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: 10517874
• 负责人: Michael Karin
• 金额: $ 97.11万
• 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/10517874
• 关键词: Carcinoma; Cell Communication; Cell Death; 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; Infiltration; Length; Ligands; Liver; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of pancreas; Mediating; Mediator of activation protein; Metabolic; Metabolism; Metastatic Neoplasm to the Liver; Mus; Neoplasm Metastasis; Nutrient; Pancreatic Ductal Adenocarcinoma; Patients; Progression-Free Survivals; Receptor Signaling; Regulation; Research; Resistance; Resolution; Role; Signal Pathway; Signal Transduction; Site; Slice; Specimen; Starvation; Testing; Therapeutic Intervention; Time; Tumor Immunity; Tumor Promotion; Tumor Suppression; Tumor-infiltrating immune cells; Vascular blood supply; Visceral metastasis; antitumor effect; base; immune activation; immune checkpoint blockade; immune clearance; improved; indexing; individualized medicine; mouse model; novel; novel strategies; novel therapeutics; pancreatic ductal adenocarcinoma cell; rational design; receptor; refractory cancer; single-cell RNA sequencing; 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.

摘要 胰腺导管腺癌（PDAC）是一种高度促纤维增生和治疗抗性的癌症。的作用 PDAC中的促结缔组织增生间质仍然难以捉摸，研究支持肿瘤促进或肿瘤- 限制功能。基质靶向治疗的失败表明，对基质靶向治疗的更深入了解是必要的。 需要复杂的癌症-基质相互作用。I型胶原（Col I）是PDAC中的主要ECM蛋白，可 物理抑制肿瘤和限制营养的可用性。然而，PDAC细胞适应并利用周围的基质 获得更严重的恶性特征此外，促结缔组织增生的富含胶原的基质可能抑制 免疫监视和激活肿瘤促进机械敏感信号传导。很可能是促肿瘤 CAF和ECM的肿瘤抑制作用平行发生，它们的平衡决定了净效应 PDAC增长。我们试图更好地了解这些对立的功能，重点放在第一上校作为一个关键的调解人 PDAC串扰。临床研究显示，在2010年， 具有“惰性基质”的患者，其特征在于广泛的ECM沉积和低纤维溶解活性，而高度 纤维溶解性间质与更短的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更重要， 区分完整和裂解的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，完整和切割的胶原蛋白通过以下途径对癌细胞代谢进行了不同的调节： 特异性受体DDR 1;以及免疫细胞上抑制性Col I受体LAIR 1的高表达， Col I在PDAC扩散至肝脏的免疫细胞浸润和活化中的作用， 转移和全身抗肿瘤免疫的抑制剂。我们的长期目标是开发出 靶向胶原蛋白受体，并通过切割转移免疫抑制和肿瘤促进的平衡， 胶原蛋白对肿瘤饥饿、生长抑制和增强的抗肿瘤免疫，而不是CAF消耗或 调制，到目前为止，这导致了不利的影响。我们的基础和临床跨学科团队- 翻译研究者将利用临床标本，肿瘤切片培养，单细胞RNA测序，空间 转录组学、小鼠模型和PDAC-ECM共培养物，以阐明胶原受体信号传导的作用 通过两个紧密结合的具体目标：1.测试胶原蛋白碎片和纤维拮抗的假设 通过PDAC内在胶原受体DDR 1控制PDAC代谢，DDR 1的抑制可以关闭 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 控制抗PDAC免疫，并可与免疫检查点抑制剂联合使用以增加抗肿瘤作用 免疫力这些研究目标的成功完成将为我们提供新的工具， 基质介导的肿瘤生长和免疫抑制转化为生长抑制和抗肿瘤免疫。