFs which promotes phenotypic changes of neutrophils in metastatic sites. Therefore, the outcome of this project will reveal novel pathological mechanisms of how neutrophil modulation by cancer-secreted factors contributes to the brain metastasis. Secondly, the exact feed-back mechanism by which N2 neutrophils promote tumor progression and radio- resistance is poorly understood. We propose to decipher the pathway of reciprocal interaction between tumor cells, N2 neutrophils and T-cells in the brain microenvironment, which we believe will lead to a discovery of novel therapeutic approaches to target N2 neutrophils. Finally, we will examine the potential utility of the BBB- permeable natural compound, PTER, as a therapeutic agent and a radiosensitizer agent for treating brain metastasis. If our hypotheses are borne out, this work has the potential to be a novel paradigm that could significantly improve the treatment and prevention of breast cancer.