Domagala, M. | bioRxiv Science

bioRxiv2021

An Agent-Based Model of monocyte differentiation into Tumour-Associated Macrophages in Chronic Lymphocytic Leukemia

Monocyte-derived macrophages help maintain tissue homeostasis and defend the organism against pathogens. In tumors, recent studies have uncovered complex macrophage populations, including tumor-associated macrophages, which support tumorigenesis through cancer hallmarks such as immunosuppression, angiogenesis or matrix remodeling. In the case of chronic lymphocytic leukemia, these macrophages are known as nurse-like cells and they protect leukemic cells from spontaneous apoptosis contributing to their chemoresistance. We propose an agent-based model of monocyte differentiation into nurse-like cells upon contact with leukemic B cells in vitro. We performed patient-specific model calibrations using cultures of peripheral blood mononuclear cells from patients. Using our model, we were able to reproduce temporal survival dynamics of cancer cells in a patient-specific manner and to identify patient groups related to distinct macrophage phenotypes. Our results show a potentially important role of phagocytosis in the polarization process of nurse-like cells and in promoting cancer cells enhanced survival.

systems biology↗

bioRxiv2020

A Boolean Model of the Formation of Tumour Associated Macrophages in an in-vitro Model of Chronic Lymphocytic Leukaemia

The tumour microenvironment is the collection of cells in and surrounding cancer cells in a tumour including a variety of immune cells, especially neutrophils and monocyte-derived macrophages. In a tumour setting, macrophages encompass a spectrum between a tumour-suppressive (M1) or tumour-promoting (M2) state. The biology of macrophages found in tumours (Tumour Associated Macrophages) remains unclear, but understanding their impact on tumour progression is highly important. In this paper, we perform a comprehensive analysis of a macrophage polarization network, following two lines of enquiry: (i) we reconstruct the macrophage polarization network based on literature, extending it to include important stimuli in a tumour setting, and (ii) we build a dynamical model able to reproduce macrophage polarization in the presence of different stimuli, including the contact with cancer cells. Our simulations recapitulate the documented macrophage phenotypes and their dependencies on specific receptors and transcription factors, while also elucidating the formation of a special type of tumour associated macrophages in an in-vitro model of chronic lymphocytic leukaemia. This model constitutes the first step towards elucidating the cross-talk between immune and cancer cells inside tumours, with the ultimate goal of identifying new therapeutic targets that could control the formation of tumour associated macrophages in patients.

systems biology↗