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.

项目概要胰腺导管腺癌（PDA）是一种高度侵袭性的疾病，预计将成为第二大癌症到 2030 年，癌症将成为西方世界癌症死亡的主要原因。最近，利用转录分析进行的研究从切除的 PDA 标本中鉴定出两种分子上不同的亚型，称为经典亚型和基础亚型。这些亚型与患者的总体生存率相关，基础亚型预测较高的生存率转移、对治疗反应不佳和最坏的结果。虽然这种分类代表了一个重要的在识别患有 PDA 最具侵袭性变体的患者方面取得了突破，PDA 的潜在电路驱动该变体的主要特征尚不清楚。如果没有清楚地了解这种生物学，我们就无法有效地治疗患有最致命形式的 PDA 的患者受到损害。因此，该领域的一个主要目标是识别驱动程序 PDA 的经典亚型和基础亚型，以便 1) 有效靶向基础 PDA 或 2) 促进转化一种攻击性较小的变体（经典），可能对治疗有更有效的反应。为了实现这一目标，我们发现 Hedgehog 通路转录因子 GLI2 发挥着作用以非规范配体独立的方式作为最具攻击性的基底亚型的关键调节剂 PDA（Adams 等人 eLife，2019；PMC6538376）。支持该模型的主要发现是：(1) GLI2 表达在基础 PDA 细胞系和患者肿瘤中升高，并预测患者的生存期较短，(2) GLI2 抑制导致 Basal 特性丧失并抑制肿瘤生长，而 Classical 中异位 GLI2 表达 PDA 细胞导致切换至基础状态 (3)。我们的研究结果强调了以前未被认识到的水平 PDA 细胞的可塑性，并强调 GLI2 在驱动这种疾病的基础特性中的全新作用。建筑在这项工作中，我们假设 GLI2 的抑制代表了 Basal PDA 的独特脆弱性对抗 KRAS* 耐药性和肿瘤进展。因此，我们提出了 2 个具体目标，即 1) 定义由 GLI2 以细胞自主方式调节的非规范转录回路，以介导耐药性 KRAS* 通路抑制和 2) 确定 GLI2 依赖性分泌因子如何调节周围细胞促进原发性和转移性肿瘤的生长。这些研究将确定控制的细胞回路基础特性，定义它们在 KRAS* 耐药、肿瘤复发和转移中的作用，并奠定基础为提高已进入临床的 KRAS 靶向疗法的有效性奠定了基础。