title: T-cell acute leukaemia exhibits dynamic interactions with bone marrow microenvironments.
abstract: It is widely accepted that complex interactions between cancer cells and their surrounding microenvironment contribute to disease development, chemo-resistance and disease relapse. In light of this observed interdependency, novel therapeutic interventions that target specific cancer stroma cell lineages and their interactions are being sought. Here we studied a mouse model of human T-cell acute lymphoblastic leukaemia (T-ALL) and used intravital microscopy to monitor the progression of disease within the bone marrow at both the tissue-wide and single-cell level over time, from bone marrow seeding to development/selection of chemo-resistance. We observed highly dynamic cellular interactions and promiscuous distribution of leukaemia cells that migrated across the bone marrow, without showing any preferential association with bone marrow sub-compartments. Unexpectedly, this behaviour was maintained throughout disease development, from the earliest bone marrow seeding to response and resistance to chemotherapy. Our results reveal that T-ALL cells do not depend on specific bone marrow microenvironments for propagation of disease, nor for the selection of chemo-resistant clones, suggesting that a stochastic mechanism underlies these processes. Yet, although T-ALL infiltration and progression are independent of the stroma, accumulated disease burden leads to rapid, selective remodelling of the endosteal space, resulting in a complete loss of mature osteoblastic cells while perivascular cells are maintained. This outcome leads to a shift in the balance of endogenous bone marrow stroma, towards a composition associated with less efficient haematopoietic stem cell function. This novel, dynamic analysis of T-ALL interactions with the bone marrow microenvironment in vivo, supported by evidence from human T-ALL samples, highlights that future therapeutic interventions should target the migration and promiscuous interactions of cancer cells with the surrounding microenvironment, rather than specific bone marrow stroma, to combat the invasion by and survival of chemo-resistant T-ALL cells.
authors.affiliation: Department of Life Sciences, Sir Alexander Fleming Building, Imperial College London, London SW7 2AZ, UK.|The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia.|Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Edwin D
authors.initials: ED
authors.lastname: Hawkins
authors.affiliation: Department of Life Sciences, Sir Alexander Fleming Building, Imperial College London, London SW7 2AZ, UK.|The Francis Crick Institute, 1 Midland Road, London NW1A 1AT, UK.
authors.forename: Delfim
authors.initials: D
authors.lastname: Duarte
authors.affiliation: Department of Life Sciences, Sir Alexander Fleming Building, Imperial College London, London SW7 2AZ, UK.
authors.forename: Olufolake
authors.initials: O
authors.lastname: Akinduro
authors.affiliation: Department of Life Sciences, Sir Alexander Fleming Building, Imperial College London, London SW7 2AZ, UK.
authors.forename: Reema A
authors.initials: RA
authors.lastname: Khorshed
authors.affiliation: The Francis Crick Institute, Haematopoietic Stem Cell Laboratory, 1 Midland Road, London NW1A 1AT, UK.
authors.forename: Diana
authors.initials: D
authors.lastname: Passaro
authors.affiliation: SIB Swiss Institute of Bioinformatics and Institute of Molecular Life Sciences, University of Zurich, Winterthurstrasse 190, 8057 Zurich, Switzerland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Nowicka
authors.affiliation: Stem Cell Regulation Unit, St Vincent's Institute of Medical Research, 41 Victoria Parade Fitzroy, Victoria 3065 Australia.
authors.forename: Lenny
authors.initials: L
authors.lastname: Straszkowski
authors.affiliation: Department of Life Sciences, Sir Alexander Fleming Building, Imperial College London, London SW7 2AZ, UK.|The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia.
authors.forename: Mark K
authors.initials: MK
authors.lastname: Scott
authors.affiliation: Imperial College Facility for Imaging by Light Microscopy, Sir Alexander Fleming Building, Imperial College London, London SW7 2AZ, UK.
authors.forename: Steve
authors.initials: S
authors.lastname: Rothery
authors.affiliation: Department of Life Sciences, Sir Alexander Fleming Building, Imperial College London, London SW7 2AZ, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Ruivo
authors.affiliation: The Francis Crick Institute, Haematopoietic Stem Cell Laboratory, 1 Midland Road, London NW1A 1AT, UK.
authors.forename: Katie
authors.initials: K
authors.lastname: Foster
authors.affiliation: Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3052, Australia.|Peter MacCallum Cancer Centre, Department of Haematology, Melbourne, Victoria 3000, Australia.
authors.forename: Michaela
authors.initials: M
authors.lastname: Waibel
authors.affiliation: Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3052, Australia.|Peter MacCallum Cancer Centre, Department of Haematology, Melbourne, Victoria 3000, Australia.
authors.forename: Ricky W
authors.initials: RW
authors.lastname: Johnstone
authors.affiliation: Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3052, Australia.|Peter MacCallum Cancer Centre, Department of Haematology, Melbourne, Victoria 3000, Australia.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Harrison
authors.affiliation: Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3052, Australia.|Peter MacCallum Cancer Centre, Department of Haematology, Melbourne, Victoria 3000, Australia.
authors.forename: David A
authors.initials: DA
authors.lastname: Westerman
authors.affiliation: Department of Haematology, St Vincent's Hospital, Fitzroy, Victoria 3065, Australia.|Department of Medicine, The University of Melbourne, Fitzroy, Victoria 3065, Australia.
authors.forename: Hang
authors.initials: H
authors.lastname: Quach
authors.affiliation: Centre of Haemato-Oncology, Cancer Research UK Clinical Centre, Barts Cancer Institute, St Bartholomew's Hospital, Queen Mary University of London, London EC1M 6BQ, UK.
authors.forename: John
authors.initials: J
authors.lastname: Gribben
authors.affiliation: SIB Swiss Institute of Bioinformatics and Institute of Molecular Life Sciences, University of Zurich, Winterthurstrasse 190, 8057 Zurich, Switzerland.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Robinson
authors.affiliation: Stem Cell Regulation Unit, St Vincent's Institute of Medical Research, 41 Victoria Parade Fitzroy, Victoria 3065 Australia.|Department of Medicine, The University of Melbourne, Fitzroy, Victoria 3065, Australia.
authors.forename: Louise E
authors.initials: LE
authors.lastname: Purton
authors.affiliation: The Francis Crick Institute, Haematopoietic Stem Cell Laboratory, 1 Midland Road, London NW1A 1AT, UK.
authors.forename: Dominique
authors.initials: D
authors.lastname: Bonnet
authors.affiliation: Department of Life Sciences, Sir Alexander Fleming Building, Imperial College London, London SW7 2AZ, UK.|The Francis Crick Institute, 1 Midland Road, London NW1A 1AT, UK.
authors.forename: Cristina
authors.initials: C
authors.lastname: Lo Celso
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology*; D002465:Cell Movement; D018450:Disease Progression; D005260:Female; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D000069416:Intravital Microscopy; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000473:pathology*; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D010006:Osteoblasts / Q000166:cytology; D059010:Single-Cell Analysis; D059016:Tumor Microenvironment