Investigating the role of mitochondrial damage-associated molecular patterns in the myeloma bone marrow microenvironment

Jibril, Aisha (2022) Investigating the role of mitochondrial damage-associated molecular patterns in the myeloma bone marrow microenvironment. Doctoral thesis, University of East Anglia.

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Mitochondrial damage-associated molecular patterns (mtDAMPs) encompass a group of mitochondrial-derived molecules such as proteins, lipids, metabolites, and DNA. Capable of activating innate immune system responses via pattern recognition receptors (PRRs), mtDAMPs possess immunoregulatory functions. Elevated levels of circulating mtDNA have been implicated in the pathogenesis of various diseases including cancer. Though
the functional outcomes of the observation remain largely undefined. Multiple myeloma (MM) is an incurable haematological malignancy. A hallmark of MM is its homing to the bone marrow (BM) niche where MM cells are heavily reliant upon interactions with cells such as macrophages for their survival. Macrophages have been shown to interact with MM cells to promote disease progression. In this thesis, I investigated the role of mtDAMPs in the protumoral BM microenvironment of MM.

This study identifies elevated levels of circulating mtDNA in the serum of MM patients compared to healthy controls. The use of an NSG xenograft mouse model of MM ascertained that circulating mtDNA is derived from MM cells. Functionally, mtDAMPs were shown to activate BM macrophages via the cGAS-STING signalling pathway. mtDAMPs activation induced a gene expression profile in macrophages that mediated pro-inflammatory and pro-chemotactic responses. Inhibition of STING led to reduced MM progression in the C57BL/KaLwRij mouse model. Moreover, mtDAMPs stimulated the upregulation of chemokines in BM macrophages which enhanced the migration of MM cells in vitro. Clodronate-mediated depletion of macrophages highlighted the crucial role of macrophages in facilitating MM cell homing to the BM. Furthermore, STING inhibition attenuated the pro-chemotactic signature in BM macrophages and resulted in the egress of MM cells from the BM into the peripheral blood circulation. Taken together, these findings establish the functional role of mtDAMPs in the activation of macrophages which promote MM disease progression and mediates BM homing and retention of MM cells in the BM niche.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: Chris White
Date Deposited: 16 Mar 2023 09:54
Last Modified: 16 Mar 2023 09:54

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