Dissecting cell composition and drug sensitivity in human adenoid cystic carcinomas (ACCs).

剖析人类腺样囊性癌 (ACC) 的细胞组成和药物敏感性。

• 批准号: 10404496
• 负责人: Piero D Dalerba
• 金额: $ 37.65万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10404496
• 关键词: 3-Dimensional; Acids; Address; Adenoid Cystic Carcinoma; Affect; Agonist; Biochemical Pathway; Biological; CRISPR/Cas technology; Cancerous; Cells; Clinical; Clinical Treatment; Data; Development; Disease; Distant; Dominant-Negative Mutation; Drug Combinations; Drug resistance; Duct (organ) structure; Elements; Epigenetic Process; Epithelial; Equilibrium; Fluorescence-Activated Cell Sorting; Gene Expression; Genetic; Goals; Growth; Human; Human Biology; Immune; In Vitro; Infiltration; KRT19 gene; Kinetics; Knowledge; Laboratories; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of salivary gland; Molecular; Morbidity - disease rate; Mus; Myoepithelial; Myoepithelial cell; Neoplasm Metastasis; Oncology; Organoids; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Phase; Phenotype; Population; Preclinical Testing; Prevention; Process; Production; Property; Quality of life; RXR; Receptor Signaling; Refractory; Regimen; Reporter; Retinoids; Salivary; Salivary Glands; Signal Pathway; Site; Surface; System; Technology; Testing; Therapeutic; Time; Tissues; Toxic effect; Transducers; Transplantation; Treatment Efficacy; Tumor Biology; Xenograft procedure; base; cancer cell; cancer stem cell; cell type; chemoradiation; design; differential expression; drug sensitivity; experimental study; human tissue; in vitro testing; in vivo; in vivo evaluation; inhibitor; mortality; new therapeutic target; novel drug combination; novel therapeutic intervention; novel therapeutics; patient derived xenograft model; patient population; perineural; prevent; progenitor; prospective; receptor; self-renewal; single-cell RNA sequencing; stem cells; transcription factor; tumor

Adenoid Cystic Carcinomas (ACCs) represent one of the most common and biologically aggressive forms of epithelial malignancy of the salivary glands, for which there are no clinically approved treatments. ACCs are characterized by a high tendency towards peri-neural infiltration and distant-site metastasis, and are largely refractory to conventional chemo-radiotherapy approaches. ACCs are also defined by a distinctive biological feature: the co-existence within malignant tissues of two phenotypically distinct sub-populations of cancer cells (ductal-like vs. myoepithelial-like) characterized by profoundly distinct gene-expression profiles and functional properties. This study will leverage a portfolio of surface markers recently identified by our laboratory that allow, for the first time, the differential purification, molecular study and functional analysis of these two cell types. The hypotheses formally tested by this study are: a) that the two cell types co-exist in a dynamic and hierarchical equilibrium, whereby one cell type functions as a progenitor for the other; and b) that biochemical pathways regulating the conversion of one cell type into the other can be leveraged to develop new therapeutic approaches against ACCs. The project envisions two specific aims: 1) to elucidate the developmental relationship between the two cellular components of ACCs: we will use fluorescence activated cell sorting (FACS) to purify the two sub-populations of cancer cells from human ACCs, and then employ prospective in vivo xenotransplantation experiments and single-cell RNA-seq technologies to test whether the two cell types: a) display robust and systematic differences in tumor-initiating capacity across patient-derived xenograft (PDX) lines from independent patients; b) are hierarchically related (i.e. whether both can plastically inter-covert into each other or whether one serves as the progenitor of the other, in a mono-directional fashion); c) contain additional, previously unrecognized cellular sub-populations, themselves characterized by distinct molecular and functional properties; 2) to test the in vitro and in vivo therapeutic efficacy of novel drug combinations against ACCs, designed to target biochemical pathways shown to affect the differential representation and preferential survival of the two cellular sub-types: we will treat 3D organoids and PDX lines shown to recapitulate the dual cell composition of primary ACCs with sequential drug regimens, designed to, in a first step, induce the differentiation of myoepithelial-like cells into ductal-like cells and, in a second step, to selectively eliminate ductal-like cells; such novel drug regimens will be tested for their capacity to: a) cause changes in the cell composition of malignant tissues (ductal/myoepithelial cell ratio); b) reduce tumor size and/or growth kinetics; c) prevent in vivo metastatic dissemination (using non-invasive bio-luminescent reporters). Significance. This study will elucidate the molecular and functional properties of the two cell types found in human ACCs, filling a major scientific gap in salivary tumor biology, and addressing an unmet clinical need in salivary gland oncology: the identification of novel drug targets for the pharmacological treatment of ACCs.

腺样囊性癌 (ACC) 是最常见且最具生物侵袭性的形式之一 唾液腺上皮恶性肿瘤，目前尚无临床批准的治疗方法。 ACC 其特点是高度倾向于神经周围浸润和远处转移，并且大部分是 传统的放化疗方法难以治愈。 ACC 还由独特的生物学特性定义 特征：两种表型不同的癌细胞亚群在恶性组织内共存 （导管样与肌上皮样）的特征是截然不同的基因表达谱和功能 特性。这项研究将利用我们实验室最近发现的一系列表面标记物， 首次允许对这两种细胞类型进行差异纯化、分子研究和功能分析。 本研究正式检验的假设是：a) 这两种细胞类型以动态和分层的方式共存。 平衡，一种细胞类型充当另一种细胞类型的祖细胞； b) 生化途径 调节一种细胞类型向另一种细胞类型的转化可用于开发新的治疗方法 反对 ACC。该项目设想了两个具体目标：1）阐明发展关系 ACC 的两个细胞成分之间：我们将使用荧光激活细胞分选 (FACS) 来 从人类 ACC 中纯化出两个癌细胞亚群，然后在体内进行前瞻性研究 异种移植实验和单细胞RNA-seq技术来测试两种细胞类型是否：a) 在患者来源的异种移植物（PDX）中显示出肿瘤启动能力的强大和系统性差异 来自独立患者的线路； b）是层次相关的（即两者是否可以塑性地相互转换成 彼此或一个是否作为另一个的祖先（以单向方式）； c) 包含 另外，以前未被识别的细胞亚群，其本身具有不同的分子和特征 功能特性； 2）测试新型药物组合的体外和体内治疗效果 针对 ACC，旨在针对影响差异表达的生化途径 以及两种细胞亚型的优先存活：我们将治疗 3D 类器官和 PDX 细胞系 用连续的药物方案概括原代 ACC 的双细胞组成，旨在第一步， 诱导肌上皮样细胞分化为导管样细胞，第二步，选择性地 消除导管样细胞；将测试此类新药物治疗方案的能力：a）引起 恶性组织的细胞组成（导管/肌上皮细胞比率）； b) 减小肿瘤大小和/或生长动力学； c) 防止体内转移扩散（使用非侵入性生物发光报告基因）。意义。这 研究将阐明人类 ACC 中发现的两种细胞类型的分子和功能特性，填补 唾液腺肿瘤生物学的重大科学差距，并解决唾液腺肿瘤学中未满足的临床需求： 鉴定用于 ACC 药物治疗的新药物靶点。