Niche hijack by malignant cells is considered to be a prominent cause of disease relapse. Barbier and colleagues uncover (E)-selectin as a novel mediator of malignant cell survival and regeneration which, upon blockade, has the potential to significantly improve therapeutic outcomes

Haltalli, Myriam L. R.

Lo Celso, Cristina

Nature Communications

Apollo (Cambridge)

COMMENTTargeting adhesion to the vascularniche to improve therapy for acutemyeloid leukemiaMyriam L. R. Haltalli 1,2,3 & Cristina Lo Celso 1,2✉Niche hijack by malignant cells is considered to be a prominent cause of diseaserelapse. Barbier and colleagues uncover (E)-selectin as a novel mediator ofmalignant cell survival and regeneration which, upon blockade, has the potentialto significantly improve therapeutic outcomes.Not-so-welcome to the neighborhoodHematopoietic stem cells (HSCs) sit at the top of the hematological hierarchy as multipotentcells with the capacity to self-renew and give rise to various progenitor populations, whichmaintain the production of short-lived mature lineages (including blood cells) throughout life.They reside within the bone marrow (BM), within specialized niches that facilitate their survivaland regulate their function via local interactions with diverse stromal and hematopoietic cells. Itis widely accepted that spatially distinct niches exist to support HSCs with a range of differ-entiation biases and quiescence states. These are broadly split into the central BM niche, locatedin the deeper BM and rich in sinusoid capillaries, and the endosteal niche, in close proximity tothe bone inner surface and rich in arterioles and transitional vessels that feed into the sinusoidalnetwork1. In both locations, HSCs reside in perivascular niches where endothelial cells (ECs) andtheir associated mesenchymal stem cells critically maintain and regulate them2.Hematological malignancies, such as acute myeloid leukemia (AML), tend to arise from theexpansion of transformed hematopoietic stem and progenitor cells (HSPCs) with subclonalgenotypes, resulting in refractory clones that are able to resist chemotherapy and ultimately leadto the relapse of disease. Leukemia stem cells (LSCs) share many features with healthy HSCs,which has led to the hypothesis that LSCs similarly reside in, and depend on, specific BM“neighborhoods” that support their expansion and survival3,4. There is a growing need for noveltherapies to reduce malignancy-associated morbidity and mortality and, due to the fact thatmany mechanisms of immune evasion and chemoresistance are partly dependant on it, the BMniche represents a unique target to improve treatment outcomes5. The recent work by Barbierand colleagues6 is therefore timely as it reveals, using AML as a model, a new cell-extrinsicniche-based pathway that directly mediates therapy resistance. The authors propose a methodwith the potential to improve AML treatment efficacy by targeting the vascular niche.Holding on tightEndothelial (E)-selectins are cell adhesion molecules expressed in the vascular niche, which havewell-characterized roles in leukocyte homing. E-selectin is constitutively expressed on BMhttps://doi.org/10.1038/s41467-020-17594-7 OPEN1 Department of Life Sciences, Imperial College London, Sir Alexander Fleming Building, SW7 2AZ London, UK. 2 The Francis Crick Institute, WC2A 3LYLondon, UK. 3Present address: Wellcome - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Jeffrey Cheah BiomedicalCentre, Cambridge Biomedical Campus, CB2 0AW Cambridge, UK. ✉email: c.lo-celso@imperial.ac.ukNATURE COMMUNICATIONS |         (2020) 11:3691 | https://doi.org/10.1038/s41467-020-17594-7 | www.nature.com/naturecommunications 11234567890():,;endothelium, aiding the homing and engraftment of circulatingHSPCs that possess the necessary counter-receptors. Previouswork had demonstrated that adhesion to E-selectin promotes theproliferation of HSCs, directly triggers their activation andinduces lineage commitment7. Interestingly, based on earlierobservations of E-selectin expression in BM areas where leukemiacells home8, the hypothesis arose that LSCs may be protectedfrom the effects of chemotherapy through their anchorage inniches enriched in its expression. The work from Winkler et al.uncovered an unexpected additional role for this adhesionmolecule as a therapeutic target when its inhibition induced HSCchemoresistance and radioresistance. Overall, their findingsraised the question whether specific binding of tumor cells withendothelium expressing E-selectin might regulate tumor growthand proliferation7. Barbier et al. address this question and showthat, in the context of disease, interaction with E-selectin plays adirect role in promoting malignant cells’ survival in the BM, atextbook example of niche hijack.Inflammation is a hallmark of cancer and we have previouslyhypothesized that it is a key player in driving remodeling of theBM niche during leukemia9. E-selectin is expressed by ECs at theleading edge of solid tumors and at pre-metastatic sites, which arealso highly inflammatory environments10,11. Barbier et al.demonstrate that the inflammation generated by AML in the BMdirectly drives the increased levels of E-selectin on BM ECs ofleukemic mice. This resulted in the postulation that the specificupregulation on tumor-associated vasculature may be lessinvolved in the homing of AML cells, but more so as a factordirectly contributing to their survival and regeneration by creat-ing a protective niche for LSCs to hold on to, thus promotingtherapy resistance.A novel target for improved therapyWhile there is an ever-increasing number of targeted therapies totreat leukemia, patient outcome remains poor, thus there is anurgent need to develop new strategies. Over the past few years,with the advance of increasingly sophisticated technologies tostudy the BM microenvironment, we have gained fascinatinginsight into this tissue. We can now appreciate that it is a complexand dynamic entity that actively interacts with healthy hemato-poietic cells, as well as their malignant counterparts, playing animportant role in directing their fates. Our knowledge of howleukemia cells co-opt and alter BM niches offers many oppor-tunities for therapeutic exploitation, and more targeted inter-ventions of novel pathways to restore healthy hematopoiesis andlimit disease relapse.By elegantly demonstrating that the leukemic blasts most likelyto survive chemotherapy were those characterized by higher E-selectin binding potential, Barbier and colleagues suggested thatthese cells were the main contributors to disease relapse. To testthe role of E-selectin in supporting malignant cells, they sought tounderstand the outcome if this adhesion molecule was absent inthe BM (using an E-selectin gene knock-out mouse model) orblocked therapeutically. E-selectin can be inhibited by adminis-tering a selective small molecule antagonist called GMI-1271 (alsoknown as uproleselan). It has been shown that this treatmenteffectively displaces chronic myeloid leukemia (CML) cells fromthe BM endothelium, promoting cell cycle progression anddownregulating the expression of the E-selectin ligand CD44—thus reinforcing the reduced adhesion of CML cells to the BMendothelium12. Using an innovative method, the authors inves-tigated whether functional LSCs were amongst those protected byE-selectin-mediated interactions in the vascular niche. Theydeveloped a quantitative in vivo LSC chemosensitivity assay,based on the principle of limiting dilution transplants widely usedfor enumerating HSCs. By comparing the number of persistingLSCs in recipients of BM cells from chemotherapy-treated, E-selectin gene-deleted, or GMI-1271-treated wild-type mice, theydemonstrated that the deletion or blockade of E-selectin drasti-cally reduced LSC survival. Therefore, E-selectin mediates sig-nificant intracellular pro-survival signaling for LSCs, and thisunique characteristic was not replicated by other adhesionmolecules and chemokines involved in BM retention.Up until now, combinations of chemotherapy with approachesthat target mainly AML-intrinsic mechanisms have been pro-posed13, including the use of CXCR4 antagonists14 and anti-inflammatory therapies15. With this work, the authors bring tolight the fact that cell-extrinsic targets could prove hugely valu-able in future phases of therapy development. By administeringGMI-1271 alongside a standard chemotherapy regime in leu-kemic mice, Barbier et al. were able to double the duration ofmouse survival over chemotherapy alone. Endogenous, healthy,HSPC populations exhibited strikingly different responses whencompared to AML blasts, suggesting that this treatment strategyprotects those populations in the BM. These intriguing datademonstrate that therapeutic blocking of this vascular niche-mediated survival pathway could complement conventional AMLtreatment regimens to improve efficacy and extend overallsurvival.Future directions and clinical impactWe must harness the progress made so far in creating a detailedmap of the BM microenvironment with all of its structures andcomponents at steady state, in order to keep elucidating theunderlying mechanisms of disease-mediated niche hijack. Thenumber of clinical trials arising from a deeper understanding ofthe HSC niche is bound to increase. Based on the work presentedby Barbier and colleagues, a phase I/II clinical trial is already inprogress to evaluate the use of GMI-1271 alongside standardtherapy in relapsed/refractory adult AML (NCT02306291). So far,they have shown greater rates of clinical remission and extendedmedian patient survival, which is consistent with the findingsin vivo presented by the authors. The future of these “nicho-therapies”16 to facilitate chemotherapy looks extremely promisinggiven the rise in demand for new agents with good tolerance in abroad range of AML patients, increased efficacy and, mostimportantly, the ability to limit disease relapse. The work pre-sented here provides hope that innovative methods of targetingmalignant BM niches could be the key to making AML a treatabledisease.Received: 19 June 2020; Accepted: 9 July 2020;References1. Pinho, S. & Frenette, P. S. Haematopoietic stem cell activity and interactionswith the niche. Nat. Rev. Mol. Cell Biol. 20, 303–320, (2019).2. Méndez-Ferrer, S. et al. Mesenchymal and haematopoietic stem cells form aunique bone marrow niche. Nature 466, 829 (2010).3. Ishikawa, F. et al. Chemotherapy-resistant human AML stem cells home toand engraft within the bone-marrow endosteal region. Nat. Biotechnol. 25,1315–1321 (2007).4. Lane, S. W., Scadden, D. T. & Gilliland, D. G. The leukemic stem cell niche:current concepts and therapeutic opportunities. Blood 114, 1150–1157 (2009).5. Duarte, D., Hawkins, E. D. & Celso, C. L. The interplay of leukemia cells andthe bone marrow microenvironment. Blood 131, 1507–1511 (2018).6. Barbier, V. et al. Vascular niche hijack via E-selectin promotes niche-mediatedacute myeloid leukemia stem cell chemoresistance and regeneration. Nat.Commun. 11, 2042 (2020).7. Winkler, I. G. et al. Vascular niche E-selectin regulates hematopoietic stem celldormancy, self renewal and chemoresistance. Nat. Med. 18, 1651 (2012).COMMENT NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-17594-72 NATURE COMMUNICATIONS |         (2020) 11:3691 | https://doi.org/10.1038/s41467-020-17594-7 | www.nature.com/naturecommunications8. Sipkins, D. A. et al. In vivo imaging of specialized bone marrow endothelialmicrodomains for tumour engraftment. Nature 435, 969–973 (2005).9. Duarte, D. et al. Inhibition of endosteal vascular niche remodeling rescueshematopoietic stem cell loss in AML. Cell Stem Cell 22, 64–77 (2018).10. Ye, C. et al. Expression of E-selectin on endothelial cells of small veins inhuman colorectal cancer. Int J. Cancer 61, 455–460 (1995).11. Shi, H. et al. Recruited monocytic myeloid-derived suppressor cells promotethe arrest of tumor cells in the premetastatic niche through an IL-1β-mediatedincrease in E-selectin expression. Int J. Cancer 140, 1370–1383 (2017).12. Godavarthy, P. S. et al. The vascular bone marrow niche influences outcome inchronic myeloid leukemia via the E-selectin - SCL/TAL1 - CD44 axis.Haematologica 105, 136–147 (2019).13. Pezeshkian, B., Donnelly, C., Tamburo, K., Geddes, T. & Madlambayan, G. J.Leukemia mediated endothelial cell activation modulates leukemia cellsusceptibility to chemotherapy through a positive feedback loop mechanism.Plos ONE 8, e60823 (2013).14. Cho, B.-S., Kim, H.-J. & Konopleva, M. Targeting the CXCL12/CXCR4 axis inacute myeloid leukemia: from bench to bedside. Korean J. Intern. Med. 32,248–257 (2017).15. Mead, A. J. et al. Niche-mediated depletion of the normal hematopoietic stemcell reservoir by Flt3-ITD–induced myeloproliferation. J. Exp. Med. 214,2005–2021 (2017).16. Levesque, J.-P., Winkler, I. G. & Rasko, J. E. J. Nichotherapy for stem cells:there goes the neighborhood. Bioessays 35, 183–190 (2012).Author contributionsM.L.R.H and C.L.C wrote the article.Competing interestsThe authors declare no competing interests.Additional informationCorrespondence and requests for materials should be addressed to C.L.C.Reprints and permission information is available at http://www.nature.com/reprintsPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Open Access This article is licensed under a Creative CommonsAttribution 4.0 International License, which permits use, sharing,adaptation, distribution and reproduction in any medium or format, as long as you giveappropriate credit to the original author(s) and the source, provide a link to the CreativeCommons license, and indicate if changes were made. The images or other third partymaterial in this article are included in the article’s Creative Commons license, unlessindicated otherwise in a credit line to the material. 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