权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Deciphering Autophagy-Dependent Secretion In Cancer Via Proximity-Based Biotinylation

通过基于邻近的生物素化破译癌症中自噬依赖性分泌

基本信息

批准号：
9178012
负责人：
Jayanta Debnath
金额：
$ 17.24万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9178012
关键词：
Ablation Address Advanced Malignant Neoplasm Angiogenic Factor Antimalarials Antineoplastic Agents Autophagocytosis Biogenesis Biological Markers Biotinylation Bypass Cancer Patient Cell Survival Cell secretion Cells Clinical Clinical Oncology Defect Endoplasmic Reticulum Exhibits Extracellular Space Family GORASP2 gene GRASP gene Genetic Goals Golgi Apparatus Growth Homeostasis Human Hydroxychloroquine KRAS2 gene Knowledge Label Laboratories Link Malignant Neoplasms Malignant neoplasm of lung Measures Metabolic Molecular Monitor Pathogenesis Pathway interactions Patients Process Proteins Proteomics Publishing Recording of previous events Reporter Role Serum Stress Therapeutic Intervention Toxic effect Tumor Cell Invasion Work base biomarker discovery cancer biomarkers cancer cell cancer therapy clinical biomarkers cytokine exosome fitness genetic approach in vivo inhibition of autophagy inhibitor/antagonist innovation insight interest loss of function mutant neoplastic cell novel release factor response therapy resistant trafficking treatment response tumor tumor progression tumorigenic

项目摘要

PROJECT SUMMARY Currently, there is immense interest in modulating autophagy against cancer. Anti-malarials, such as hydroxychloroquine (HCQ), have been aggressively repurposed as autophagy inhibitors in numerous clinical oncology trials. Despite this enthusiasm, we still do not fully understand how autophagy impacts cancer progression and treatment. To date, the primary rationale for targeting autophagy against cancer is because this catabolic pathway promotes tumor cell survival and metabolic adaptation. However, recent findings challenge this prevailing idea in the field. Although traditionally viewed as an “auto-digestive” pathway, emerging genetic evidence now implicates autophagy as an important regulator of cellular secretion. For example, we recently discovered new roles for autophagy regulators (ATGs) in promoting the coordinate secretion of cytokines required for tumor cell invasion. Nevertheless, our understanding of autophagy- dependent secretion in cancer remains rudimentary because of major conceptual and technical barriers that hamper deciphering how autophagy enables secretion. Most importantly, studies to date have exclusively relied on phenotypic analysis following genetic ablation of specific pathway components, such as ATGs; such loss-of-function approaches are limited because they fail to discern whether secretory defects represent a direct versus indirect consequence of impaired autophagy. To overcome these major obstacles in the field, we have created novel reporters utilizing proximity-based biotinylation (BioID) to specifically label proteins that rely upon the autophagy machinery for their release into the extracellular space. We will now leverage these innovative reporters to decipher the autophagy-dependent secretome and rigorously define the mechanisms by which autophagy promotes secretion. In Aim 1, we will elaborate the repertoire of autophagy-dependent secreted products using quantitative proteomics and assess their utility as biomarkers for monitoring tumor progression and treatment in vivo. For these studies, we will focus on KRAS mutant lung cancer cells exhibiting high levels of basal autophagy and secretion. In Aim 2, we will define the mechanisms by which autophagy controls tumor cell secretion. We will utilize proximity-based biotinylation strategies, combined with genetic approaches, to dissect the intracellular trafficking of autophagy-dependent secreted proteins as they exit the cell, with the long-term goal of identifying targets in these pathways for therapeutic intervention in cancer. Overall, these studies provide timely mechanistic insight into an entirely new role for autophagy in cancer progression and therapeutic response.

项目总结