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

由于其高转移潜力和有限的治疗选择，三阴性乳腺癌 癌症（TNBC）仍然是妇女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。我们的实验室 显示Abelson（ABL）家族的非受体酪氨酸激酶促进肿瘤的转移， 乳腺癌细胞通过激活下游转录变化。但如何 这些变化存在于全球染色质动力学的更大背景下，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- 调控转录组可能是一种有前途的治疗转移性肝癌的新策略。 三阴性乳腺癌该提案的总体假设是，ABL的抑制 激酶导致染色质景观的明显变化，使TNBC细胞对 用靶向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，以促进转移进展，并了解这些动态变化， 可用于在转移性TNBC模型中引发治疗益处。方法用于 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.