Tracing and targeting the epigenetic heterogeneity in breast cancer metastasis

追踪和靶向乳腺癌转移中的表观遗传异质性

• 批准号: 10446911
• 负责人: Igor Landry Bado
• 金额: $ 12.9万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10446911
• 关键词: 3-Dimensional; Address; Advanced Malignant Neoplasm; Advisory Committees; Advocate; Affect; Anemia; Bar Codes; Bone Matrix; Brain; Breast; Breast Cancer Cell; Breast Cancer Model; Breast cancer metastasis; Calcium; Calcium Signaling; Cancer Etiology; Career Mobility; Cell Survival; Cells; Cessation of life; Chromatin; Clinical Management; Clinical Trials; Coculture Techniques; Coma; Complex; Comprehensive Cancer Center; DNA Sequence Alteration; DNA methylation profiling; Data; EZH2 gene; Endocrine; Epigenetic Process; Estrogen Receptors; Estrogen receptor positive; Estrogens; Evolution; FDA approved; FGF2 gene; FGFR1 gene; Fibroblast Growth Factor; Fostering; Gap Junctions; Genetic; Genetic Heterogeneity; Genetic Transcription; Genomics; Goals; Growth; Growth Factor; Heterogeneity; Hypercalcemia; Incidence; Individual; Inherited; Institution; International; Lesion; Libraries; Liver; Lung; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Medicine; Mentors; Metastatic Neoplasm to the Bone; Micrometastasis; Molecular; Mutation; Neoplasm Metastasis; Numbness; Oncologist; Organ; Osteoblasts; Osteoclasts; Pain; Paralysed; Pathological fracture; Patients; Perfusion; Phase; Phenotype; Platelet-Derived Growth Factor; Positioning Attribute; Process; Proteomics; Receptor Protein-Tyrosine Kinases; Recurrence; Research; Resistance; Resources; Scientist; Seeds; Senior Scientist; Signal Pathway; Signal Transduction; Site; Spatial Distribution; System; TRANCE protein; Techniques; Technology; Testing; Therapeutic; Tissue Microarray; Transforming Growth Factor beta; Transitional Epithelium; Validation; Variant; XCL1 gene; anticancer research; base; bone; cancer cell; cancer diagnosis; cancer subtypes; clinically relevant; college; conventional therapy; epigenetic drug; epigenomics; epithelial to mesenchymal transition; exome sequencing; in vivo evaluation; inflammatory breast cancer; laser capture microdissection; malignant breast neoplasm; mammary gland development; multiple omics; non-genomic; novel; novel therapeutic intervention; osteoblast differentiation; overexpression; parathyroid hormone-related protein; professor; public health relevance; receptor expression; single cell analysis; single-cell RNA sequencing; stemness; therapy resistant; trait; transcriptomics; treatment response; tumor; tumor growth; tumor heterogeneity; tumor progression

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.

项目概要 标题：追踪和靶向乳腺癌转移中的表观遗传异质性。 转移是癌症相关死亡的主要原因，也是最具挑战性的治疗。除了深入研究之外 尽管癌症中存在基因组突变，但我们对非基因组改变的理解仍然有限。拟议的 方法是剖析乳腺癌非基因组内转移异质性的机制。 最近，我们证明成骨细胞（骨形成细胞）促进染色质的整体改变 与增加干性、上皮到间质转化相关的组织，以及 多种受体酪氨酸激酶的过度表达，包括 FGFR1 和 PDGFRβ。最终，雌激素 信号传导受到抑制，同时内分泌抵抗力增加。从机制上讲，我们鉴定了 FGF2/PDBFβ/ EZH2 轴作为乳腺癌骨转移表观遗传重编程的新型调节剂。然而，几个 悬而未决的问题仍然没有得到解答：（i）驱动表型变异的机制是什么？ 骨转移中的邻近细胞，(ii) 是在转移进展过程中可遗传的表观遗传特征，并且 (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 骨转移瘤内异质性并确定表观遗传异质性如何影响治疗 反应超出了已被广泛研究的遗传异质性。我们的目标是追踪和剖析 使用尖端条形码策略（K99 相）分析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 脑。贝勒医学院（BCM）是国际知名的乳腺癌研究机构， 这让我有机会与顶尖科学家密切互动、交流想法并分享我的发现， 临床医生和患者权益倡导者。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 其中包括我的导师张翔教授，他在乳腺癌骨转移方面有着丰富的经验。我的 联合导师 Jeffrey Rosen 教授是乳腺发育和乳腺领域的杰出科学家 癌症建模。由于该项目的临床相关性，我还邀请了 C. Kent Osborne 教授， Dan L. Duncan 综合癌症中心 (DLDCCC) 的创始主任 Matthew J. Ellis 教授， 世界著名肿瘤学家、乳腺中心主任 Bora Lim 博士，侵袭性亚型专家 Susan G. Hilsenbeck 教授是一位杰出的乳腺癌（例如炎性乳腺癌） 生物统计学家，刘占东博士是计算生物学家和统计学家，具有单细胞专业知识 分析。将我的顾问团队的专业知识融入到丰富的智力资源和尖端技术中 BCM 的职位将有助于我成功过渡到顶级研究机构的独立职位。