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: 10623282
• 负责人: Piero D Dalerba
• 金额: $ 17.87万
• 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/10623282
• 关键词: 3-Dimensional; Acids; Address; Adenoid Cystic Carcinoma; Affect; Agonist; Biochemical Pathway; Biological; CRISPR/Cas technology; Cancerous; Cells; Clinical; Clinical Treatment; Combined Modality Therapy; Data; Development; Disease; Distant; Dominant-Negative Mutation; Drug Combinations; Drug resistance; Duct (organ) structure; Elements; Epigenetic Process; Epithelium; Equilibrium; Fluorescence-Activated Cell Sorting; Gene Expression; Genetic; Goals; Growth; Human; Human Biology; Immune; In Vitro; Infiltration; Invaded; 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; Phase; Phenotype; Population; Preclinical Testing; Prevention; Process; Production; Property; Quality of life; RXR; Receptor Signaling; Refractory; Regimen; Reporter; Retinoids; Salivary; Salivary Glands; Signal Induction; Signal Pathway; Site; Surface; System; Technology; Testing; Therapeutic; Time; Tissues; Toxic effect; Transducers; Transplantation; Treatment Efficacy; Tumor Biology; Xenograft procedure; cancer cell; cancer stem cell; candidate identification; 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; pharmacologic; prevent; progenitor; prospective; receptor; self-renewal; single-cell RNA sequencing; stem cells; transcription factor; tumor; tumor initiation

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.

腺样性囊性癌（ACC）代表了最常见和生物学上的一种形式之一 唾液腺上皮性恶性肿瘤，没有临床批准的治疗方法。 ACC 其特征是高度倾向神经周围浸润和远处转移的趋势，并且在很大程度上是 对常规化学放射疗法方法的难治性。 ACC还由独特的生物学定义 特征：两种表型不同的癌细胞的恶性组织中的共存 （类似导管状的与肌上皮状的），其特征是深度不同的基因表达曲线和功能 特性。这项研究将利用我们实验室最近确定的表面标记物组合 首次允许这两种细胞类型的差分纯化，分子研究和功能分析。 这项研究正式检验的假设是：a）两种细胞类型在动态和分层中共存 平衡，一种细胞类型作为另一种细胞的祖细胞的功能； b）生化途径 可以利用调节一种细胞类型向另一种细胞类型的转换来开发新的治疗方法 反对ACC。该项目设想了两个具体目标：1）阐明发展关系 在ACC的两个细胞组件之间：我们将使用荧光激活的细胞分选（FACS） 净化来自人类ACC的癌细胞的两个亚种群，然后在体内使用前瞻性 异种移植实验和单细胞RNA-seq技术测试是否两种细胞类型：A） 在患者衍生的异种移植物（PDX）上显示出牢固且系统的差异 来自独立患者的线； b）在层次上相关（即两者是否都可以塑料间交流 彼此彼此，或者是以单向方式充当另一个的祖细胞）； c）包含 其他以前未被认可的细胞亚群，其本身以独特的分子和 功能特性； 2）测试新型药物组合的体外和体内治疗功效 反对ACC，旨在靶向显示出影响差异表示的生化途径 和两个细胞亚型的优先存活：我们将处理3D类器官和PDX线 用顺序药物方案概括了初级ACC的双细胞组成，该方案旨在在第一步中 诱导肌上皮样细胞分化为导管样细胞，并在第二步中选择性地分化 消除导管样细胞；这种新型药物方案将测试其能力：a）导致变化 恶性组织的细胞组成（导管/肌上皮细胞比）； b）减少肿瘤大小和/或生长动力学； c）防止体内转移性传播（使用非侵入性生物发光记者）。意义。这 研究将阐明在人ACC中发现的两种细胞类型的分子和功能特性，以填充A 唾液肿瘤生物学的主要科学差距，并满足唾液腺肿瘤学未满足的临床需求： 鉴定新型药物靶标的ACC药理治疗。