Exploring Interactions Between Retinoid and Vitamin D Signaling in Salivary Gland Homeostasis and Cancer

探索类视黄醇和维生素 D 信号在唾液腺稳态和癌症中的相互作用

基本信息

批准号：
9754574
负责人：
Kara A DeSantis
金额：
$ 6.24万
依托单位：
STATE UNIVERSITY OF NEW YORK AT ALBANY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9754574
关键词：
Acute Myelocytic Leukemia Address Adult Affect Agonist All-Trans-Retinol Apoptosis Archives Area Basal Cell Breast Cancer Model Cell Differentiation process Cell Fate Control Cell Lineage Cell Proliferation Cell division Cells Cryoultramicrotomy Cytokeratin Data Development Ductal Epithelial Cell Epithelial Genes Homeostasis Human Immunohistochemistry Incidence Individual Knock-out Laboratories Ligands Link Malignant Neoplasms Mammary Duct Mammary Neoplasms Mammary gland Monocytic leukemia Mus Myelogenous Neurons Nuclear Nuclear Receptors Ontology Organ Osteoblasts Oxides Pathology Pathway interactions Patients Pharmacologic Substance Pharmacology Physiological Population Prevention Proliferation Marker Property Protein Isoforms RNA Receptor Signaling Regulation Reporter Research Resistance Retinoic Acid Receptor Retinoids Role Salivary Salivary Gland Neoplasms Salivary Gland Tissue Salivary Glands Sampling Signal Pathway Signal Transduction Stem cells System Testing Tissue Microarray Tissues Tretinoin Vitamin A Vitamin D Vitamin D3 Receptor Vitamins Work aldehyde dehydrogenases cancer stem cell cell motility dimethylbenzanthracene druggable target granulocyte human disease human population study irradiation malignant breast neoplasm neoplastic cell novel therapeutic intervention outcome forecast receptor receptor expression retinoic acid receptor alpha salivary cell skeletal small molecule synergism targeted delivery three dimensional cell culture transcriptome sequencing tumor tumorigenesis tumorigenic

项目摘要

Abstract: Basal cell derived salivary and breast cancers are correlated with poor patient prognosis, increased cancer reoccurrence and lack of definitive therapies1. In both branching organs, cytokeratin 5-positive (K5+) basal cells contribute to ductal cells during normal development2–4 and recent research has highlighted similarities in the K5+ basal cell origin of mammary and salivary squamous cells5,6. In mammary tumors of basal origin, irradiation- resistant cancer stem cells (CSCs) demonstrate K5 positivity1. Both Vitamin D and Vitamin A signaling pathways have been implicated in prevention of tumorigenesis7,8. In the developing9 salivary gland, we and others10 have recently demonstrated that retinoic acid receptor (RAR) signaling contributes to expansion of K5+ basal cells, a phenomena conserved in the adult salivary gland11. In both mammary12 and salivary glands13, CSCs display an upregulated level of ALDH, an aldehyde dehydrogenase that oxidizes Vitamin A to retinol, the precursor to retinoic acid and signaling through RARs. The relationship between RAR signaling and K5+ basal cells during tumorigenesis has yet to be explored. Work in the Welsh laboratory has shown that deletion of the Vitamin D receptor (VDR) in mice leads to increased cell proliferation and tumorigenesis in the breast7 where VDR activity is linked to K5+ cell fate transition4. In human population studies, low levels of Vitamin D are associated with increased cancer incidence and progression14–16. In the submandibular salivary gland (SMG), progenitor cell populations are highly positive for VDR17 and in humans, VDR localizes to epithelial cells18; yet, Vitamin D signaling has not been specifically explored in the salivary gland. We will test the hypothesis that co- activating VDR and RAR signaling will reduce K5+ basal cell expansion and tumorigenesis in the SMG. In this proposal we will address the following questions: 1) What is the role of VDR signaling in K5+ basal cell expansion and differentiation in the SMG? 2) Does VDR signaling synergize with RARα signaling to negatively regulate K5+ basal cell expansion in the SMG? 3) Will loss of VDR signaling synergize with inhibition of RARα signaling to enhance K5+ tumorigenesis in the SMG? 4) Will activation of VDR and RARα signaling in K5- TdTomato-positive tumor cells using directed delivery of vitamin derivatives and small molecules decrease tumorigenic cell properties? To determine if RARα and VDR signaling synergize in negatively regulating the K5+ population in the SMG, in Aim 1 we will inhibit RARα signaling in a VDR knockout K5 reporter mouse and trace K5+ basal cell fate. In Aim 2, we will determine if VDR and RARα pathways synergize to regulate K5+ cell expansion in basal salivary tumors. This aim will be achieved with targeted pharmacological inhibition of RARα signaling in a VDR knockout K5 reporter mouse induced for tumorigenesis with DMBA. Additionally, we will determine if activation of VDR and RARα signaling in K5-TdTomato-positive tumor cells using small molecules and vitamin derivatives in 3D culture will affect cell division and motility.

抽象的：基底细胞来源的唾液癌和乳腺癌与患者预后不良、癌症增加相关复发且缺乏明确的治疗方法1 在两个分支器官中，细胞角蛋白 5 阳性 (K5+) 基底细胞。在正常发育过程中对导管细胞有贡献2-4，最近的研究强调了导管细胞的相似之处乳腺和唾液鳞状细胞的 K5+ 基底细胞起源5,6 在基底起源的乳腺肿瘤中，辐射- 抗性癌症干细胞 (CSC) 表现出 K5 阳性，维生素 D 和维生素 A 信号通路均呈阳性。与预防肿瘤发生有关7,8 在发育中的9唾液腺中，我们和其他人10已经发现。最近证明，视黄酸受体 (RAR) 信号传导有助于 K5+ 基底细胞的扩增，这是一种成人唾液腺中保留的现象 11 在乳腺 12 和唾液腺 13 中，CSC 均表现出 ALDH 水平上调，ALDH 是一种乙醛脱氢酶，可将维生素 A 氧化为视黄醇，视黄醇是维生素 A 的前体视黄酸和 RAR 信号传导过程中 RAR 信号传导与 K5+ 基底细胞之间的关系。威尔士实验室的研究表明，维生素 D 的缺失导致肿瘤发生。小鼠中的 VDR 受体（VDR）会导致乳房细胞增殖和肿瘤发生增加7，其中 VDR 活性与 K5+ 细胞命运转变有关4。在人群研究中，维生素 D 水平低与此相关。下颌下唾液腺 (SMG) 祖细胞的癌症发病率和进展增加14-16。人群中 VDR17 呈高度阳性，而在人类中，VDR 定位于上皮细胞18；然而，维生素 D 信号传导尚未在唾液腺中进行专门研究，我们将检验以下假设：激活 VDR 和 RAR 信号传导将减少 SMG 中 K5+ 基底细胞的扩增和肿瘤发生。在本提案中，我们将解决以下问题：1）VDR 信号在 K5+ 基底细胞中的作用是什么 SMG 中的扩增和分化？ 2) VDR 信号传导是否与 RARα 信号传导产生负协同作用？调节 SMG 中 K5+ 基底细胞的扩增？ 3) VDR 信号传导的丧失是否会与 RARα 的抑制产生协同作用？信号传导增强 SMG 中的 K5+ 肿瘤发生？ 4) K5- 中的 VDR 和 RARα 信号传导会激活吗？使用直接递送维生素衍生物和小分子的 TdTomato 阳性肿瘤细胞减少致瘤细胞特性？确定 RARα 和 VDR 信号传导是否协同负向调节 K5+ SMG 中的群体，在目标 1 中，我们将抑制 VDR 敲除 K5 报告小鼠中的 RARα 信号传导并进行追踪在目标 2 中，我们将确定 VDR 和 RARα 通路是否协同调节 K5+ 细胞。通过靶向药物抑制 RARα 可以实现基底唾液腺肿瘤的扩张。使用 DMBA 诱导 VDR 敲除 K5 报告小鼠中的信号传导以诱导肿瘤发生。确定使用小分子是否激活 K5-TdTomato 阳性肿瘤细胞中的 VDR 和 RARα 信号传导 3D培养中的维生素衍生物会影响细胞分裂和运动。