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

• 批准号: 10404053
• 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
• 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/10404053
• 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; Metastatic to; Modeling; Molecular; Mus; Neoplasm Metastasis; Outcome; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Pharmacology; 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; programs; resistance mechanism; targeted treatment; transcription factor; treatment response; tumor; tumor growth; tumor progression; tumorigenic

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.

项目总结