B細胞関連の小児癌の再発を含めた経時的評価とその改善余地

//Background//---
One of the demanding challenges in the cancer therapy is adapting nature in the tumor. This adapting nature makes cancer cell relapse emerge. In pediatric cancer therapy, relapse free effective treatment is ideal, given their long remaining lifetime. Therefore, investigating adapting mechanism for chemo- or/and radiation- or/and immune- therapies is crucial. Furthermore, in the childhood, the tissues are in the development stage. Therefore, any strong perturbation including drug treatment could significantly affect their maturation. Actually, molecular multi-omics study for the residual pediatric cancer disease provides the most potent indicator of long-term clinical outcome(4,5). However, very few studies have explored the genetic and epigenetic landscape of the disease residue at single-cell resolution for the long-term cancer treatment(2,3). In treatment of B-cell precursor acute lymphoblastic leukemia (BCP-ALL), multi-drugs are generally used up to 36 months. The challenging matter is following:
*Lack of appropriated material for analysis when cell numbers are limiting(Sampling difficulty).
*Universal tumor cell-surface makers are lacking in hematological malignancy
*Uncertain determinant from stochastic selection in the fingerprint of the cancer treatment
 Virginia A. Turati, José Afonso Guerra-Assunção, Nicola E. Potter et al. investigate the mechanism of emergent evolution (chemotherapy-induced clonal selection) in childhood B-cell  precursor acute lymphoblastic leukemia (BCP-ALL) in the case where maximal cytoreduction occurs, meaning high clinical response is shown(1).
 
//Methods(1)//---
To overcome above(*) technical and logistic hurdles, they used a child patient-derived xenograft model in which identical leukemia is developed in the mice(1). These mice are treated with following medicine similar to actual the first 28 days BCP-ALL treatment.
*Vincristine (a microtubule poison) / *Dexamethasone (a glucocorticoid)
(Analyzed method)
 High-resolution, single-cell whole-genome sequencing (scWGS).
 
//Result(1)//---
*Intratumor genetic heterogeneity is unaffected before/after treatment of Vincristine and Dexamethasone in the xenograft mice from Shannon entropy analysis(See Fig.3h,i).
*Clonal trait is drastically changed immediately after chemotherapy (Day 0) to <Day 10, after which clonal trait become stable up to Day 28(See Fig.4e). The nature of childhood BCP-ALL is polyclonal, some of which have the key transcriptional features of the chemotherapy-resistant causing refractory trait. This transcriptome persists through relapse in vivo. Resistant gene is MME/CD10, E2F1 and EZH2.
*Allele frequency (Gene variant rate) is not prone to change in the whole gene from Day 0 to Day 28 after chemotherapy, meaning depending on the gene(See Fig.6e, 6f).
*Chemotherapy resistant nature including cancer cell dormancy (G0 cycle cell arrest) is dominantly confirmed after treatment. This is generally linked in BCP-ALL(6-8). They confirm low hallmark MYC and E2F in the treatment which are cell progression factor(Fig.7c).
 
//Discussion//---
 Intervention of resistant gene indicated in Virginia A. Turati et al. including MME/CD10, E2F1 and EZH2 is the matter to debate. In other words, as long as MME/CD10, E2F1 and EZH2 mutation (dormant) cell existing in the children’s body, the relapse risk may remain in the future. At least, awaking mechanism from dormancy needs to be investigated in detail.
 
//The cell-specific drug delivery system//---
 Cancer dormancy is one of the causes of relapse and drug-resistant.
In order to “control”
:”meaning the aggressive intervention is open matter, but eliminating highly quiescent cancer cells may be required for prolonged (2-3 years) maintenance therapy to achieve durable remission and minimal rate for relapse(6,10,11).)”
the activity of and awaking from dormant cancer cell, we need to discern its cell and deliver nanoparticles. For example, we can harness the surface receptor specific to dormant cancer cell. For instance, DDR, Syndecan, FZD, integrin are possible candidates for specific recognition(Ref.(9) See Fig.1). However, integrin is broadly expressed such as in vascular system, so we need to find specific binding pocket or epitope through detailed structural analysis. Furthermore, many challenges remain. For example, heterogeneity of the structure of the surface protein may be large and we need to know the binding site in the whole body, which is extremely daunting task. Therefore, we need to efficiently and rationally narrow down to the rare bind site through (computational) analysis of the large number of the dormant specific cancer (BCP-ALL).
 
//Contributions//---
V.A.T., T.E., M.G. and S.E.J. conceived the study. V.A.T., M.L., J.B., A.W. and M.H. conducted the methodology. V.A.T., N.P., I.M. and A.D. did the investigations. J.A.G.-A., M.T., P.V.L., S.B. and J.H. carried out the formal analysis. J.A.G-A., A.W., S.E., C.D., C.J., C.L. and J.H. curated the data. S.E.J., G.W.H., A.B., L.R., S.I., P.A., G.C. and L.R. provided the resources. T.E., S.E.J and M.G. supervised the project. V.A.T., R.G., G.M., T.E. and M.G. wrote the manuscript. T.E. and M.G. acquired the funding.
 
(Reference)
(1)
Virginia A. Turati, José Afonso Guerra-Assunção, Nicola E. Potter, Rajeev Gupta, Simone Ecker, Agne Daneviciute, Maxime Tarabichi, Amy P. Webster, Chuling Ding, Gillian May, Chela James, John Brown, Lucia Conde, Lisa J. Russell, Phil Ancliff, Sarah Inglott, Giovanni Cazzaniga, Andrea Biondi, Georgina W. Hall, Mark Lynch, Mike Hubank, Iain Macaulay, Stephan Beck, Peter Van Loo, Sten E. Jacobsen, Mel Greaves, Javier Herrero & Tariq Enver
Chemotherapy induces canalization of cell state in childhood B-cell precursor acute lymphoblastic leukemia
Nature Cancer (2021)
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Author information
Author notes
These authors contributed equally: José Afonso Guerra-Assunção, Nicola E. Potter.
Affiliations
UCL Cancer Institute, University College London, London, UK
Virginia A. Turati, José Afonso Guerra-Assunção, Rajeev Gupta, Simone Ecker, Agne Daneviciute, Amy P. Webster, Chuling Ding, Gillian May, Chela James, John Brown, Lucia Conde, Stephan Beck, Javier Herrero & Tariq Enver
Institute of Cancer Research, Sutton, UK
Nicola E. Potter, Mike Hubank & Mel Greaves
The Francis Crick Institute, London, UK
Maxime Tarabichi & Peter Van Loo
Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle University, Newcastle, UK
Lisa J. Russell
Great Ormond Street Hospital, London, UK
Phil Ancliff & Sarah Inglott
Centro Ricerca M. Tettamanti, University of Milano-Bicocca, Monza, Italy
Giovanni Cazzaniga
Department of Pediatrics, University of Milano-Bicocca, Fondazione MBBM/Ospedale San Gerardo, Monza, Italy
Andrea Biondi
John Radcliffe Hospital, Oxford, UK
Georgina W. Hall
Fluidigm Corporation, San Francisco, CA, USA
Mark Lynch
Royal Marsden Hospital, Sutton, UK
Mike Hubank
The Earlham Institute, Norwich, UK
Iain Macaulay
MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK
Sten E. Jacobsen
Center for Hematology and Regenerative Medicine, Department of Medicine and Department of Cell and Molecular Biology, Karolinska Institutet and Karolinska University Hospital Huddinge, Stockholm, Sweden
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Centro Ricerca Tettamanti, Clinica Pediatrica Univ. Milano Bicocca, Ospedale San Gerardo, Monza, Italy
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Author information
Affiliations
School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea
So-Yeon Park & Jeong-Seok Nam
Cell Logistics Research Center, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea
So-Yeon Park & Jeong-Seok Nam
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