Identifying Molecular Drivers of Cellular Plasticity in Pancreatic Cancer

项目摘要 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 到2030年，癌症将成为西方世界的主要死因。最近，利用转录谱的研究 从切除的PDA标本中鉴定出两种分子上不同的亚型，称为经典型和基底型。 这些亚型与患者的总体生存率相关，其中基础亚型预测较高的生存率。 转移，对治疗的反应差和最差的结果。虽然这种分类代表了一个重要的 这是一项突破，用于识别患有最具侵略性的PDA变体的患者， 该变种的主要特征尚不清楚。如果没有对这种生物学的清晰理解，我们有效地 治疗最致命的动脉导管未闭患者的能力受到了影响。因此，该领域的一个主要目标是确定驱动因素 为了1）有效靶向基础PDA或2）促进转化， 一种攻击性较低的变异（经典型），可能对治疗反应更有效。 为了实现这一目标，我们发现Hedgehog途径转录因子GLI 2， 以非典型配体独立的方式作为最具侵袭性的基底亚型的关键调节剂， PDA（亚当斯等人eLife，2019; PMC 6538376）。支持这一模型的关键发现是，（1）GLI 2表达 在基底PDA细胞系和患者肿瘤中升高，并预测患者的生存期较短，（2）GLI 2 抑制导致基底细胞特性丧失并抑制肿瘤生长，而在经典肿瘤中异位GLI 2表达 PDA细胞导致转换为基础状态（3）。我们的研究结果强调了以前未被认识到的 这一发现揭示了PDA细胞的可塑性，并突出了GLI 2在这种疾病中驱动基底细胞身份的全新作用。建筑 在这项工作中，我们假设GLI 2的抑制代表了基底动脉粥样硬化的独特脆弱性， 对抗KRAS* 抗性和肿瘤进展。因此，我们提出了2个具体目标，1）定义 GLI 2以细胞自主方式调节的非经典转录回路介导对 KRAS* 通路抑制和2）确定GLI 2依赖性分泌因子如何调节周围细胞 以促进原发性和转移性肿瘤生长。这些研究将确定细胞回路控制 基础身份，定义其在KRAS* 耐药、肿瘤复发和转移背景下的作用，并奠定基础。 为提高已进入临床的KRAS靶向治疗的有效性奠定了基础。

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.