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