Project 2: Targeting signaling networks to overcome therapeutic resistance in pancreatic cancer

项目 2：靶向信号网络克服胰腺癌的治疗耐药性

• 批准号: 10629064
• 负责人: TONY R. HUNTER
• 金额: $ 49.76万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-06 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629064
• 关键词: Acceleration; Affect; Antibodies; Automobile Driving; Autophagocytosis; Blocking Antibodies; CA-19-9 Antigen; Cell Compartmentation; Cell Proliferation; Cell membrane; Cells; Chemoresistance; Clinical; Coculture Techniques; Combined Modality Therapy; Common Carcinoma; Complex; Cytokine Signaling; Data; Diagnosis; Disease; Disease Resistance; Epidermal Growth Factor Receptor; Epithelial Cells; Epithelium; Epitopes; Family; Fibroblasts; Genes; Genetic; Genetically Engineered Mouse; Growth; Heterogeneity; Human; IL6 gene; Immune; Immune checkpoint inhibitor; Intercept; KRAS2 gene; Kinetics; LIF gene; Malignant Neoplasms; Malignant neoplasm of pancreas; Maps; Mediating; Mediator; Methodology; Methods; Modeling; Molecular; Mus; Mutation; Organoids; Pancreas; Pancreatic Ductal Adenocarcinoma; Paracrine Communication; Pathway interactions; Patients; Phenotype; Play; Polysaccharides; Post-Translational Protein Processing; Production; Proteins; Receptor Protein-Tyrosine Kinases; Refractory; Residual state; Resistance; Resistance development; Resolution; Role; STAT3 gene; Signal Pathway; Signal Transduction; Specimen; Stromal Cells; TP53 gene; Therapeutic; Time; Tissues; Tumor Promotion; Work; biobank; cancer cell; cell type; checkpoint inhibition; chemotherapy; conventional therapy; cytokine; experimental study; glycosylation; in vivo; leukemia inhibitory factor receptor; loss of function; mouse model; neoplastic cell; novel; organoid transplantation; pancreatic ductal adenocarcinoma model; pancreatic tumorigenesis; paracrine; pharmacologic; preempt; response; success; targeted treatment; therapy resistant; treatment response; treatment strategy; tumor; tumor growth; tumor microenvironment; tumor-immune system interactions; tumorigenesis

PROJECT SUMMARY – Project 2: Signaling Pancreatic ductal adenocarcinoma (PDA) is most commonly diagnosed at late stages, at which time the disease is refractory to most conventional treatment options. Identifying therapeutic strategies that pre-empt the development of resistance and achieve durable tumor control has been hampered by the enormous complexity of the paracrine signaling network in PDA. STAT3 is a major node in this resistance network. The Hunter lab has shown that production of leukemia inhibitory factor (LIF) by cancer associated fibroblasts (CAFs) is a major driver of STAT3 signaling in tumor cells and promotes chemoresistance. Further, they have shown that LIF and the related cytokines IL6 and OSM may also play a role in STAT3 signaling in the immune microenvironment (IME). In Aim 1, the team will investigate the extent to which induction of STAT3 signaling by these cytokines contributes to tumor growth and therapeutic resistance. High-resolution spatial profiling and single-cell approaches will be used to delineate the cell type-specific alterations in STAT3 activation using syngeneic orthotopic models of PDA following treatment with chemotherapy and blockade of LIF, IL6, and/or OSM, which will be corroborated with the colocalization of cytokines and STAT3 signaling in human patient specimens. As LIF can activate several pro-survival pathways, the importance of STAT3-dependent and -independent mechanisms to PDA growth and chemoresistance will be determined. In addition to chemotherapy, the ability of cytokine blockade to potentiate immune checkpoint inhibition (ICI) will be investigated. Further, the team has discovered that aberrant glycosylation can also modulate the STAT3 pathway. Elevation of the glycan CA19-9 in organoids and in vivo resulted in increased STAT3 signaling in both the epithelial and stromal compartments. In Aim 2, the mechanism by which CA19-9 elevation activates STAT3 will be determined and the role of this signaling pathway in chemoresistance will be dissected in a cell type-specific manner using a novel organoid co-culture platform and a first of its kind genetically engineered mouse model with pancreas-specific KRAS and TRP53 mutations and inducible CA19-9 expression. In addition to STAT3, CA19-9 elevation promotes receptor tyrosine kinase signaling, including activation of the EGFR pathway, which also drives chemoresistance. However, inhibition of either pathway has yielded limited clinical success. The team’s preliminary studies have revealed correlations between elevated CA19-9, resistance to chemotherapy, and induction of autophagy, a pathway known to mediate resistance to both chemotherapeutics and targeted therapies. Therefore, experiments proposed in Aim 3 will systematically dissect how CA19-9 modulation of STAT3, EGFR, and autophagy contribute to therapeutic resistance. It is important to note that most previous mouse studies on these resistance pathways have been performed in the absence of CA19-9 and that >90% of PDA patients are CA19-9 positive. Advanced organoid methodologies will be used to investigate both genetic and pharmacologic perturbation of these pathways, culminating in in vivo explorations of the efficacies of combination treatment strategies in CA19-9-positive PDA.

项目摘要 - 项目2：信号传导 胰腺导管腺癌（PDA）最常见于晚期诊断，此时疾病 对大多数常规治疗方案的难治性。确定抢占的治疗策略 巨大的复杂性阻碍了阻力和达到耐用肿瘤控制的发展 PDA中的旁分泌信号网络。 STAT3是此电阻网络中的主要节点。猎人实验室有 表明癌症相关成纤维细胞（CAF）的产生白血病抑制因子（LIF）是主要的驱动因素 肿瘤细胞中的STAT3信号传导的作用并促进化学抗性。此外，他们已经证明了Lif和 相关的细胞因子IL6和OSM也可能在免疫微环境（IME）中的STAT3信号中发挥作用。 在AIM 1中，团队将研究这些细胞因子对STAT3信号传导的诱导程度 高分辨率的空间分析和单细胞方法将是 用于描述使用PDA的Syngeneic Orthotoic模型来描述STAT3激活中细胞类型特定的变化 用化学疗法和LIF封锁IL6和/或OSM处理后，将通过 人类患者标本中细胞因子和STAT3信号的共定位。因为LIF可以激活几个 亲生途径，STAT3依赖性和非依赖性机制对PDA生长和 将确定化学抗性。除了化学疗法外，细胞因子封锁对电势的能力 将研究免疫检查点抑制（ICI）。此外，团队发现异常 糖基化还可以调节STAT3途径。类器官和体内的聚糖Ca19-9升高 导致上皮和基质室中的STAT3信号增加。在AIM 2中，机制 CA19-9高程将激活STAT3，并在此信号传导途径中的作用 化学抗性将使用新型的Organoid共培养平台和 首先，具有胰腺特异性KRA和TRP53突变的同类小鼠模型， 诱导CA19-9表达。除STAT3外，CA19-9高程促进受体酪氨酸激酶 信号传导，包括EGFR途径的激活，这也驱动化学抗性。但是，抑制 这两种途径都取得了有限的临床成功。该团队的初步研究揭示了相关性 在CA19-9升高，对化学疗法的抗性和自噬的诱导之间，该途径已知 介导对化学治疗剂和靶向疗法的耐药性。因此，AIM提出的实验 3将系统剖析CA19-9 STAT3，EGFR和自噬的调节如何有助于治疗 反抗。重要的是要注意，大多数对这些抗性途径的小鼠研究已经 在没有CA19-9的情况下进行，> 90％的PDA患者为CA19-9阳性。晚期器官 方法将用于研究这些途径的遗传和药物扰动， 在CA19-9阳性PDA中的组合治疗策略效率的体内探索最终。