Bone marrow microenvironment: ageing, senescence and infection
Most recently we have developed our studies on the tumour microenvironment into our latest stream of work investigating the effects of infection, senescence and ageing on the bone marrow.
We found that AML cells induce a senescent associated secretory phenotype (SASP) in the BM microenvironment, which supports the survival and proliferation of the leukaemic blasts. The senescence response and SASP is driven by superoxide generated locally by the tumour and targeting these senescent p16INK4a-expressing stromal cells slows leukaemic growth.
Under the stress of acute bacterial infection, hematopoietic stem cells (HSCs) within the bone marrow undergo rapid expansion in order to rapidly facilitate the hosts immune response. We have shown that infection by Gram-negative bacteria drives an increase in mitochondrial mass in mammalian HSCs, which results in a metabolic transition from glycolysis toward oxidative phosphorylation. We discovered that mitochondria are transferred from the BMSCs into HSCs under the regulation of superoxide and importantly, that mitochondrial transfer occurs before an increase in mitochondrial biogenesis, in a system which has evolved in mammals to generate the intracellular energy necessary to drive the required rapid granulocytic response to bacterial infection. Moreover, we think it likely that these mechanisms, which support bone marrow cell metabolism and which are hi-jacked by AML and myeloma to support tumor growth, are a fundamental reason why blood cancers arising in the bone marrow microenvironment are presently so difficult to treat.
Work is ongoing to further develop our understanding of stress, age and senescence on bone marrow function in the benign and malignant setting, with a view to developing improved treatments for cancer and age-related diseases.