Metastasis-associated Macrophages Orchestrate the Formation of a Hospitable Metastatic Niche in Pancreatic Cancer


Nielsen, SR (2017) Metastasis-associated Macrophages Orchestrate the Formation of a Hospitable Metastatic Niche in Pancreatic Cancer. PhD thesis, University of Liverpool.

[img] Text
200997162_May2017.pdf - Unspecified
Download (35MB)

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with an overall 5-year survival rate <5%, a rate that has not improved for a long time. The dismal prognosis for PDAC is part due to late detection, often at advanced stages of the disease where patients have developed distant metastases, but also due to chemotherapeutical resistance. Patients eligible for surgical resection of the pancreatic tumour has the best prognosis, but even when resection is successful, patients often relapse with distant metastases within 2 years after surgery. Macrophages promote tumourigenesis and enhance metastasis in many cancer types; however, the role of macrophages in PDAC metastasis is poorly understood. Using an experimental mouse model of liver metastasis, we find that PDAC liver metastasis critically depends on the early recruitment of granulin-secreting metastasis-associated macrophages (MAMs) to the liver that promote metastatic colonisation. Mechanistically, we demonstrate that granulin secretion by MAMs activates resident hepatic stellate cells (HSTCs) into myofibroblasts that secrete extracellular matrix components, including periostin, resulting in a fibrotic microenvironment that sustains metastatic tumour growth. Disruption of MAM recruitment in PI(3)Kγ-deficient mice, chemical depletion of MAMs from established lesions or genetic ablation of granulin reduces HSTC activation and liver metastasis. Adjuvant CTX is standard for patients after surgical resection to eliminate any residual cancer cells, and it improves survival for patients after resection. We find that 45% of mice with metastatic lesions respond to gemcitabine treatment with a reduction in metastatic burden. The metastatic lesions in these mice are characterised by a reduction in αSMA+ myofibroblasts. HSTCs do not seem to promote cancer cell survival in the presence of chemotherapy, but rather constitutes a protective niche that promotes relapse by promoting the growth of pancreatic cancer cells after gemcitabine treatment.

Item Type: Thesis (PhD)
Divisions: Faculty of Health and Life Sciences > Faculty of Health and Life Sciences
Depositing User: Symplectic Admin
Date Deposited: 07 Sep 2017 11:06
Last Modified: 19 Jan 2023 07:04
DOI: 10.17638/03007527
Supervisors:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3007527
Dimensions
Altmetric
CORE (COnnecting REpositories)