Characterising the tumour-associated macrophage niche

Macrophages are found in all tissues of the body where they play important roles in tissue remodelling and homeostasis. Macrophages were also among the first immune cells shown to modulate stem cell function. For example, mammary gland stem cells require signals from tissue macrophages during ductal morphogenesis, which was shown to be mediated by Wnt ligands produced by macrophages in response to Notch signalling between macrophages and mammary gland stem cells. We recently identified a subset of tissue-resident macrophages that co-express Tim4 and CD163 in a mouse model of ovarian cancer. Upon specific depletion of these macrophages we observed a significant reduction in the frequency of tumour cells with cancer stem cell (CSC)-characteristics and the metastatic spread of disease.



Aim of the investigation (up to 150 words)

State primary research question and where appropriate the primary hypotheses being tested



This project will test the hypothesis that Tim4+ CD163+ tissue-resident macrophages represent an important component of the cancer stem cell (CSC) niche in ovarian cancer. We predict that specific axes of cross-talk between tissue-resident macrophages and ovarian cancer cells leads to the acquisition of stem cell characteristics that aid the metastatic spread of disease.



Proposed plan of work (up to 1000 words)

Please include key aspects of study design, key research methods (including statistical methods and appropriate power calculations for the primary hypotheses. Ensure that it is clear how the design and methods will address the study aims.



This project will address 5 main research aims:

Fate-map resident Tim4+ CD163+ macrophages in mouse models of ovarian carcinomas and their association with CSCs.

Specific depletion of Tim4+ CD163+ macrophages and determine the effects of tumour progression and acquisition of CSC-characteristics.

Identify the molecular axes of cross-talk between resident tissue macrophages and ovarian cancer cells that promote stem cell characteristics.

Establish human iPSC-derived macrophages that reflect tissue-resident cells and assess their impact on stem cell functions in organotypic culture systems.



These studies will utilise new and unique genetic tools that have recently been developed in our laboratories to dissect the roles of Tim4+ CD163+ tissue resident macrophages and iPSC-derived human macrophages.