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

我们最近发现Src通过增强生存反应介导骨转移 乳腺癌细胞对CXCL 12和IGF 1的反应。这两种细胞因子都在骨转移瘤中富集， 微环境这一发现为转移潜伏期的机制提供了新的见解，并建议 Src抑制作为消除骨或骨髓中播散性癌细胞的潜在策略。在 本项目，我们最初的目的是进一步测试Src在潜在骨转移中的作用，并阐明 增强的Src活性如何在不同亚型的乳腺肿瘤中获得。基于来自 根据文献，我们假设Src激活与ERBB 2和ERBB 2+中的ER信号传导有关， ER+乳腺癌。我们已经在K99阶段确认了这些连接。在ROO 我们将进一步研究Src是如何介导骨转移和抗ERBB 2和抗 这两种亚型乳腺癌的ER疗法（目的2和3）。关于ER-/ERBB 2-肿瘤，我们的 初步分析表明，Src活性与CXCL 12和IGF 1富集有关， 肿瘤，这代表了骨转移的微环境相似。虽然CXCL 12 IGF 1不直接激活Src，它们以Src依赖的方式促进细胞存活。因此我们 假设了“转移种子预选”模型，假定Src增强的癌细胞 活性在CXGL 12/IGF 1高原发性肿瘤中富集，这是由于Src赋予的存活优势。 由于与原发肿瘤相似，这些肿瘤易发生骨定植 骨转移瘤的微环境。在K99阶段，我们获得了多条 支持种子预选模型的证据。此外，我们证明了来源于 间充质干细胞是原发性肿瘤中CXCL 12和IGF 1的主要来源。这些结果不仅 提供了关于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， 转移的进展。因此，我们将通过确证和 推广这一模式。

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.