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：
10388701
负责人：
Kara A DeSantis
金额：
$ 2.31万
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 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10388701
关键词：
Address Adipocytes 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 Cells Genes Homeostasis Human Immunohistochemistry Incidence Individual Knock-out Laboratories Leukemic Cell Ligands Link Malignant Neoplasms Mammary Duct Mammary Neoplasms Monocytic leukemia Mus Myeloid Cells Natural regeneration Neurons Nuclear Nuclear Receptors Oligodendroglia Ontology Organ Osteoblasts Oxides Pathology Pathway interactions Patients Pharmacologic Substance Pharmacology Physiological Population Prevention Prognosis Proliferation Marker Property Protein Isoforms RNA Receptor Signaling Regulation Reporter Research Retinoic Acid Receptor Retinoids Role Salivary Salivary Gland Neoplasms Salivary Gland Tissue Salivary Glands Sampling Signal Pathway Signal Transduction Skeletal Muscle Squamous Cell System Testing Tissue Microarray Tissues Tretinoin Vitamin A Vitamin D Vitamin D3 Receptor Vitamins Work acute myeloid leukemia cell aldehyde dehydrogenases cancer stem cell cell motility dimethylbenzanthracene druggable target granulocyte human disease human population study irradiation malignant breast neoplasm mammary mammary epithelium neoplastic cell novel therapeutic intervention receptor receptor expression refractory cancer retinoic acid receptor alpha salivary cell small molecule stem cells 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 therapies 1. In both branching organs, cytokeratin 5-positive (K5+) basal cells contribute to ductal cells during normal development 2–4 and recent research has highlighted similarities in the K5+ basal cell origin of mammary and salivary squamous cells 5,6. In mammary tumors of basal origin, irradiation- resistant cancer stem cells (CSCs) demonstrate K5 positivity 1. Both Vitamin D and Vitamin A signaling pathways have been implicated in prevention of tumorigenesis 7,8. In the developing 9 salivary gland, we and others 10 have recently demonstrated that retinoic acid receptor (RAR) signaling contributes to expansion of K5+ basal cells, a phenomena conserved in the adult salivary gland 11. In both mammary 12 and salivary glands 13, 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 breast 7 where VDR activity is linked to K5+ cell fate transition 4. In human population studies, low levels of Vitamin D are associated with increased cancer incidence and progression 14–16. In the submandibular salivary gland (SMG), progenitor cell populations are highly positive for VDR 17 and in humans, VDR localizes to epithelial cells 18; 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：基底细胞衍生的唾液和乳腺癌与患者提示不佳，癌症增加再发生和缺乏确定的疗法1。在两个分支器官中，细胞角蛋白5阳性（K5+）碱性细胞在正常发育过程中有助于导管细胞2-4，最近的研究强调了相似之处 K5+乳腺和唾液鳞状细胞的基本细胞起源5,6。在基本起源的乳腺肿瘤中，辐照 - 抗性癌干细胞（CSC）表现出K5阳性1。维生素D和维生素A信号通路已经暗示预防肿瘤发生7,8。在开发的9种唾液腺中，我们和其他人有10个最近证明，视黄酸受体（RAR）信号传导有助于K5+碱性细胞的扩展，A 在成年唾液腺11中保守的现象11。在乳腺12和唾液腺13中，CSC显示 ALDH的上调水平，一种氧化维生素A至视黄醇的醛脱氢酶视黄酸和通过RAR的信号传导。 RAR信号传导与K5+基本单元之间的关系肿瘤发生尚未探索。威尔士实验室的工作表明，维生素D的缺失小鼠的受体（VDR）导致乳腺7的细胞增殖和肿瘤发生增加，其中VDR活性与K5+细胞命运转变相关。在人群研究中，低水平的维生素D与癌症发病率和进展增加14-16。在下颌下唾液腺（SMG）中，祖细胞 VDR 17和人类的种群高度为阳性，VDR定位于上皮细胞18。但是，维生素d 在唾液腺中尚未特别探索信号传导。我们将检验以下假设激活VDR和RAR信号将减少SMG中的K5+基本细胞膨胀和肿瘤发生。在此提案中，我们将解决以下问题：1）VDR信号在K5+基本单元中的作用是什么 SMG的扩展和差异化？ 2）vdr信号与RARα信号传导协同为负调节SMG中的K5+基本细胞扩展？ 3）将损失VDR信号传导协同抑制RARα 信号传导以增强SMG中的K5+肿瘤发生？ 4）将激活K5-中的VDR和RARα信号传导 TDTOMATO阳性肿瘤细胞，使用维生素衍生物的定向递送和小分子降低肿瘤细胞的特性？确定RARα和VDR信号在负调控K5+方面是否协同作用 SMG中的人群，在AIM 1中，我们将抑制VDR基因敲除K5报告鼠的RARα信号传导和痕迹 K5+基本细胞命运。在AIM 2中，我们将确定VDR和RARα途径是否协同调节K5+细胞基本唾液肿瘤的扩张。通过靶向药物抑制RARα将实现此目标 VDR敲除K5报告基因小鼠的信号传导诱导DMBA肿瘤发生。此外，我们会的使用小分子确定K5-TDTOMATO阳性肿瘤细胞中VDR和RARα信号的激活是否激活 3D培养中的维生素衍生物将影响细胞分裂和运动。