Identifying Molecular Drivers of Cellular Plasticity in Pancreatic Cancer

项目总结 胰腺导管腺癌(Pda)是一种高度侵袭性的疾病，预计将成为第二大疾病。 到2030年，成为西方世界癌症死亡的主要原因。最近，利用转录特征分析的研究 从切除的PDA标本中，已经鉴定出两个分子上不同的亚型，即经典和基本。 这些亚型与患者的总存活率相关，基本亚型预示着较高的 转移，治疗反应差，预后最差。虽然这种分类代表着一个重要的 在识别患有最激进的PDA变种的患者方面取得突破，PDA是驱动 这个变种的主要特征是未知的。如果没有对这种生物学的清楚了解，我们有效地 治疗最致命形式的PDA的患者受到了损害。因此，该领域的一个主要目标是识别司机 传统和基本类型的PDA，以便1)有效地瞄准基本PDA或2)促进转换 一种攻击性较弱的变种(经典)，可能对治疗更有效。 为此，我们发现了Hedgehog途径转录因子GLI2的功能 以非正则配体独立的方式作为最具侵略性的碱基亚型的关键调节因子 PDA(Adams等人，2019年；PMC6538376)。支持这一模型的主要发现是：(1)GLI2的表达 在基础PDA细胞系和患者肿瘤中升高，并预测患者的存活时间较短，(2)GLI2 GLI2异位表达时抑制肿瘤生长并导致碱基同一性丧失 PDA信元导致切换到基本状态(3)。我们的发现强调了一个以前未被认识到的水平 GLI2在PDA细胞中的可塑性，并突显了GLI2在推动这种疾病的基本认同感方面的全新角色。建房 在这项工作中，我们假设GLI2的抑制代表了Basal PDA中的一个独特的漏洞 对抗KRAS*耐药性和肿瘤进展。因此，我们提出两个具体目标：1)定义 由GLI2以细胞自主的方式调节的非规范转录电路，以介导对 KRAS*途径抑制和2)决定GLI2依赖的分泌因子如何影响细胞周围 以促进原发和转移肿瘤的生长。这些研究将确定控制细胞电路的 基本同一性，确定它们在KRAS*耐药、肿瘤复发和转移的背景下的作用，并奠定 为提高已进入临床的KRAS靶向治疗的有效性奠定基础。

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.