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，起源于 间充质血统，每年影响全球近20万人。最多的 成人的侵袭性和转移性亚型是那些具有复杂核型和多发性 基因变异。这些肉瘤患者的总体存活率在#年并没有太大的改善。 近年来，化疗和放射治疗的替代方法，如 到目前为止，免疫疗法只带来了微乎其微的好处。UPS治疗新进展 由于对复杂基因组的功能后果缺乏了解而受到阻碍 在患者中发现的改变和肿瘤微环境(TME)的有限特征， 这将揭示对肉瘤进展至关重要的非细胞自主机制。 实验工具和可用的动物模型目前还没有解决这些限制。 然而，适当的模型可以促进有效地发现新的靶点和免疫- 这些肿瘤的基础治疗，发病率相对较低，对于 临床试验的发展往往是具有挑战性的。因此，我们建议产生肉瘤 包含在患者身上观察到的实际体细胞畸变的小鼠模型。此外， 我们将使用这些模型来促进治疗反应和TME成分的研究。这个 这些新模型的应用，加上单细胞RNA等较新的技术-- 测序(scRNA-seq)、细胞飞行时间和成像质量细胞术(IMC)最终将阐明 单个肿瘤细胞的关键表达谱，转移机制，耐药 可能影响这种机制的常规治疗和TME组件。最终， 这些模式将转化为临床上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， 概述了在人类肉瘤中发现的遗传缺陷，并提供了全面的功能 这些模型的特征(目标1)，II)阐明了肿瘤细胞的表达谱 以及它们的离散子群，以了解这些剖面如何影响TME组成 (目标2)，III)测试这些模型如何响应不同的放射治疗计划 不同肿瘤遗传学、表达谱和环境的异质性环境 要素(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).