ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease for which better therapies are urgently needed. Fibroblasts and macrophages are heterogeneous cell populations able to enhance metastasis, but the role of a macrophage-fibroblast crosstalk in regulating their pro-metastatic functions remains poorly understood. Here we deconvolve how macrophages regulate metastasis-associated fibroblast (MAF) heterogeneity in the liver. We identify three functionally distinct MAF populations, among which the generation of pro-metastatic and immunoregulatory myofibroblastic-MAFs (myMAFs) critically depends on macrophages. Mechanistically, myMAFs are induced through a STAT3-dependent mechanism driven by macrophage-derived progranulin and cancer cell-secreted leukaemia inhibitory factor (LIF). In a reciprocal manner, myMAF secreted osteopontin promotes an immunosuppressive macrophage phenotype resulting in the inhibition of cytotoxic T cell functions. Pharmacological blockade of STAT3 or myMAF-specific genetic depletion of STAT3 restores an anti-tumour immune response and reduces metastases. Our findings provide molecular insights into the complex macrophage-fibroblast interactions in tumours and reveal potential targets to inhibit PDAC liver metastasis.
Subject(s)
Carcinoma, Pancreatic Ductal , Liver Neoplasms , Macrophages , Pancreatic Neoplasms , STAT3 Transcription Factor , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/immunology , Animals , Liver Neoplasms/secondary , Liver Neoplasms/metabolism , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Liver Neoplasms/immunology , STAT3 Transcription Factor/metabolism , STAT3 Transcription Factor/genetics , Macrophages/metabolism , Macrophages/immunology , Carcinoma, Pancreatic Ductal/pathology , Carcinoma, Pancreatic Ductal/metabolism , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/immunology , Humans , Mice , Cell Line, Tumor , Signal Transduction , Janus Kinases/metabolism , Mice, Inbred C57BL , Fibroblasts/metabolism , Fibroblasts/pathology , Male , Cancer-Associated Fibroblasts/metabolism , Cancer-Associated Fibroblasts/pathology , FemaleABSTRACT
Pancreatic ductal adenocarcinoma is a highly metastatic disease and macrophages support liver metastases. Efferocytosis, or engulfment of apoptotic cells by macrophages, is an essential process in tissue homeostasis and wound healing, but its role in metastasis is less well understood. Here, we found that the colonization of the hepatic metastatic site is accompanied by low-grade tissue injury and that efferocytosis-mediated clearance of parenchymal dead cells promotes macrophage reprogramming and liver metastasis. Mechanistically, progranulin expression in macrophages is necessary for efficient efferocytosis by controlling lysosomal acidification via cystic fibrosis transmembrane conductance regulator and the degradation of lysosomal cargo, resulting in LXRα/RXRα-mediated macrophage conversion and upregulation of arginase 1. Pharmacological blockade of efferocytosis or macrophage-specific genetic depletion of progranulin impairs macrophage conversion, improves CD8+ T cell functions, and reduces liver metastasis. Our findings reveal how hard-wired functions of macrophages in tissue repair contribute to liver metastasis and identify potential targets for prevention of pancreatic ductal adenocarcinoma liver metastasis.
Subject(s)
Carcinoma, Pancreatic Ductal , Liver Neoplasms , Macrophages , Pancreatic Neoplasms , Phagocytosis , Tumor Microenvironment , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/metabolism , Humans , Liver Neoplasms/secondary , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Animals , Mice , Macrophages/metabolism , Carcinoma, Pancreatic Ductal/pathology , Carcinoma, Pancreatic Ductal/metabolism , Cell Line, Tumor , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Apoptosis , Lysosomes/metabolism , Arginase/metabolism , EfferocytosisABSTRACT
INTRODUCTION: Pancreatic cancer is a leading cause of cancer deaths worldwide. Screening for this disease has potential to improve survival. It is not feasible, with current screening modalities, to screen the asymptomatic adult population. However, screening of individuals in high-risk groups is recommended. Our study aims to provide resources and data that will inform strategies to screen individuals with new-onset diabetes (NOD) for pancreatic cancer. METHODS AND ANALYSIS: The United Kingdom Early Detection Initiative (UK-EDI) for pancreatic cancer is a national, prospective, observational cohort study that aims to recruit 2500 individuals with NOD (<6 months postdiagnosis) aged 50 years and over, with follow-up every 6 months, over a 3-year period. For study eligibility, diagnosis of diabetes is considered to be clinical measurement of haemoglobin A1c ≥48 mmol/mol. Detailed clinical information and biospecimens will be collected at baseline and follow-up to support the development of molecular, epidemiological and demographic biomarkers for earlier detection of pancreatic cancer in the high-risk NOD group. Socioeconomic impacts and cost-effectiveness of earlier detection of pancreatic cancer in individuals with NOD will be evaluated. The UK-EDI NOD cohort will provide a bioresource for future early detection research to be conducted. ETHICS AND DISSEMINATION: The UK-EDI study has been reviewed and approved by the London-West London and GTAC Research Ethics Committee (Ref 20/LO/0058). Study results will be disseminated through presentations at national and international symposia and publication in peer-reviewed, Open Access journals.