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）是一种高度促纤维增生和治疗耐药的癌症。的作用 PDAC 中的促纤维增生基质仍然难以捉摸，有研究支持肿瘤促进或肿瘤抑制 限制功能。基质靶向治疗的失败表明，对基质的更深入了解 需要复杂的癌症-基质相互作用。 I 型胶原蛋白 (Col I) 是 PDAC 中的主要 ECM 蛋白，可以 物理上抑制肿瘤并限制营养的利用。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，富含促纤维增生胶原的基质可能会抑制 免疫监视并激活促进肿瘤的机械敏感信号传导。很可能促进肿瘤 CAF 和 ECM 的肿瘤抑制作用是并行发生的，它们的平衡决定了净效应 关于 PDAC 的增长。我们力求通过关注 I 上校作为关键调解人来更好地理解这些对立的职能 基质-PDAC 串扰。临床研究表明，切除术后无进展生存期 (PFS) 得到改善 具有“惰性基质”的患者的特征是广泛的 ECM 沉积和低纤维溶解活性，而高度 纤维溶解基质与更短的 PFS 时间相关。基于这一发现，我们假设 比 CAF 和基质的绝对数量、胶原纤维溶解和受体的差异效应 区分完整和切割的 Col I 决定肿瘤生长和免疫。我们的初步数据支持 这一假设表明，完整和裂解的胶原蛋白通过以下方式对癌细胞代谢进行差异调节： 特定受体DDR1；以及免疫细胞上抑制性 Col I 受体 LAIR1 的高表达 Col I 在免疫细胞浸润和激活 PDAC 扩散到肝脏（最常见的部位）中发挥作用 转移和全身抗肿瘤免疫的抑制剂。我们的长期目标是开发能够 靶向胶原蛋白受体并通过裂解改变免疫抑制和肿瘤促进的平衡 胶原蛋白可以导致肿瘤饥饿、生长抑制和增强抗肿瘤免疫力，而不是消除 CAF 或 调制，迄今为止已导致不良影响。我们的跨学科团队由基础和临床组成 转化研究人员将利用临床标本、肿瘤切片培养物、单细胞 RNA 测序、空间 转录组学、小鼠模型和 PDAC-ECM 共培养物阐明胶原蛋白受体信号传导的作用 通过两个紧密结合的具体目标： 1. 检验胶原蛋白碎片和纤维拮抗的假设 通过 PDAC 内在胶原蛋白受体 DDR1 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. 检验刺激性和抑制性胶原受体的假设 控制抗PDAC免疫，可与免疫检查点抑制剂联合使用以增强抗肿瘤作用 免疫。这些研究目标的成功完成将为我们提供转换的新工具 基质介导的肿瘤生长和免疫抑制到生长抑制和抗肿瘤免疫。