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

我们最近发现，Src通过增强生存反应来介导骨转移。 乳腺癌细胞对CXCL12和IGF1的作用。这两种细胞因子在骨转移中都是富含的。 微环境。这一发现为转移潜伏期的机制提供了洞察力，并提示 SRC抑制作为一种潜在的策略来消除骨髓或骨髓中的播散性癌细胞。在……里面 这个项目，我们最初的目的是进一步测试src在潜伏性骨转移中的作用，并阐明 不同亚型乳腺肿瘤中如何获得增强的Src活性。基于来自以下方面的知识 文献中，我们推测，在ERBB2+和ERBB2+中，Src的激活与ERBB2和ER信号有关 分别为ER+乳腺癌。我们已经在K99阶段确认了这些联系。在Roo中 阶段，我们将进一步研究Src如何介导骨转移以及对抗ERBB2和抗ERBB2的耐药性 这两个亚型的ER治疗乳腺癌(目标2和3)。关于ER-/ERBB2-肿瘤，我们 初步分析表明，原生生物中Src活性与CXCL12和IGF1的富集性有关 肿瘤，这与骨转移的微环境相似。虽然CXCL12 和IGF1不直接激活Src，它们以一种依赖于Src的方式促进细胞存活。因此，我们 提出了一个“转移种子预选择”模型，假设癌细胞具有增强的来源 由于Src的生存优势，CXGL12/IGF1-HLH原发肿瘤中活性丰富。 由于与原发肿瘤相似，这些肿瘤更容易在骨中定植。 微环境对骨转移的影响。在K99阶段，我们已经获得了多条线路 支持种子预选模式的证据。此外，我们还证明了成纤维细胞来源于 间充质干细胞是原发肿瘤中CXCL12和IGF1的主要来源。这些结果不仅是 提供了对癌细胞如何获得增强的Src活性的见解，但也描绘了一个有趣的过程 转移进展的可能性。因此，我们将通过证实和证实来扩展最初的目标(目标1) 推广这一模型。

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.