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：信令 胰腺导管腺癌(PDA)最常见的诊断是在晚期，此时疾病 对大多数传统的治疗方案来说都是难治的。确定先发制人的治疗策略 抗药性的发展和实现持久的肿瘤控制一直受到巨大复杂性的阻碍 掌上电脑旁分泌信令网络。STAT3是这个阻力网络中的一个主要节点。亨特实验室已经 研究表明，肿瘤相关成纤维细胞(CAF)产生白血病抑制因子(LIF)是主要驱动力 抑制肿瘤细胞中的STAT3信号转导，促进化疗耐药。此外，他们还表明，LIF和 相关的细胞因子IL6和OSM也可能在免疫微环境(IME)的STAT3信号转导中发挥作用。 在目标1中，研究小组将调查这些细胞因子对STAT3信号的诱导作用 对肿瘤生长和治疗耐药的影响。高分辨率空间剖面图和单细胞方法将 用于利用同种PDA原位模型描述STAT3激活中的细胞类型特异性改变 在接受化疗和阻断LIF、IL6和/或OSM治疗后，这将得到证实 细胞因子和STAT3信号在人类患者标本中的共存。因为LIF可以激活几个 支持生存的途径，STAT3依赖和非依赖机制对PDA生长和 化疗耐药性将被确定。除了化疗外，细胞因子阻断的能力增强 将调查免疫检查点抑制(ICI)。此外，该团队还发现了这种反常现象 糖基化也可以调节STAT3途径。糖链CA19-9在有机体和体内的升高 导致上皮室和间质室中STAT3信号的增加。在目标2中，机制 将确定CA19-9上调激活STAT3的方式以及该信号通路在 将使用一种新的有机类共培养平台以特定细胞类型的方式剖析化疗耐药性，并 首例胰腺特异性KRAS和Trp53突变的基因工程小鼠模型 诱导表达CA19-9。除STAT3外，CA19-9上调还促进受体酪氨酸激酶 信号转导，包括EGFR通路的激活，这也是化疗耐药性的驱动因素。然而，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 在CA19-9升高、化疗耐药和诱导自噬之间，这是一条已知的 调解对化疗药物和靶向治疗的耐药性。因此，在AIM中提出的实验 3将系统地剖析CA19-9对STAT3、EGFR和自噬的调节如何有助于治疗 抵抗。值得注意的是，以前对这些抗性途径的大多数小鼠研究都是 在CA19-9缺失的情况下进行检测，90%的PDA患者CA19-9阳性。高级有机化合物 将使用方法学来研究这些途径的遗传和药物扰动， 最终在体内探索联合治疗策略对CA19-9阳性PDA的疗效。