Combining single cell approaches and a developmental perspective to discover stem cell control circuits and the cellular and molecular bases of cancer heterogeneity

结合单细胞方法和发育视角来发现干细胞控制回路以及癌症异质性的细胞和分子基础

• 批准号: 9115083
• 负责人: Geoffrey Myles Wahl
• 金额: $ 112.98万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9115083
• 关键词: Antigens; Attention; BRCA1 gene; Bioinformatics; Breeding; Cancer Biology; Cells; Cessation of life; Cytokeratin; Development; Developmental Biology; Diagnosis; Disease; Drug resistance; Effectiveness; Embryo; Embryonic Development; Exhibits; Gene Expression Profile; Genes; Genetic Heterogeneity; Goals; Grant; Health; Heterogeneity; Human; Immune; Incidence; Inflammation; Malignant - descriptor; Malignant Neoplasms; Mammary gland; Molecular; Molecular Medicine; Molecular Target; Mutation; Neoplasm Metastasis; Obesity; Outcome; Pathway interactions; Patients; Population; Societies; Solid Neoplasm; Stem cells; TP53 gene; Taxonomy; Technology; Time; Treatment Failure; base; cancer cell; cancer heterogeneity; cancer stem cell; cancer subtypes; cell type; chemotherapy; drug development; embryonic antigen; fetal; human disease; improved; innovation; malignant breast neoplasm; mouse model; neoplastic cell; programs; response; single cell sequencing; stem; stem cell biology; stemness; targeted treatment; tumor; tumor heterogeneity; tumorigenic

 DESCRIPTION (provided by applicant): Intra-tumoral heterogeneity confounds molecular taxonomy, fuels metastasis, and increases the chances of treatment failure. Understanding the origins of intra-tumoral heterogeneity and developing effective countermeasures should improve cancer outcomes. This proposal focuses on the cellular and molecular origins of intra-tumoral heterogeneity in basal-like breast cancer (BLBC), as these cancers frequently resist chemotherapy and currently lack molecular targets for drug development. BLBC is distinguishable from other breast cancer subtypes, as it exhibits a gene expression signature that is associated with fetal mammary stem cells (fMaSCs) generated during embryogenesis. Importantly, fMaSC-like cancer cells are very tumorigenic and differ significantly from the "breast cancer stem cells" that have received much recent attention. This project will determine the molecular programs that drive embryonic mammary cells into the stem cell state, and use gene editing technologies to generate a new mouse model that will enable the lab to identify fMaSCs in real time based on the cytokeratins they express. This experimental approach will allow the lab to selectively eliminate these cells to determine unambiguously if these are the only stem cells within the mammary gland, and whether other cells can acquire stemness in response to wounding, inflammation, obesity, etc. p53 mutations are frequently found in BLBC and contribute to both genetic heterogeneity and increased reprogramming efficiency. This project will induce p53 mutations in fMaSCs or their differentiated progeny and ask whether different types of tumors arise, and assess cellular and molecular heterogeneity. This project will determine whether other BLBC relevant mutations, such as BRCA1 (alone or in combination with p53 mutations) or environmental challenges (such as inflammation or obesity) elicit the same effects. Gene expression signatures of resulting tumors will be compared to those of human BLBC to generate mouse models that reflect the human disease more faithfully. Finally, this project will apply single cell sequencing and sophisticated bioinformatic approaches to: 1) decipher the mechanisms by which the stem cell state is generated, 2) assess heterogeneity within the tumor cell population, and 3) determine whether fMaSC embryonic antigens are detectable in human BLBC. Such antigens, and the pathways discovered to drive the fMaSC state, will provide new targets for developing tumor-selective, immune- and molecularly targeted therapies. The fMaSC-like cells in BLBC resemble bona-fide multi-potent embryonic mammary stem cells, and comprise a new and understudied cell type in cancer. Cells with similar stem-like attributes have been described in diverse solid tumors, indicating that findings from these studies will likely have general relevance for cancer biology.