Research Group Head, Walter and Eliza Hall Institute of Medical Research
12 June, 12-1pm, Seminar room 1, TRF
It is widely accepted that complex interactions between blood cells and their surrounding microenvironments contribute to homeostatic cell function and disease development. In light of this interdependency, novel interventions that target specific stromal cell lineages and their interactions with blood cell subsets in disease are being investigated. To investigate this, we are studying mouse and humanised models of autoimmunity, hematological malignancies and protective immunity. We have developed intravital microscopy methods that allow us to monitor the same cells and microenvironments in the bone marrow (BM) and peripheral immune organs long-term including repeated imaging sessions over multiple days. Using this approach, we have observed lineage specific interactions of haematopoetic cells with stroma and microenvironments in the BM. For example, we observed highly dynamic interactions and promiscuous distribution of T-ALL cells throughout the BM, without any preferential association with microenvironments. Unexpectedly, this environment-agnostic behaviour was maintained during development of chemotherapy resistance. Interestingly, this behavior is not a conserved feature of blood cells from other immune cell lineages.
Our results reveal that T-ALL does not depend on specific microenvironments for propagation of disease, nor the selection of chemo-resistant clones, suggesting a stochastic mechanism underlies these processes. Yet, while progression is independent of the stroma, accumulation of malignant lymphocytes leads to rapid, selective remodeling of the endosteal space, resulting in a complete loss of mature osteoblastic cells. This outcome shifts the balance of endogenous BM stroma towards a composition associated with less efficient hematopoiesis. However, we observe lineage specific tissue remodeling hardwired to the origin of the malignant cells. This novel, dynamic analysis highlights that future therapeutic interventions should target cell-specific mechanisms, in order to combat the invasion and survival of pathogenic blood cells. These studies provide the foundation for future studies investigating the metastasis of other tumours as well as homeostatic hematopoiesis.
Biography: Edwin Hawkins is an immunologist and cancer biologist. His laboratory uses in vitro and in vivo live cell microscopy to understand development of immune disorders, hematological malignancies and the development of chemotherapy resistance. He conducted his PhD in the Immunology division at WEHI. After being awarded an NHMRC early career fellowship in 2008, Edwin relocated to the Peter MacCallum Cancer Centre where he studied mechanisms that regulate lymphocyte fate and development of leukemia. In 2012, Edwin relocated to Imperial College London with fellowships from the Welcome Trust and the European Haematology Association to establish 2-photon microscopy techniques that allow long-term tracking of immune cells and leukemia development in vivo. Edwin returned to WEHI October 2015 as an NHMRC RD Wright Fellow to establish his own research program.