hiPSC-derived bone marrow milieu identifies a clinically actionable driver of niche-mediated treatment resistance in leukemia

Deepali Pal; Helen Blair; Jessica Parker; Sean Hockney; Melanie Beckett; Mankaran Singh; Ricky Tirtakusuma; Ryan Nelson; Hesta McNeill; Sharon H. Angel; Aaron Wilson; Salem Nizami; Sirintra Nakjang; Peixun Zhou; Claire Schwab; Paul Sinclair; Lisa J. Russell; Jonathan Coxhead; Christina Halsey; James M. Allan; Christine J. Harrison; Anthony V. Moorman; Olaf Heidenreich; Josef Vormoor

doi:10.1016/j.xcrm.2022.100717

hiPSC-derived bone marrow milieu identifies a clinically actionable driver of niche-mediated treatment resistance in leukemia

Deepali Pal^*, Helen Blair, Jessica Parker, Sean Hockney, Melanie Beckett, Mankaran Singh, Ricky Tirtakusuma, Ryan Nelson, Hesta McNeill, Sharon H. Angel, Aaron Wilson, Salem Nizami, Sirintra Nakjang, Peixun Zhou, Claire Schwab, Paul Sinclair, Lisa J. Russell, Jonathan Coxhead, Christina Halsey, James M. AllanChristine J. Harrison, Anthony V. Moorman, Olaf Heidenreich, Josef Vormoor

^*Corresponding author for this work

Obstetrics and Gynecology

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

Abstract

Leukemia cells re-program their microenvironment to augment blast proliferation and enhance treatment resistance. Means of clinically targeting such niche-driven treatment resistance remain ambiguous. We develop human induced pluripotent stem cell (hiPSC)-engineered niches to reveal druggable cancer-niche dependencies. We reveal that mesenchymal (iMSC) and vascular niche-like (iANG) hiPSC-derived cells support ex vivo proliferation of patient-derived leukemia cells, affect dormancy, and mediate treatment resistance. iMSCs protect dormant and cycling blasts against dexamethasone, while iANGs protect only dormant blasts. Leukemia proliferation and protection from dexamethasone-induced apoptosis is dependent on cancer-niche interactions mediated by CDH2. Consequently, we test CDH2 antagonist ADH-1 (previously in Phase I/II trials for solid tumors) in a very aggressive patient-derived xenograft leukemia mouse model. ADH-1 shows high in vivo efficacy; ADH-1/dexamethasone combination is superior to dexamethasone alone, with no ADH-1-conferred additional toxicity. These findings provide a proof-of-concept starting point to develop improved, potentially safer therapeutics targeting niche-mediated cancer dependencies in blood cancers.

Original language	English (US)
Article number	100717
Journal	Cell Reports Medicine
Volume	3
Issue number	8
DOIs	https://doi.org/10.1016/j.xcrm.2022.100717
State	Published - Aug 16 2022

Funding

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.). 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.). Conceptualization, D.P. Methodology, D.P. and H.B. Investigation, D.P. H.B. J.P. S.H. M.B. M.S. R.T. R.N. H.M. S.H.A. A.W. S.L.N. S.N. P.Z. C.S. P.S. L.J.R. and J.C. Visualization, D.P. and H.B. Validation, D.P. and H.B. Resources, D.P. H.B. J.V. and O.H. Funding acquisition, D.P. J.V. and O.H. Project administration, D.P. and H.B. Supervision, D.P. H.B. J.V. and O.H. Writing – original draft, D.P. and H.B. Writing – review & editing, D.P. J.V. O.H. A.V.M. C.J.H. J.M.A. and C.H. The authors declare no competing interests.

Keywords

cancer microenvironment
dormancy
drugging cancer niche
iPSC-niche
treatment resistance

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.xcrm.2022.100717

Cite this

Pal, D., Blair, H., Parker, J., Hockney, S., Beckett, M., Singh, M., Tirtakusuma, R., Nelson, R., McNeill, H., Angel, S. H., Wilson, A., Nizami, S., Nakjang, S., Zhou, P., Schwab, C., Sinclair, P., Russell, L. J., Coxhead, J., Halsey, C., ... Vormoor, J. (2022). hiPSC-derived bone marrow milieu identifies a clinically actionable driver of niche-mediated treatment resistance in leukemia. Cell Reports Medicine, 3(8), Article 100717. https://doi.org/10.1016/j.xcrm.2022.100717

@article{42d8cc690fd440e283471357920ae7dc,

title = "hiPSC-derived bone marrow milieu identifies a clinically actionable driver of niche-mediated treatment resistance in leukemia",

abstract = "Leukemia cells re-program their microenvironment to augment blast proliferation and enhance treatment resistance. Means of clinically targeting such niche-driven treatment resistance remain ambiguous. We develop human induced pluripotent stem cell (hiPSC)-engineered niches to reveal druggable cancer-niche dependencies. We reveal that mesenchymal (iMSC) and vascular niche-like (iANG) hiPSC-derived cells support ex vivo proliferation of patient-derived leukemia cells, affect dormancy, and mediate treatment resistance. iMSCs protect dormant and cycling blasts against dexamethasone, while iANGs protect only dormant blasts. Leukemia proliferation and protection from dexamethasone-induced apoptosis is dependent on cancer-niche interactions mediated by CDH2. Consequently, we test CDH2 antagonist ADH-1 (previously in Phase I/II trials for solid tumors) in a very aggressive patient-derived xenograft leukemia mouse model. ADH-1 shows high in vivo efficacy; ADH-1/dexamethasone combination is superior to dexamethasone alone, with no ADH-1-conferred additional toxicity. These findings provide a proof-of-concept starting point to develop improved, potentially safer therapeutics targeting niche-mediated cancer dependencies in blood cancers.",

keywords = "cancer microenvironment, dormancy, drugging cancer niche, iPSC-niche, treatment resistance",

author = "Deepali Pal and Helen Blair and Jessica Parker and Sean Hockney and Melanie Beckett and Mankaran Singh and Ricky Tirtakusuma and Ryan Nelson and Hesta McNeill and Angel, {Sharon H.} and Aaron Wilson and Salem Nizami and Sirintra Nakjang and Peixun Zhou and Claire Schwab and Paul Sinclair and Russell, {Lisa J.} and Jonathan Coxhead and Christina Halsey and Allan, {James M.} and Harrison, {Christine J.} and Moorman, {Anthony V.} and Olaf Heidenreich and Josef Vormoor",

note = "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{\textquoteright}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.). 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.). Conceptualization, D.P. Methodology, D.P. and H.B. Investigation, D.P. H.B. J.P. S.H. M.B. M.S. R.T. R.N. H.M. S.H.A. A.W. S.L.N. S.N. P.Z. C.S. P.S. L.J.R. and J.C. Visualization, D.P. and H.B. Validation, D.P. and H.B. Resources, D.P. H.B. J.V. and O.H. Funding acquisition, D.P. J.V. and O.H. Project administration, D.P. and H.B. Supervision, D.P. H.B. J.V. and O.H. Writing – original draft, D.P. and H.B. Writing – review & editing, D.P. J.V. O.H. A.V.M. C.J.H. J.M.A. and C.H. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2022 The Author(s)",

year = "2022",

month = aug,

day = "16",

doi = "10.1016/j.xcrm.2022.100717",

language = "English (US)",

volume = "3",

journal = "Cell Reports Medicine",

issn = "2666-3791",

publisher = "Cell Press",

number = "8",

}

Pal, D, Blair, H, Parker, J, Hockney, S, Beckett, M, Singh, M, Tirtakusuma, R, Nelson, R, McNeill, H, Angel, SH, Wilson, A, Nizami, S, Nakjang, S, Zhou, P, Schwab, C, Sinclair, P, Russell, LJ, Coxhead, J, Halsey, C, Allan, JM, Harrison, CJ, Moorman, AV, Heidenreich, O & Vormoor, J 2022, 'hiPSC-derived bone marrow milieu identifies a clinically actionable driver of niche-mediated treatment resistance in leukemia', Cell Reports Medicine, vol. 3, no. 8, 100717. https://doi.org/10.1016/j.xcrm.2022.100717

TY - JOUR

T1 - hiPSC-derived bone marrow milieu identifies a clinically actionable driver of niche-mediated treatment resistance in leukemia

AU - Pal, Deepali

AU - Blair, Helen

AU - Parker, Jessica

AU - Hockney, Sean

AU - Beckett, Melanie

AU - Singh, Mankaran

AU - Tirtakusuma, Ricky

AU - Nelson, Ryan

AU - McNeill, Hesta

AU - Angel, Sharon H.

AU - Wilson, Aaron

AU - Nizami, Salem

AU - Nakjang, Sirintra

AU - Zhou, Peixun

AU - Schwab, Claire

AU - Sinclair, Paul

AU - Russell, Lisa J.

AU - Coxhead, Jonathan

AU - Halsey, Christina

AU - Allan, James M.

AU - Harrison, Christine J.

AU - Moorman, Anthony V.

AU - Heidenreich, Olaf

AU - Vormoor, Josef

N1 - 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.). 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.). Conceptualization, D.P. Methodology, D.P. and H.B. Investigation, D.P. H.B. J.P. S.H. M.B. M.S. R.T. R.N. H.M. S.H.A. A.W. S.L.N. S.N. P.Z. C.S. P.S. L.J.R. and J.C. Visualization, D.P. and H.B. Validation, D.P. and H.B. Resources, D.P. H.B. J.V. and O.H. Funding acquisition, D.P. J.V. and O.H. Project administration, D.P. and H.B. Supervision, D.P. H.B. J.V. and O.H. Writing – original draft, D.P. and H.B. Writing – review & editing, D.P. J.V. O.H. A.V.M. C.J.H. J.M.A. and C.H. The authors declare no competing interests. Publisher Copyright: © 2022 The Author(s)

PY - 2022/8/16

Y1 - 2022/8/16

N2 - Leukemia cells re-program their microenvironment to augment blast proliferation and enhance treatment resistance. Means of clinically targeting such niche-driven treatment resistance remain ambiguous. We develop human induced pluripotent stem cell (hiPSC)-engineered niches to reveal druggable cancer-niche dependencies. We reveal that mesenchymal (iMSC) and vascular niche-like (iANG) hiPSC-derived cells support ex vivo proliferation of patient-derived leukemia cells, affect dormancy, and mediate treatment resistance. iMSCs protect dormant and cycling blasts against dexamethasone, while iANGs protect only dormant blasts. Leukemia proliferation and protection from dexamethasone-induced apoptosis is dependent on cancer-niche interactions mediated by CDH2. Consequently, we test CDH2 antagonist ADH-1 (previously in Phase I/II trials for solid tumors) in a very aggressive patient-derived xenograft leukemia mouse model. ADH-1 shows high in vivo efficacy; ADH-1/dexamethasone combination is superior to dexamethasone alone, with no ADH-1-conferred additional toxicity. These findings provide a proof-of-concept starting point to develop improved, potentially safer therapeutics targeting niche-mediated cancer dependencies in blood cancers.

AB - Leukemia cells re-program their microenvironment to augment blast proliferation and enhance treatment resistance. Means of clinically targeting such niche-driven treatment resistance remain ambiguous. We develop human induced pluripotent stem cell (hiPSC)-engineered niches to reveal druggable cancer-niche dependencies. We reveal that mesenchymal (iMSC) and vascular niche-like (iANG) hiPSC-derived cells support ex vivo proliferation of patient-derived leukemia cells, affect dormancy, and mediate treatment resistance. iMSCs protect dormant and cycling blasts against dexamethasone, while iANGs protect only dormant blasts. Leukemia proliferation and protection from dexamethasone-induced apoptosis is dependent on cancer-niche interactions mediated by CDH2. Consequently, we test CDH2 antagonist ADH-1 (previously in Phase I/II trials for solid tumors) in a very aggressive patient-derived xenograft leukemia mouse model. ADH-1 shows high in vivo efficacy; ADH-1/dexamethasone combination is superior to dexamethasone alone, with no ADH-1-conferred additional toxicity. These findings provide a proof-of-concept starting point to develop improved, potentially safer therapeutics targeting niche-mediated cancer dependencies in blood cancers.

KW - cancer microenvironment

KW - dormancy

KW - drugging cancer niche

KW - iPSC-niche

KW - treatment resistance

UR - http://www.scopus.com/inward/record.url?scp=85135921416&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85135921416&partnerID=8YFLogxK

U2 - 10.1016/j.xcrm.2022.100717

DO - 10.1016/j.xcrm.2022.100717

M3 - Article

C2 - 35977468

AN - SCOPUS:85135921416

SN - 2666-3791

VL - 3

JO - Cell Reports Medicine

JF - Cell Reports Medicine

IS - 8

M1 - 100717

ER -

hiPSC-derived bone marrow milieu identifies a clinically actionable driver of niche-mediated treatment resistance in leukemia

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UN SDGs

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