Intratumoral Heterogeneity and Tumor Evolution in Lymphoma

 描述（由申请方提供）：本项目的长期目标是表征肿瘤抑制机制如何影响肿瘤内异质性。具体而言，p53丢失对细胞-细胞遗传多样性的发展和维持的后果将根据小鼠模型的初步数据进行研究。肿瘤内异质性为进化选择和适应不断变化的环境提供了底物，例如，当细胞扩散到新的部位或受到治疗干预的挑战时（13）。获得性耐药是实现B细胞淋巴瘤和其他癌症持久治疗的主要障碍（4）。在许多情况下，已显示耐药性源自预先存在的耐药亚克隆（19，20），因此，肿瘤中的遗传变异水平是肿瘤对临床干预的稳健性的基础。中心假设：随着遗传异常的发生，它们在人群中持续存在的可能性更大，因为缺乏p53通过减少更广泛的非可行基因型之间的相对适应性差异来“平衡竞争环境”。不可避免的结果是肿瘤内异质性的积累。具体目标：1）将使用单细胞测序方法测量一组人弥漫性大B细胞淋巴瘤（DLBCL）的瘤内遗传多样性（29）。将研究异质性与p53状态的相关性。2)将在小鼠B细胞淋巴瘤模型中对p53在异质性淋巴瘤发展中的作用进行功能评估。3)肿瘤内异质性的机制将通过谱系追踪和通过灭活各种p53相关的传感器和效应器来探索，以确定各种p53相关过程的修饰，包括DNA损伤反应、细胞周期控制、细胞凋亡和谱系定型，是否可以重现p53缺失所实现的多样性表型。培训计划：申请人将依靠导师和合作者组成的跨学科团队，发展细胞和分子生物学，小鼠遗传学和基因组数据计算分析方面的专业知识。将追求充分的肿瘤学临床暴露，以优化实验室研究的相关性，并获得培养未来临床和转化伙伴关系所需的技能。影响/相关性：该奖学金将通过促进有关人类疾病（即治疗失败）的原因和治疗的创造性和创新性研究，并通过开发申请人长期为国家预防疾病和经济福祉的能力做出贡献，有效地实现NIH的目标。

 DESCRIPTION (provided by applicant): The long term objective of this project is to characterize how intratumoral heterogeneity is influenced by tumor suppressive mechanisms. Specifically, the consequence of p53 loss on the development and maintenance of cell-cell genetic diversity will be investigated, based on preliminary data from mouse models. Intratumoral heterogeneity produces a substrate for evolutionary selection and adaptation to a changing environment, for example, as cells disseminate to a new site or are challenged by therapeutic intervention (13). Acquired resistance to therapy is a major roadblock in achieving durable cures for B-cell lymphomas and other cancers (4). In many contexts, resistance has been shown to originate from pre-existing drug-resistant subclones (19, 20), and thus, the level of genetic variation in the tumor underlies the robustness of the tumor to clinical intervention. Central Hypothesis: As genetic abnormalities occur, they have a greater probability of persisting in the population, as a lack of p53 "levels the playing field" by reducing the differences in relatve fitness between a broader array of otherwise nonviable genotypes. The inevitable result is the accumulation of intratumoral heterogeneity. Specific aims: 1) Intratumoral genetic diversity of a collection of human diffuse large B-cell lymphomas (DLBCLs) will be measured using a single cell sequencing approach (29). The association of heterogeneity and p53 status will be investigated. 2) The role of p53 in the development of heterogeneous lymphomas will be functionally evaluated in a mouse model of B-cell lymphoma. 3) The mechanism of intratumoral heterogeneity will be explored by lineage tracing and by inactivating various p53-related sensors and effectors to determine if modification of a variety of p53-realted processes, including the DNA-damage response, cell cycle control, apoptosis, and lineage commitment, can recapitulate the diversity phenotype achieved with the loss of p53. Training Plan: The applicant will rely on an interdisciplinary team of mentors and collaborators to develop an expertise in cell & molecular biology, mouse genetics, and computational analysis of genomic data. Sufficient oncology clinical exposure will be pursued to optimize the relevance of laboratory investigations and to obtain the skills necessary for cultivating future clinical and translational partnerships. Implications/Relevance: This fellowship will effectively realize the goals of the NIH by fostering creative and innovative research regarding the cause and cure of human disease (i.e. treatment failure), and by developing the applicant to contribute over the long term to the Nation's capability to prevent disease and economic well-being through biomedical innovation.