Identifying Molecular Drivers of Cellular Plasticity in Pancreatic Cancer

识别胰腺癌细胞可塑性的分子驱动因素

基本信息

批准号：
10626914
负责人：
Rushika Miriam Perera
金额：
$ 36.2万
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：
2020
资助国家：
美国
起止时间：
2020-09-03 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10626914
关键词：
Address Automobile Driving Biology Cancer Etiology Cell Line Cells Cessation of life Classification Clinic Coculture Techniques Disease Effectiveness Epithelial Cells Erinaceidae GLI2 gene Gene Expression Profiling Genetic Genetic Transcription Goals Human KRAS2 gene Ligands Maintenance Malignant neoplasm of pancreas Mediating Modeling Molecular Mus Neoplasm Metastasis Outcome Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Phenotype Primary Neoplasm Process Prognosis Relapse Resected Resistance Role Specimen Up-Regulation Variant Western World Work autocrine chemotherapy clinically relevant combat conditioning disorder subtype effective therapy gain of function human model in vivo mutant neoplastic cell osteopontin overexpression pancreatic ductal adenocarcinoma cell paracrine pharmacologic programs resistance mechanism targeted treatment transcription factor treatment response tumor tumor growth tumor progression tumorigenic

项目摘要

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDA) is a highly aggressive disease that is projected to become the second leading cause of cancer deaths in the Western world by 2030. Recently, studies utilizing transcriptional profiling from resected PDA specimens have identified two molecularly distinct subtypes termed Classical and Basal. These subtypes correlate with overall patient survival, with the Basal subtype predictive of higher rates of metastasis, poor response to therapy and the worst outcomes. While this classification represents an important breakthrough for identifying patients with the most aggressive variant of PDA, the underlying circuits that drive key features of this variant are unknown. Without a clear understanding of this biology, our ability to effectively treat patients with the deadliest form of PDA is compromised. Thus, a major goal in the field is to identify drivers of the Classical and Basal subtypes of PDA in order to 1) effectively target Basal PDA or 2) promote conversion to a less aggressive variant (Classical) that may respond more effectively to therapy. Towards this goal, we have discovered that the Hedgehog pathway transcription factor, GLI2, functions in a non-canonical ligand independent manner as a critical regulator of the most aggressive Basal subtype of PDA (Adams et al eLife, 2019; PMC6538376). The key findings in support of this model are, (1) GLI2 expression is elevated in Basal PDA cell lines and patient tumors and predicts shorter survival in patients, (2) GLI2 suppression leads to loss of Basal identity and inhibits tumor growth while ectopic GLI2 expression in Classical PDA cells causes a switch to the Basal state (3). Our findings underscore a previously unrecognized level of plasticity in PDA cells and highlight an entirely new role for GLI2 in driving Basal identity in this disease. Building on this work, we hypothesize that suppression of GLI2 represents a unique vulnerability in Basal PDA to combat KRAS* resistance and tumor progression. Thus, we propose 2 specific aims that will 1) define the non-canonical transcriptional circuits regulated by GLI2 in a cell-autonomous manner to mediate resistance to KRAS* pathway suppression and 2) determine how GLI2-dependent secreted factors condition surrounding cells to promote primary and metastatic tumor growth. These studies will determine the cellular circuits that control Basal identity, define their role in the context of KRAS* resistance, tumor relapse and metastasis and lay the groundwork for increasing the effectiveness of KRAS-targeted therapies that have entered the clinic.

项目摘要胰腺导管腺癌（PDA）是一种高度侵略性疾病，预计将成为第二种到2030年，西方世界的癌症死亡的主要原因。最近，利用转录分析的研究从切除的PDA标本中，已经确定了两个分子不同的亚型，称为经典和基础。这些亚型与总体患者生存相关，基础亚型可预测较高的速率转移，对治疗的反应不佳以及最坏情况。虽然该分类代表了一个重要的识别PDA最具侵略性变体的患者的突破，即驱动的基础电路该变体的关键特征未知。在没有清楚地了解这种生物学的情况下，我们有效的能力用最致命的PDA治疗患者受到损害。因此，该领域的主要目标是确定驾驶员 PDA的经典和基础子类型的范围为1）有效靶向基础PDA或2）促进转化对于不太积极的变体（经典），可能对治疗的反应更有效。为了实现这一目标，我们发现刺猬途径转录因子Gli2，功能以非典型的配体独立方式作为最具侵略性的基础亚型的关键调节剂 PDA（Adams等人Elife，2019; PMC6538376）。支持该模型的主要发现是（1）GLI2表达在基底PDA细胞系和患者肿瘤中升高，并预测患者的较短生存率，（2）GLI2 抑制会导致基础认同的丧失并抑制肿瘤的生长，而异位GLI2在经典中表达 PDA细胞会导致切换到基础状态（3）。我们的发现强调了以前未被认为的水平 PDA细胞中的可塑性，突出显示GLI2在推动该疾病基础身份中的全新作用。建筑在这项工作中，我们假设抑制Gli2代表了基底PDA中的独特脆弱性战斗KRAS*抗性和肿瘤进展。因此，我们提出了2个特定目标，这些目标将是1）定义由GLI2调节的非典型转录电路以细胞自主的方式调节对 Kras*途径抑制和2）确定GLI2依赖性分泌因子如何条件周围细胞促进原发性和转移性肿瘤生长。这些研究将确定控制的细胞电路基础身份，定义其在Kras*抗性，肿瘤复发和转移的背景下的作用提高进入诊所的KRAS靶向疗法的有效性的基础。