Presented by A/Prof.
Edwin Hawkins
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.
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