KLF4-mediated myeloid plasticity in breast cancer recurrence

乳腺癌患者有非常高的复发率或从休眠后复发， 手术或免疫疗法。人们对什么调节休眠缺乏了解， 这一领域急需转化研究。因此，新的细胞类型的表征和细胞的生物学特性是重要的。 肿瘤复发的潜在信号分子可能揭示最佳治疗靶点， 预防/治疗乳腺癌休眠复发。在细胞水平上，我们认为一种特定类型的 一种叫做纤维细胞的骨髓源性细胞抑制乳腺癌的休眠。这项建议是 数据显示：（1）。纤维细胞促进小鼠转移性肿瘤生长 黑色素瘤模型。2）。纤维细胞通过免疫逃避促进肿瘤进展。3）。纤维细胞 具有产生成纤维细胞的能力，成纤维细胞是支持高级别细胞生长的主要类型的基质细胞。 乳腺癌在分子水平上，我们提出一种名为Kruppel样因子4（KLF 4）的核蛋白， 在调节乳腺癌休眠中对纤维细胞的产生至关重要，因为：1）。KLF 4缺乏 在小鼠乳腺癌模型中， 转移这伴随着纤维细胞数量的减少。2）。KLF 4表达水平为 与纤维细胞生成的效率和一种名为 成纤维细胞特异性蛋白1（FSP 1）。高表达的FSP 1与复发性乳腺肿瘤有关。 因此，我们假设纤维细胞促进乳腺癌从休眠状态复发， KLF 4/FSP 1轴依赖性表达。我们设计了以下三个具体目标来测试我们的 假说.在目标1中，我们将从KLF 4缺陷小鼠中分离KLF 4缺陷纤维细胞前体细胞。在 目的2，我们将进行因果关系研究，检测KLF 4缺陷是否在纤维细胞前体细胞中 在两种乳腺癌小鼠模型中导致肿瘤复发减少。在目标3中，我们将建立一个 KLF 4/FSP 1信号传导与乳腺癌复发之间的机制联系。我们预计， 研究将揭示KLF 4控制的纤维细胞在乳腺癌复发中的新功能， 休眠该项目的成功完成将非常有助于确定KLF 4或其 下游分子是延长肿瘤休眠或根除休眠肿瘤的新的治疗靶点 乳腺癌患者体内的细胞。

Breast cancer patients have an anomalously high rate of relapse or recurrence from dormancy after surgery or immunotherapy. There is a major lack of understanding of what regulates dormancy, and basic and translational research is badly needed in this area. Thus, characterization of novel cell types and the underlying signaling molecules in tumor recurrence will likely reveal optimal therapeutic targets to prevent/treat breast cancer recurrence from dormancy. At a cellular level, we propose that a specific type of bone marrow-originated cells known as fibrocytes inhibit breast cancer dormancy. This proposal is supported by published data showing that: 1). fibrocytes promote metastatic tumor growth in a mouse model of melanoma. 2). fibrocytes contribute to tumor progression via immune evasion. 3). fibrocytes possess the ability to generate fibroblasts, a major type of stromal cells supporting growth of high grade breast cancer. At a molecular level, we propose that a nuclear protein named Kruppel like factor 4 (KLF4) is critical to the generation of fibrocytes in regulating breast cancer dormancy because: 1). KLF4 deficiency drastically decreased the tumor growth in the metastatic lung in mouse models of breast cancer metastasis. This was accompanied by decreased numbers of fibrocytes. 2). KLF4 expression levels were tightly associated with the efficiencies of fibrocyte generation and expression levels of a protein named fibroblast-specific protein 1 (FSP1). Highly expressed FSP1 has been linked to recurrent mammary tumors. We thus hypothesize that fibrocytes promote breast cancer recurrence from dormancy in a KLF4/FSP1 axis-dependent manner. We designed the following three specific aims to test our hypothesis. In Aim 1, we will isolate KLF4-deficient fibrocyte precursor cells from KLF4-deficient mice. In Aim 2, we will perform a cause-effect study testing whether KLF4 deficiency in fibrocyte precursor cells leads to reduced tumor recurrence in two mouse models of breast cancer. In Aim 3, we will establish a mechanistic link between the KLF4/FSP1 signaling and breast cancer recurrence. We anticipate that our studies will reveal a novel function of KLF4-controlled fibrocytes in breast cancer recurrence from dormancy. Successful completion of the project will be very helpful to determine whether KLF4 or its downstream molecules is a novel therapeutic target to extend tumor dormancy or eradicate dormant tumor cells in breast cancer patients.