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: 10219974
• 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/10219974
• 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; Heterogeneity; Human; Immune Targeting; Incidence; Inflammation; Malignant - descriptor; Malignant Neoplasms; Mammary gland; Molecular; Molecular Medicine; Mutation; Neoplasm Metastasis; Obesity; Outcome; Pathway interactions; Patients; Population; Societies; Solid Neoplasm; TP53 gene; Taxonomy; Technology; Time; Treatment Failure; antigen detection; base; cancer cell; cancer heterogeneity; cancer stem cell; cancer subtypes; cell type; chemotherapy; drug development; embryonic stem cell; fetal; human disease; improved; innovation; malignant breast neoplasm; mammary; molecular drug target; molecular targeted therapies; mouse model; neoplastic cell; programs; public health relevance; response; single cell sequencing; stem; stem cell biology; stem cells; stem-like cell; stemness; tumor; tumor heterogeneity; tumorigenic; wound

 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.

 描述（由应用提供）：肿瘤内异质性混淆了分子分类法，燃料转移，并增加了治疗失败的机会。了解肿瘤内异质性的起源并发展有效的对策应改善癌症的预后。该提议着重于基本乳腺癌（BLBC）中肿瘤内异质性的细胞和分子起源，因为这些癌症经常抵抗化学疗法，目前缺乏用于药物开发的分子靶标。 BLBC与其他乳腺癌亚型可区别，因为它表现出与胚胎发生过程中产生的胎儿乳腺干细胞（FMASC）相关的基因表达特征。重要的是，FMASC样癌细胞具有非常肿瘤性，与“乳房”显着不同 癌症干细胞“已经引起了最近关注。该项目将确定将胚胎乳腺细胞驱动到干细胞状态的分子程序，并使用基因编辑技术生成一个新的鼠标模型，以使实时识别实时识别FMASC的新鼠标模型，如果它们表达的cytoker searty允许这些实验的细胞，如果这些实验可以选择这些细胞。可以在BLBC中发现p53突变，并有助于遗传性异质性和提高重编程效率。结合p53突变）或环境挑战（例如炎症或肥胖症）会引起相同的影响。将所得肿瘤的基因表达特征与人类BLBC的肿瘤进行比较，以产生更忠实地反映人类疾病的小鼠模型。最后，该项目将采用单细胞测序和复杂的生物信息学方法：1）解解产生干细胞态的机制，2）评估肿瘤细胞种群中的评估异质性，3）确定在人类BLBC中是否可以检测到FMASC胚胎抗原。这种抗原以及发现驱动FMASC状态的途径将为发展肿瘤选择性，免疫和分子靶向疗法提供新的靶标。 BLBC中的FMASC样细胞类似于善意的多位胚胎乳腺干细胞，并构成了一种新的癌症细胞类型。在潜水员实体瘤中已经描述了具有类似茎状属性的细胞，表明这些研究的发现可能与癌症生物学具有一般相关性。