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Targeting asymmetric ciliary signaling in cancer

针对癌症中的不对称纤毛信号传导

基本信息

批准号：
9751534
负责人：
ERICA A. GOLEMIS
金额：
$ 19.9万
依托单位：
RESEARCH INST OF FOX CHASE CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9751534
关键词：
Adenocarcinoma Cell Affect Attention Biological Process Blood Cells CRISPR/Cas technology Cancer Etiology Cell Line Cell surface Cells Cessation of life Cilia Clinical Communication Cues Cytotoxic agent DNA Damage Desmoplastic Drug Targeting Drug effect disorder Extracellular Matrix Extracellular Matrix Proteins Fibroblasts Genes Goals Growth IGF1 gene IRAK4 gene Immune Immune signaling Interruption Investigation Knock-out Knowledge Laboratories Libraries Ligands Maintenance Malignant Neoplasms Mediating Mediator of activation protein Modeling Organelles Pancreas Pancreatic Adenocarcinoma Pancreatic Ductal Adenocarcinoma Patients Pharmaceutical Preparations Phosphotransferases Platelet-Derived Growth Factor alpha Receptor Process Production Proprotein Convertase 1 Proprotein Convertase 2 Proteins Public Health Regulation Resistance Role SHH gene STK6 gene Signal Pathway Signal Transduction Signaling Protein Small Interfering RNA Specificity Stromal Cells Stromal Neoplasm Survival Rate System Therapeutic antibodies Time Tumor Biology Vertebrates Work aurora-A kinase autocrine base cancer cell cancer type cell type experimental study extracellular high throughput screening improved in vivo insight kinase inhibitor neoplastic cell notch protein novel novel strategies pancreas development pancreatic cancer cells paracrine receptor response small molecule libraries smoothened signaling pathway stellate cell targeted agent therapeutic effectiveness tool treatment response tumor tumor growth virtual

项目摘要

Project Summary/Abstract The primary monocilium, or cilium, is a specialized organelle that provides a spatially concentrated platform for receipt of extracellular cues and induction of intracellular response for signaling pathways downstream of Sonic Hedgehog (SHH), WNT, PDGFRα, and other extracellular ligands. In non-pathological conditions, single cilia are present on virtually all cell types (except blood cells) in vertebrates. However, ciliary dynamics are frequently altered in cancer, resulting in asymmetry of expression between tumor cells, which typically downregulate cilia, and tumor-associated stroma, which maintain them. This asymmetry supports the ability of cancer cells to condition the growth of surrounding stroma via paracrine SHH signaling, while limiting autocrine SHH responsiveness, and is important in biological processes such as the creation and maintenance of desmoplastic stroma in pancreatic adenocarcinoma (PDAC). Desmoplasia, in turn, promotes tumor resistance to cytotoxic and targeted agents, regulates the immune microenvironment, and otherwise supports aggressive tumor growth. This proposal is based on the idea that better understanding of the mechanisms regulating ciliary integrity and signaling capacity in tumors versus stromal cells, and identification of agents to manipulate these processes, may offer a way to interrupt critical signaling for cancer and improve therapeutic response. We have used candidate and high throughput screening approaches to identify a set of kinase inhibitors of known target specificity (including some FDA agents in clinical use) that caused loss or abnormal retention of cilia. We hypothesize that these drugs, some of which are under investigation for PDAC, may function in part through previously unanticipated activity in enhancing or disrupting tumor-stromal communications. In preliminary studies, we have used siRNA depletion of drug targets for drug hits to confirm and refine understanding of their mechanism of action. We have also shown that some of the drugs regulate cellular response to SHH, revealing entirely novel signaling pathway connections mediated by control of ciliary integrity. The goal of the Aims is to elucidate and target asymmetric cilia-mediated SHH signaling in PDACs. In Aim 1, we will determine how candidate cilia-regulating drugs alter paracellular SHH-initiated communication between pancreatic stellate cells, tumor associated fibroblasts, and PDAC cells. In Aim 2, we will explore in depth the mechanistic role of IRAK4 and other components of the innate immune signaling system we have for the first time identified as mediators of ciliation. This work is expected to provide important insights into novel mechanisms regulating ciliary dynamics, PDAC tumor biology, and the action of currently approved drugs, and may result in entirely new approaches to improve therapeutic effectiveness for PDAC and other cancers.

项目总结/文摘