Comparative modeling of sarcoma microenvironments for the discovery of biomarkers and tumor vulnerabilities

摘要 软组织肉瘤是一种异质性肿瘤，其起源于属于 间充质谱系，每年影响全球近20万人。最 成人中的侵袭性和转移性亚型是那些具有复杂核型和多个 基因畸变这些肉瘤患者的总体生存率在2005年没有很大提高， 近年来，化疗和放疗的替代方法，如 免疫疗法迄今为止仅提供了边际效益。UPS治疗的新进展 由于缺乏对复杂基因组的功能性后果的了解， 在患者中发现的改变和肿瘤微环境（TME）的有限表征， 这将揭示非细胞自主机制对肉瘤进展至关重要。 实验工具和现有的动物模型目前没有解决这些限制。 然而，适当的模型可以促进新靶点的有效发现， 这些肿瘤的基础疗法，发病率相对较低， 临床试验的开展往往具有挑战性。因此，我们建议生成肉瘤 包括在患者中观察到的实际体细胞畸变的小鼠模型。此外，委员会认为， 我们将使用这些模型来促进治疗反应和TME组成的研究。的 这些新模型的使用，以及更新的技术，如单细胞RNA， 测序（scRNA-seq）、CyTOF和成像质谱细胞术（IMC）将最终阐明 单个肿瘤细胞的关键表达谱、转移机制、耐药性、 常规治疗和TME成分可能会影响这些机制。最后， 这些模型将转化为临床更有效的治疗组合和方案。 该项目的成功完成将i）产生新的复杂肉瘤小鼠模型， 概括了在人类肉瘤中发现的遗传缺陷，并提供了一个全面的功能， 这些模型的表征（目的1），ii）阐明肿瘤细胞的表达谱 以及它们的离散亚组，以了解这些概况如何影响TME组成 (Aim 2），iii）测试这些模型如何响应不同的放射治疗给药方案， 不同的肿瘤遗传学、表达谱和环境的异质性设置 （目标3）。

ABSTRACT Soft-tissue sarcomas are heterogeneous tumors that originate from cells belonging to the mesenchymal lineages, and that affect almost 200,000 individuals worldwide each year. The most aggressive and metastatic sub-types in adults are those with complex karyotypes and multiple genetic aberrations. The overall survival of these sarcoma patients has not greatly improved in recent years, and alternative approaches to chemotherapy and radiotherapy such as immunotherapy have so far provided only marginal benefits. Novel therapeutic advances for UPS are hindered by the lack of knowledge about the functional consequences of the complex genomic alterations found in patients and limited characterizations of the tumor microenvironment (TME), which would reveal non-cell-autonomous mechanisms critical to sarcoma progression. Experimental tools and available animal models currently do not address these limitations. However, appropriate models could facilitate the efficient discovery of new targets and immune- based therapies for these tumors, which have relatively low incidence and for which the development of clinical trials is often challenging. Accordingly, we propose to generate sarcoma mouse models that encompass the actual somatic aberrations observed in patients. Moreover, we will use these models to facilitate studies of treatment response and TME composition. The employment of these new models, together with newer technologies such as single-cell RNA- sequencing (scRNA-seq), CyTOF and Imaging Mass Cytometry (IMC) will ultimately illuminate the key expression profile of the single tumor cells, mechanisms of metastasis, resistance to conventional treatments and TME components that may influence such mechanisms. Ultimately, these models will translate to the clinic more effective therapeutic combinations and regimens. Successful completion of this project will i) generate new mouse models of complex sarcoma that recapitulate the genetic defects found in human sarcoma and provide a comprehensive functional characterization of these models (Aim 1), ii) illuminate the expression profile of the tumor cells and discrete sub-groups of them, to understand how these profiles influence the TME composition (Aim 2), iii) test how these models respond to different radiotherapy administration schedules in the heterogeneous settings of distinct tumor genetics, expression profiles and environmental elements (Aim 3).