Tracing and targeting the epigenetic heterogeneity in breast cancer metastasis

项目摘要 标题：追踪和定位乳腺癌转移的表观遗传异质性。 转移是癌症相关死亡的主要原因，也是最具挑战性的治疗方法。除了经过深思熟虑的 对于癌症中的基因组突变，我们对非基因组变化的了解仍然有限。建议数 方法是剖析乳腺癌中非基因组内转移异质性的机制。 最近，我们证明了成骨细胞(骨形成细胞)促进染色质的整体改变。 与增加的茎、上皮向间充质转变相关的组织，以及 多受体酪氨酸激酶的高表达包括FGFR1和PDGFRNAsβ。归根结底，雌激素 信号转导受到抑制，内分泌抵抗增加。从机制上讲，我们确定了FGF2/PDBFβ/ EZH2轴作为乳腺癌骨转移表观遗传重编程的新调节因子。然而，有几个 悬而未决的问题仍然没有得到回答：(I)是什么机制导致了 骨转移中的邻近细胞，(Ii)是在转移过程中可遗传的表观遗传特征，以及(Ii) 如果是，它们如何影响治疗反应？在这个项目中，我们的目标是了解 骨转移瘤内异质性及表观遗传学异质性如何影响治疗 对已被广泛研究的遗传异质性以外的反应。我们的目标是追踪和剖析 使用尖端条形码策略(K99阶段)的表观遗传肿瘤内异质性(EITH)，识别 通过整合单细胞多组学(K99-R00期)的表观遗传调节剂，测试新的治疗方法 并最终将我们的发现扩展到其他乳腺癌转移部位(R00期)，包括肺、肝和 大脑。贝勒医学院(BCM)是国际知名的乳腺癌研究机构， 这让我有机会与领先的科学家密切互动，交流思想，分享我的发现， 临床医生和患者代言人。为了我的职业转型，我组建了一支由资深科学家和专家组成的团队 包括我的导师张海峰教授，他在乳腺癌骨转移方面很有名气。我的 共同导师杰弗里·罗森教授是乳腺发育和乳房领域的杰出科学家。 癌症模型。由于该项目的临床相关性，我还邀请了C.Kent Osborne教授， 丹·L·邓肯综合癌症中心(DLDCCC)创始主任马修·J·埃利斯教授， 世界著名肿瘤学家、乳腺中心主任Bora Lim博士，侵略性亚型专家 研究乳腺癌(例如炎症性乳腺癌)的苏珊·G·希尔森贝克教授，著名的 生物统计学家刘占东博士，计算生物学家和统计学家，擅长单细胞 分析。将我的顾问团队的专业知识添加到丰富的智力资源和尖端技术中 在BCM获得的职位将有助于我成功地过渡到一家顶级研究机构的独立职位。

Project Summary Title: Tracing and targeting the epigenetic heterogeneity in breast cancer metastasis. Metastasis is major cause of cancer-related death and is the most challenging to treat. Besides the well-studied genomic mutations in cancer, our understanding of non-genomic alterations remains limited. The proposed approach is to dissect the mechanisms of non-genomic intra-metastasis heterogeneity in breast cancer. Recently, we demonstrated that osteoblasts (bone forming cells) promote a global alteration of chromatin organization which associates with increased stemness, epithelial to mesenchymal transition, and overexpression of multiple receptor tyrosine kinases included FGFR1 and PDGFRβ. Ultimately, estrogen signaling was inhibited while endocrine resistance was increased. Mechanistically, we identified FGF2/PDBFβ/ EZH2 axis as a novel regulator of epigenetic reprogramming in breast cancer bone metastasis. However, several outstanding questions remained unanswered: (i) what mechanisms drive phenotypic variations between neighboring cells in bone metastasis, (ii) are epigenetic traits inheritable during metastasis progression, and (ii) if yes, how do they influence therapeutic response? In this project, our goal is to understand the mechanisms of intra-tumor heterogeneity in bone metastases and determine how epigenetic heterogeneity affects therapeutic response beyond the genetic heterogeneity that has been extensively studied. We aim to trace and dissect the epigenetic intra-tumor heterogeneity (eITH) using a cutting-edge barcoding strategy (K99 phase), identify epigenetic modulators by integrating single cell multi-omics (K99-R00 phase), test new therapeutic approaches and eventually expand our findings to other breast cancer metastasis sites (R00 phase) including lung, liver, and brain. Baylor College of Medicine (BCM) is an internationally renowned institution for breast cancer research, which gives me the opportunity to closely interact, exchange ideas, and share my findings with leading scientists, clinicians and patient advocates. For my career transition, I assembled a team of senior scientists and experts including my mentor, Professor Xiang H-F Zhang, who is well-established in breast cancer bone metastasis. My co-mentor, Professor Jeffrey Rosen, is a distinguished scientist in mammary gland development and breast cancer modeling. Because of the clinical relevance of the project, I also included Professor C. Kent Osborne, founding director of the Dan L. Duncan Comprehensive Cancer Center (DLDCCC), Professor Matthew J. Ellis, a world-renowned oncologist and director of the Breast Center, Dr. Bora Lim, an expert in aggressive subtypes of breast cancer (e.g. inflammatory breast cancer), Professor Susan G. Hilsenbeck, a distinguished biostatistician, and Dr. Zhandong Liu a computational biologist and statistician with expertise in single cell analysis. Adding the expertise of my advisory team to the rich intellectual resource and cutting-edge technology available at BCM will facilitate my successful transition into an independent position at a top research institution.