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.

项目摘要： 造血干细胞（HSC）位于骨髓（BM）中，其功能受其调节 与BM微环境的相互作用。白血病干细胞（LSC）已证明能够 引发和维持急性髓样白血病（AML）和急性淋巴细胞白血病（ALL）。此外， LSC与它们的微环境的相互作用已被证明在阻力中起关键作用 LSC进行治疗。调查LSC和抗白血病药物对其的影响的传统方法 一直是2D单层细胞培养。随着复杂的单元格相互作用继续阐明，它是 很明显，该模型不再是BM生态位复杂性的充分代表。那， 开发更好地模拟这种微环境的模型必须研究LSC特性， 以及在反映微环境贡献的系统中测试药物效应。我们 假设能够概括BM利基条件以维持LSC的培养系统将允许 为了更好地了解其生物学以及发现可以采取行动的新型治疗方法 BM中的LSC。我们建议实施新颖的方法来评估BM-LSC相互作用以改善 以患者特异性方式评估LSC的功能，耐药性和干细胞特性。我们的 初步数据表明，3D球体（类带状结构）可以概括BM的特征， 例如缺氧。此外，我们已经观察到LSC可以更好地维护并保持功能 与更常规的培养系统相比，使用3D基质方法的干性特性。那， 我们建议评估AML（具有良好的突变曲线）以确定其存活率 利基相互作用的依赖项。该项目的最终目标是确定新的治疗性 直接或通过破坏BM-LSC保护性相互作用的方法来靶向LSC。