Pal, Deepali, Blair, Helen J., Parker, Jessica, Hockney, Sean, Beckett, Melanie, Singh, Mankaran, Tirtakusuma, Ricky, Nelson, Ryan, McNeill, Hesta, Angel, Sharon Hanmy, Wilson, Aaron, Nizami, Salem, Nakjang, Sirintra, Sankar, Shalini, Zhou, Peixun, Schwab, Claire, Sinclair, Paul B., Russell, Lisa J., Coxhead, Jonathan, Halsey, Christina, Allan, James M., Harrison, Christine J., Moorman, Anthony Vincent, Olaf, Heidenreich and Vormoor, Josef (2022) hiPSC-derived bone marrow milieu identifies a clinically actionable driver of niche-mediated treatment resistance in leukemia. Cell Reports Medicine, 3 (8). p. 100717. ISSN 2666-3791
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Abstract
Leukaemia cells re-program their microenvironment to provide proliferation support and protection from standard chemotherapy, molecularly targeted therapies, and immunotherapy. Although much is becoming known about molecules that drive niche-dependent treatment resistance; means of targeting these in the clinics has remained a key obstacle. To address this challenge, we have developed human induced pluripotent stem cell engineered niches ex vivo to reveal insights into druggable cancer-niche dependencies. We show that mesenchymal (iMSC) and vascular niche-like (iANG) cells support ex vivo proliferation of patient-derived leukaemia cells, impact dormancy and mediate therapy resistance. iMSC protected both non-cycling and cycling blasts against dexamethasone treatment while iANG protected only dormant blasts. Leukaemia proliferation and protection from dexamethasone induced-apoptosis was dependent on direct cell-cell contact and mediated by CDH2. To explore the therapeutic potential of disrupting this cell-cell interaction, we tested the CDH2 antagonist ADH-1 (previously in phase I / II for solid tumours) in a very aggressive patient-derived xenograft leukaemia mouse model. ADH-1 showed high in vivo efficacy. ADH-1/ dexamethasone combination therapy was superior to dexamethasone alone with no ADH1 conferred additional toxicity. These findings provide a proof-of-concept starting point to develop novel, potentially safer therapeutics that target niche-mediated cancer cell dependencies in haematological malignancies.Summary CDH2 mediated niche-dependent cancer proliferation and treatment resistance is clinically targetable via ADH-1, a low toxic agent that could be potentially repurposed for future clinical trials in acute leukaemia.Competing Interest StatementThe authors have declared no competing interest.
| Item Type: | Article |
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| Additional Information: | Funding information: This study was funded by NC3Rs grants to D.P.; a CCLG project grant to D.P., J.V., and O.H.; and a Wellcome Trust NUSCU award to D.P. We would like to further thank CRUK for program grant no. C27943/A12788 to J.V. and O.H. and NECCR for funding core infrastructure at Wolfson Childhood Cancer Research Centre, Newcastle University. C.J.H. and A.V.M. were funded by Blood Cancer UK (grant no. 15036). The IVIS Spectrum was funded by grant 087961 from the Wellcome Trust. We thank Dr. Malgorzata Firczuk, Medical University of Warsaw, for the PDX samples. We thank Sophie Boyd, Asmida Isa, and Shalini Shankar for technical assistance. We thank the BSU, Newcastle University, for performing the bioinformatics analysis; and Andrew Filby, Andrew Fuller, and Carly Knill at the Flow Cytometry Core Facility, Newcastle University, for assistance with flow cytometry. The study was also funded by the National Centre for the Replacement Refinement and Reduction of Animals in Research (NC3Rs) (NC/P002412/1 and NC/V001639/1, to D.P.), the Children’s Cancer and Leukaemia Group (CCLG) (CCLGA 2016 05 BH160568, to D.P., J.V., and O.H.), Wellcome Trust NUSCU award (OSR/0190/DPAL/NUSC [to D.P.]), Cancer Research UK (CRUK) grant no. C27943/A12788 (to J.V. and O.H.), and Blood Cancer UK grant no. 15036 (to C.J.H. and A.V.M.). |
| Uncontrolled Keywords: | cancer microenvironment, dormancy, treatment resistance, iPSC-niche, drugging cancer niche |
| Subjects: | B100 Anatomy, Physiology and Pathology B900 Others in Subjects allied to Medicine C700 Molecular Biology, Biophysics and Biochemistry |
| Department: | Faculties > Health and Life Sciences > Applied Sciences |
| Related URLs: | |
| Depositing User: | Elena Carlaw |
| Date Deposited: | 03 Aug 2022 10:49 |
| Last Modified: | 17 Aug 2022 08:15 |
| URI: | http://nrl.northumbria.ac.uk/id/eprint/49710 |
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