The impact of sepsis-induced inflammation on pancreatic cancer liver metastasis

脓毒症引起的炎症对胰腺癌肝转移的影响

基本信息

批准号：
10679730
负责人：
Nicole Sivetz
金额：
$ 4.77万
依托单位：
COLD SPRING HARBOR LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-16 至 2025-07-15
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10679730
关键词：
ATAC-seq Address Adult Biological Assay Blood Bone Marrow CXCL10 gene CXCL9 gene Cancer Patient Cells Cessation of life Clinical Communication Data Development Disseminated Malignant Neoplasm Endotoxemia Endotoxins Epigenetic Process Excision Genes Health Human Immune Immune response Immunity Immunosuppression Incidence Infiltration Inflammation Injections Knowledge Lesion Link Lipopolysaccharides Liver Malignant Neoplasms Malignant neoplasm of pancreas Metastatic Neoplasm to the Liver Modeling Mus Myeloid Cells Natural Killer Cells Neoplasm Metastasis Operative Surgical Procedures Pancreas Transplantation Pancreatic Ductal Adenocarcinoma Patients Perioperative Plasma Postoperative Period Predisposition Preventive therapy Primary Neoplasm Prognostic Factor Receptor Signaling Recurrence Reporting Resected Risk Role Sepsis Signal Transduction Site Sterility TLR4 gene Testing Therapeutic Toll-like receptors Transgenic Mice Tumor Promotion Up-Regulation anti-tumor immune response cecal ligation puncture clinically relevant cytotoxicity experience experimental study mortality risk mouse model neutrophil new therapeutic target pancreatic cancer cells pancreatic cancer patients pancreatic ductal adenocarcinoma cell polymicrobial sepsis response septic patients single-cell RNA sequencing therapeutic target transcriptome sequencing tumor tumor-immune system interactions

项目摘要

1 PROJECT SUMMARY 2 Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic malignancy and the third-leading cause of 3 cancer-related death in adults. A majority of patients who undergo surgery for primary PDAC resection will later 4 develop lethal metastases, despite intra-operative examination confirming the absence of macrometastatic 5 lesions. Liver metastases constitute nearly half of recurrences detected within six months after PDAC resection, 6 which is significantly earlier in the postoperative period compared to other metastatic sites. Several clinical and 7 experimental studies have shown that perioperative inflammation, including infectious complications like sepsis, 8 can promote liver metastasis. This is intriguing because bacterial-derived endotoxin is elevated in PDAC patient 9 plasma during tumor resection. Furthermore, PDAC patients are at increased risk of developing sepsis, which 10 suggests that tumor-systemic communication in part rewires systemic immunity and, consequently, sepsis 11 susceptibility. Despite these observations, we currently lack mechanistic studies investigating the relationship 12 between perioperative inflammation and PDAC liver metastasis. The overarching objective of this project is to 13 determine how pro-metastatic immune responses can be suppressed to protect against liver metastasis during 14 PDAC resection and sepsis-induced inflammation. To define how sepsis-induced inflammation impacts the liver 15 immune microenvironment, I first modeled the perioperative inflammation that PDAC patients may experience 16 during surgery by using the lipopolysaccharide (LPS) model of sterile endotoxemia, and the more clinically 17 relevant cecal and ligation puncture (CLP) model of polymicrobial sepsis. My preliminary data demonstrates that 18 performing CLP prior to seeding PDAC cells in the liver had a pro-metastatic effect. However, LPS challenge 19 had an anti-metastatic effect marked by increased CXCL9 and CXCL10 release and natural killer cell infiltration 20 in the liver during early sepsis response. Therefore, this approach presents an exciting opportunity to define how 21 LPS-induced sepsis elicits an anti-metastatic cascade to reduce liver metastasis. The central hypothesis of this 22 project is that determining how sepsis-induced immune responses influence liver metastasis will reveal critical 23 mechanisms that can be targeted to create a protective ‘anti-metastatic niche’. To test this hypothesis, Aim 1 will 24 elucidate the anti-metastatic signaling mechanisms underpinning LPS-induced sepsis, and uncover potential 25 therapeutic targets that can be exploited to reduce PDAC liver metastasis. Aim 2 will examine the therapeutic 26 potential of targeting pro-metastatic inflammation during sepsis by evaluating how the quality of sepsis-induced 27 immune responses are impacted by systemic immunosuppression, which is a well-established hallmark of 28 PDAC. The findings of these experiments will uncover critical regulators of perioperative inflammation and 29 systemic immunosuppression in PDAC, and set the stage for the development of preventative therapies to 30 reduce the incidence of liver metastasis among resected PDAC patients.

1 项目概要 2 胰腺导管腺癌 (PDAC) 是一种高度转移性恶性肿瘤，是导致胰腺癌的第三大原因。 3 成人癌症相关死亡大多数接受原发性 PDAC 切除手术的患者随后会死亡。尽管术中检查证实不存在大转移，但仍有 4 人发生致命转移 5 个肝转移占 PDAC 切除后六个月内检测到的复发的近一半， 6 与其他几个临床和转移部位相比，术后明显提前。 7 项实验研究表明，围手术期炎症，包括败血症等感染性并发症， 8 可以促进肝转移，这一点很有趣，因为 PDAC 患者中细菌源性内毒素升高。 9 肿瘤切除期间的血浆此外，PDAC 患者患败血症的风险增加。图 10 表明肿瘤与系统的通讯在一定程度上重新连接了系统免疫，从而导致脓毒症 11 尽管有这些观察结果，但我们目前缺乏调查这种关系的机制研究。 12 围手术期炎症与 PDAC 肝转移之间的关系该项目的总体目标是。 13 确定如何抑制促转移免疫反应以防止肝转移 14 PDAC 切除和脓毒症引起的炎症明确脓毒症引起的炎症如何影响肝脏。 15免疫微环境，我首先模拟了PDAC患者可能经历的围手术期炎症 16 手术过程中采用脂多糖（LPS）建立无菌内毒素血症模型，临床上更 17 多种微生物败血症的相关盲肠和结扎穿刺（CLP）模型我的初步数据表明。 18 在将 PDAC 细胞接种到肝脏之前进行 CLP 具有促转移作用，然而，LPS 攻击。 19 具有抗转移作用，其特点是 CXCL9 和 CXCL10 释放增加以及自然杀伤细胞浸润增加 20 在早期败血症反应期间的肝脏中，因此，这种方法提供了一个令人兴奋的机会来定义如何。 21 LPS 诱导的脓毒症会引发抗转移级联反应，从而减少肝转移。这一假设的核心假设。 22 项目的目的是确定脓毒症引起的免疫反应如何影响肝转移将揭示关键的 23 种机制可用于创建保护性“抗转移生态位” 为了检验这一假设，目标 1 将进行。 24 阐明 LPS 诱导脓毒症的抗转移信号传导机制，并揭示潜在的潜力目标 2 将检查可用于减少 PDAC 肝转移的 25 个治疗靶点。 26 通过评估脓毒症引起的质量如何靶向脓毒症期间促转移炎症的潜力 27 免疫反应受到全身性免疫抑制的影响，这是免疫系统的一个公认标志 28 PDAC 这些实验的结果将揭示围手术期炎症和炎症的关键调节因子。 29 PDAC 中的系统性免疫抑制，并为预防性疗法的开发奠定了基础 30 降低 PDAC 切除患者肝转移的发生率。