Investigating the Impact of ABL Kinase Signaling on Epigenetic Reprogramming in Metastatic Triple Negative Breast Cancer

由于其高度转移潜力和有限的治疗选择，三阴性乳腺癌 癌症（TNBC）仍然是女性癌症相关死亡的主要原因。最近的研究 已经表明，不同的染色质景观对应于转移性复发。我们实验室有 研究表明非受体酪氨酸激酶 Abelson (ABL) 家族可促进肿瘤转移 乳腺癌细胞通过激活下游转录变化。然而，如何 这些变化存在于全球染色质动态的更大背景下，尚待探索。 我的初步数据表明，同时针对表观基因组和 ABL 激酶 调控转录组可能是治疗转移性肿瘤的一种有前途的新治疗策略 三阴性乳腺癌。该提案的总体假设是抑制 ABL 激酶导致染色质景观发生明显变化，使 TNBC 细胞对 使用针对表观遗传调节蛋白的药物治疗导致 TNBC 细胞死亡。的 该提案的目的是阐明与 ABL 激酶相关的表观遗传景观 信号传导促进转移进展，并了解这些动态变化是如何发生的 可能会被用来在转移性 TNBC 模型中产生治疗效果。所采用的方法 解决这些目标将包括 CRISPR/Cas9 筛选、ATAC-seq 以及体外和体内 分别使用细胞系和小鼠进行药物治疗实验。

Because of its highly metastatic potential and limited treatment options, triple-negative breast cancer (TNBC) remains a leading cause of cancer associated deaths in women. Recent studies have shown that distinct chromatin landscapes correspond to metastatic relapse. Our lab has shown that the Abelson (ABL) family of non-receptor tyrosine kinases promote metastasis of breast cancer cells through activation of downstream transcriptional changes. However, how these changes exist in the greater context of global chromatin dynamics has yet to be explored. My preliminary data suggest that simultaneously targeting the epigenome and the ABL kinase- regulated transcriptome might be a promising new therapeutic strategy for treating metastatic triple negative breast cancer. The overall hypothesis of the proposal is that inhibition of ABL kinases leads to distinct changes in the chromatin landscape that sensitizes TNBC cells to treatment with drugs targeting epigenetic regulatory proteins leading to TNBC cell death. The aims of the proposal are to elucidate the epigenetic landscape associated with ABL kinase signaling to promote metastatic progression, and to understand how these dynamic changes might be exploited to elicit therapeutic benefit in metastatic TNBC models. Approaches used to address these objectives will include CRISPR/Cas9 screens, ATAC-seq, and in vitro and in vivo drug treatment experiments using cell lines and mice respectively.