MECHANISMS OF SRC ACTIVATION AND ITS ROLE IN LATENT BONE METASTASIS OF BREAST AND

SRC激活机制及其在乳腺和隐性骨转移中的作用

• 批准号: 8337360
• 负责人: Xiang Zhang
• 金额: $ 24.15万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8337360
• 关键词: Adjuvant Therapy; Affect; Biological; Bone Marrow; Breast; Breast Cancer Cell; CXCL12 gene; Cancer Patient; Cell Survival; Distant; ERBB2 gene; Fibroblasts; Goals; Grant; IGF1 gene; In Vitro; Knowledge; Literature; Lung; Malignant neoplasm of prostate; Mammary Neoplasms; Mediating; Mesenchymal Stem Cells; Metastatic Neoplasm to the Bone; Modeling; Neoplasm Metastasis; Organ; Pathway interactions; Phase; Population; Primary Neoplasm; Relapse; Resistance; Role; Seeds; Signal Transduction; Solid Neoplasm; Source; Structure of parenchyma of lung; Tamoxifen; Testing; base; bone; cancer cell; cytokine; in vivo; insight; macrophage; malignant breast neoplasm; novel; response; tumor

We have recently discovered that Src mediates bone metastasis through potentiating the survival response of breast cancer cells to CXCL12 and IGF1. Both of these cytokines are enriched in the bone metastasis microenvironment. This finding provided insights into the mechanisms of metastatic latency, and suggested Src inhibition as a potential strategy to eliminate disseminated cancer cells in the bone or bone marrow. In this project, our original aims were to further test the role of Src in latent bone metastasis, and to elucidate how the enhanced Src activity is acquired in different subtypes of breast tumors. Based on knowledge from the literature, we postulated that Src activation was connected to ERBB2 and ER signaling in ERBB2+ and ER+ breast cancer, respectively. We have confirmed these connections during the K99 phase. In the ROO phase, we will further investigate how Src mediates bone metastasis and resistance to anti-ERBB2 and anti- ER therapies in these two subtypes on breast cancer (Aim 2 and 3). Regarding ER-/ERBB2- tumors, our preliminary analyses indicated that Src activity associates with CXCL12 and IGF1 enrichment in primary tumors, which represents a resemblance to the microenvironment of bone metastasis. Although CXCL12 and IGF1 do not directly activate Src, they promote cell survival in a Src dependent manner. We therefore hypothesized a model of "metastasis seed pre-selection", postulating that cancer cells with enhanced Src activity are enriched in CXGL12/IGF1-hlgh primary tumors due to the survival advantages conferred by Src. These tumors are predisposed for bone colonization because ofthe resemblance of primary tumor microenvironment to that ofthe bone metastases. During the K99 phase, we have obtained multiple lines of evidence supporting the seed pre-selection model. In addition, we demonstrated that fibroblasts derived from mesenchymal stem cells are a major source of CXCL12 and IGF1 in primary tumors. These results not only provided insights into how cancer cells acquire enhanced Src activity, but also depicted an intriguing course of metastasis progression. We are therefore going to extend the original aim (Aim 1) by corroborating and generalizing this model.

我们最近发现 Src 通过增强生存反应来介导骨转移 乳腺癌细胞CXCL12和IGF1。这两种细胞因子在骨转移中富集 微环境。这一发现提供了对转移潜伏期机制的见解，并表明 Src 抑制是消除骨或骨髓中播散性癌细胞的潜在策略。在 在这个项目中，我们最初的目的是进一步测试Src在潜伏骨转移中的作用，并阐明 如何在不同亚型的乳腺肿瘤中获得增强的 Src 活性。基于来自的知识 根据文献，我们假设 Src 激活与 ERBB2+ 和 ERBB2 中的 ER 信号传导有关 分别为 ER+ 乳腺癌。我们在 K99 阶段已经确认了这些联系。在原产地规则中 阶段，我们将进一步研究Src如何介导骨转移以及抗ERBB2和抗- 这两种亚型乳腺癌的 ER 疗法（目标 2 和 3）。关于 ER-/ERBB2- 肿瘤，我们的 初步分析表明，Src 活性与原代细胞中 CXCL12 和 IGF1 的富集相关。 肿瘤，这与骨转移的微环境相似。虽然CXCL12 IGF1不直接激活Src，它们以Src依赖的方式促进细胞存活。我们因此 假设了“转移种子预选”模型，假设癌细胞具有增强的Src 由于 Src 赋予的生存优势，CXGL12/IGF1-hlgh 活性在原发性肿瘤中富集。 由于原发肿瘤的相似性，这些肿瘤易于骨定植 骨转移的微环境。在K99阶段，我们获得了多条线 支持种子预选模型的证据。此外，我们还证明，成纤维细胞来源于 间充质干细胞是原发性肿瘤中CXCL12和IGF1的主要来源。这些成果不仅 提供了关于癌细胞如何获得增强的 Src 活性的见解，同时也描绘了一个有趣的过程 转移进展。因此，我们将通过证实和扩展最初的目标（目标 1） 推广这个模型。