Regulation of PDAC metabolism and immunity by collagen and its cleavage products

胶原及其裂解产物对 PDAC 代谢和免疫的调节

• 批准号: 10708168
• 负责人: Michael Karin
• 金额: $ 95.5万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-21 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10708168
• 关键词: Carcinoma; Cell Communication; Cell Death Induction; Cells; Clinic; Clinical; Clinical Research; Coculture Techniques; Collagen; Collagen Fiber; Collagen Receptors; Collagen Type I; Complex; DDR1 gene; Data; Deposition; Desmoplastic; Environment; Equilibrium; Excision; Extracellular Matrix; Extracellular Matrix Proteins; Failure; Fiber; Fibroblasts; Goals; Growth; Human; Immune; Immune checkpoint inhibitor; Immunity; Immunologic Surveillance; Immunosuppression; Length; Ligands; Liver; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of pancreas; Mediating; Mediator; Metabolic; Metabolism; Metastatic Neoplasm to the Liver; Mus; Neoplasm Metastasis; Nutrient availability; Pancreatic Ductal Adenocarcinoma; Patients; Physical Restraint; Progression-Free Survivals; Receptor Signaling; Regulation; Research; Resistance; Resolution; Role; Signal Pathway; Signal Transduction; Site; Slice; Specimen; Starvation; Testing; Therapeutic Intervention; Tumor Immunity; Tumor Promotion; Tumor Suppression; Vascular blood supply; Visceral metastasis; antitumor effect; clinical translation; immune activation; immune cell infiltrate; immune checkpoint blockade; immune clearance; improved; indexing; individualized medicine; mouse model; novel; novel strategies; novel therapeutics; pancreatic ductal adenocarcinoma cell; pancreatic ductal adenocarcinoma model; rational design; receptor; refractory cancer; single-cell RNA sequencing; synergism; targeted treatment; therapy development; therapy resistant; tool; trait; transcriptomics; translational scientist; tumor; tumor growth; tumor metabolism

ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic and therapy-resistant cancer. The role of the desmoplastic stroma in PDAC remains elusive with studies supporting both tumor-promoting or tumor- restricting functions. The failure of stroma targeting therapies suggests that a deeper understanding of the complex cancer-stroma interaction is needed. Type I collagen (Col I), the major ECM protein in PDAC, can physically restrain tumors and limit nutrient availability. Yet, PDAC cells adapt and exploit the surrounding stroma to acquire more advanced malignant traits. Moreover, the desmoplastic collagen-rich stroma may suppress immunosurveillance and activate tumor-promoting mechanosensitive signaling. It is likely that tumor-promoting and tumor-suppressive effects of CAF and ECM occur in parallel and that their balance determines the net effect on PDAC growth. We seek to better understand these opposing functions by focusing on Col I as a key mediator of stroma-PDAC crosstalk. Clinical studies show improved progression-free survival (PFS) after resection in patients with “inert stroma” characterized by extensive ECM deposition and low fibrolytic activity, whereas highly fibrolytic stroma is associated with much shorter PFS times. Based on this finding we hypothesize that rather than the sheer quantity of CAF and stroma, collagen fibrolysis and differential effects of receptors that discriminate between intact and cleaved Col I dictate tumor growth and immunity. Our preliminary data support this hypothesis, indicating differential regulation of cancer cell metabolism by intact and cleaved collagen through a specific receptor, DDR1; as well as high expression of the inhibitory Col I receptor LAIR1 on immune cells and a role for Col I in immune cell infiltration and activation in PDAC spread to the liver, the most common site of metastasis and a suppressor of systemic anti-tumor immunity. Our long-term goal is to develop therapies that target collagen receptors and shift the balance from immunosuppression and tumor promotion by cleaved collagen to tumor starvation, growth inhibition and enhanced anti-tumor immunity, rather than CAF depletion or modulation, which so far had resulted in untoward effects. Our interdisciplinary team of basic and clinical- translational investigators will utilize clinical specimens, tumor slice cultures, single cell RNA-sequencing, spatial transcriptomics, mouse models and PDAC-ECM co-cultures to elucidate the role of collagen receptor signaling via two closely integrated specific aims: 1. Test the hypothesis that collagen fragments and fibers antagonistically control PDAC metabolism through the PDAC-intrinsic collagen receptor DDR1, whose inhibition can switch off tumor metabolism and induce cell death. 2. Test the hypothesis that stimulatory and inhibitory collagen receptors control anti-PDAC immunity and can be combined with immune checkpoint inhibitors to increase anti-tumor immunity. The successful completion of these research goals will provide us with novel tools for converting stroma-mediated tumor growth and immunosuppression to growth inhibition and anti-tumor immunity.

抽象的 胰腺导管腺癌（PDAC）是一种高度脱糖和耐药的癌症。的作用 PDAC中的脱肿瘤基质仍然难以捉摸，研究支持肿瘤或肿瘤 - 限制功能。基质靶向疗法的失败表明，对 需要复杂的癌症融合。 I型胶原蛋白（Col I），PDAC中的主要ECM蛋白 物理上限制肿瘤并限制营养物的可用性。然而，PDAC细胞适应并利用周围的基质 获得更高级的恶性特征。此外，富含胶原蛋白的基质可能会抑制 免疫监视并激活促进肿瘤的机械敏感信号传导。可能是肿瘤促进 CAF和ECM的肿瘤抑制作用并联出现，它们的平衡决定了净效应 关于PDAC的增长。我们试图通过将Col I作为关键调解员来更好地理解这些对立的功能 基质-PDAC串扰。临床研究表明，切除后无进展生存率（PFS）改善 具有广泛ECM沉积和低纤维化活性的“惰性基质”患者 纤维化基质与较短的PFS时间有关。基于这一发现，我们假设 比大量的CAF和基质，胶原蛋白纤维分解以及接收器的差异作用 区分完整的和清除的Col I决定了肿瘤的生长和免疫力。我们的初步数据支持 该假设表明通过完整的癌细胞代谢进行了不同调节，并通过 特定的受体DDR1；以及抑制性Col I受体Lair1在免疫细胞和 Col I在PDAC中的免疫细胞浸润和激活中的作用扩散到肝脏，这是最常见的部位 转移和全身抗肿瘤免疫的抑制剂。我们的长期目标是开发疗法 靶向胶原蛋白受体，并通过裂解将平衡从免疫抑制和肿瘤促进 胶原蛋白至肿瘤饥饿，生长抑制和增强的抗肿瘤免疫，而不是CAF耗竭或 调制，到目前为止，这导致了不良影响。我们的基础和临床跨学科团队 - 转化研究者将利用临床标本，肿瘤切片培养物，单细胞RNA顺序，空间 转录组学，小鼠模型和PDAC-ECM共培养，以阐明胶原受体信号的作用 通过两个紧密整合的特定目的：1。测试胶原蛋白片段和纤维拮抗的假设 通过PDAC - 内膜胶原受体DDR1来控制PDAC代谢，其抑制作用可以关闭 肿瘤代谢并诱导细胞死亡。 2。检验刺激和抑制性胶原蛋白受体的假设 对照抗PDAC免疫，可以与免疫粘点抑制剂合并以增加抗肿瘤 免疫。这些研究目标的成功完成将为我们提供转换的新颖工具 基质介导的肿瘤生长和对生长抑制和抗肿瘤免疫膜的免疫抑制。