3D co-culture system to characterize and target leukemia stem cells

用于表征和靶向白血病干细胞的 3D 共培养系统

• 批准号: 10044631
• 负责人: Monica L Guzman
• 金额: $ 43.58万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10044631
• 关键词: 3-Dimensional; Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Affect; Aftercare; Biological Assay; Biological Markers; Biology; Bone Marrow; Bone Marrow Stem Cell; Cell Communication; Cell Culture Techniques; Cell Line; Cell physiology; Cells; Clinic; Clinical; Coculture Techniques; Complex; Cues; Data; Dependence; Development; Disease; Drug Evaluation; Drug resistance; Epigenetic Process; Evaluation; Genetic; Genetic Markers; Goals; Hematopoiesis; Hematopoietic stem cells; Heterogeneity; Hypoxia; Image; Incidence; Laboratories; Leukemic Cell; Malignant - descriptor; Measurement; Mesenchymal; Modeling; Morbidity - disease rate; Mutation; Organoids; Outcome; Pathogenesis; Patient Care; Patients; Pharmaceutical Preparations; Phenotype; Play; Population; Predisposition; Property; Recurrent disease; Relapse; Residual state; Resistance; Role; Sampling; Selection for Treatments; Signal Transduction; Specific qualifier value; Stromal Cells; Structure; System; Testing; Therapeutic; acute myeloid leukemia cell; antileukemic agent; base; burden of illness; cancer stem cell; cancer therapy; cell stroma; drug testing; epigenetic marker; improved; individual patient; leukemic stem cell; mesenchymal stromal cell; monolayer; mortality; novel; novel strategies; novel therapeutic intervention; optimal treatments; patient population; patient response; peripheral blood; personalized medicine; personalized strategies; prevent; response; self-renewal; single cell sequencing; stem cell therapy; stem cells; stemness; success; targeted treatment; treatment response; treatment strategy

PROJECT SUMMARY: Hematopoietic stem cells (HSCs) reside in the bone marrow (BM) and their function is regulated by their interactions with the BM microenvironment. Leukemia stem cells (LSCs) have been shown to be capable of initiating and maintaining acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Furthermore, the interactions of LSCs with their microenvironment have been shown to play a critical role in the resistance of LSCs to therapy. The traditional approach of investigating LSCs and anti- leukemic agents’ effects on them has been the 2D monolayer cell culture. As complex cell-matrix interactions continue to be elucidated, it is clear that this model is no longer a sufficient representative of the intricacies of the BM niche. Thus, the development of a model that better mimics this microenvironment is imperative, both to study LSC properties, as well as for testing drug effects in a system that reflects the contributions of the microenvironment. We hypothesize that a culture system capable of recapitulating the BM niche conditions to maintain LSCs will allow for the better understanding of their biology and the discovery of novel therapeutic approaches that can act on LSCs in the BM. We propose to implement novel approaches to evaluate BM-LSC interactions to improve the assessment of the function, drug resistance and stem cell properties of LSCs in a patient-specific manner. Our preliminary data suggest that the 3D spheroids (organoid-like structures) can recapitulate BM niche features, such as hypoxia. In addition, we have observed that the LSCs are better maintained and retain functional stemness properties using the 3D stromal approach compared to more conventional culture systems. Thus, we propose to evaluate AML (with a well-characterized mutational profile) to determine their survival dependencies in the context of niche interactions. The ultimate goal of this project is to identify new therapeutic approaches to target LSCs either directly or through disruption of the BM-LSC protective interactions.

项目概要： 造血干细胞 (HSC) 存在于骨髓 (BM) 中，其功能受其自身的调节 与骨髓微环境的相互作用已被证明能够。 引发和维持急性髓细胞白血病（AML）和急性淋巴细胞白血病（ALL）。 LSC与其微环境的相互作用已被证明在耐药性中发挥着关键作用 研究 LSC 和抗白血病药物对其影响的传统方法。 随着复杂的细胞-基质相互作用不断被阐明，它是二维单层细胞培养。 显然，该模型不再能够充分代表 BM 领域的复杂性。 开发更好地模拟这种微环境的模型势在必行，既可以研究 LSC 特性， 以及在反映微环境贡献的系统中测试药物效果。 培育能够重现 BM 生态位条件以维持 LSC 的文化系统将允许 为了更好地了解它们的生物学并发现可以作用的新治疗方法 我们建议实施新方法来评估 BM-LSC 相互作用，以改善 以针对患者的方式评估 LSC 的功能、耐药性和干细胞特性。 初步数据表明 3D 球体（类器官结构）可以概括 BM 生态位特征， 此外，我们还观察到 LSC 得到了更好的维护并保留了功能。 与更传统的培养系统相比，使用 3D 基质方法的干性特性因此， 我们建议评估 AML（具有明确的突变特征）以确定其生存 该项目的最终目标是确定新的治疗方法。 直接或通过破坏 BM-LSC 保护性相互作用来靶向 LSC 的方法。