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Medulloblastoma with Patient Ips Cell-Derived Neural Stem Cells

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Medulloblastoma with Patient Ips Cell-Derived Neural Stem Cells Modeling SHH-driven medulloblastoma with patient iPS cell-derived neural stem cells Evelyn Susantoa, Ana Marin Navarroa, Leilei Zhoua, Anders Sundströmb, Niek van Breea, Marina Stantica, Mohsen Moslemc, Jignesh Tailord,e, Jonne Rietdijka, Veronica Zubillagaa, Jens-Martin Hübnerf,g, Holger Weishauptb, Johanna Wolfsbergera, Irina Alafuzoffb, Ann Nordgrenh,i, Thierry Magnaldoj, Peter Siesjök,l, John Inge Johnsenm, Marcel Koolf,g, Kristiina Tammimiesm, Anna Darabil, Fredrik J. Swartlingb, Anna Falkc,1, and Margareta Wilhelma,1 aDepartment of Microbiology, Tumor and Cell biology (MTC), Karolinska Institutet, 171 65 Stockholm, Sweden; bDepartment of Immunology, Genetics, and Pathology, Science For Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden; cDepartment of Neuroscience, Karolinska Institutet, 171 65 Stockholm, Sweden; dDevelopmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; eDivision of Neurosurgery, University of Toronto, Toronto, ON M5S 1A8, Canada; fHopp Children’s Cancer Center (KiTZ), 69120 Heidelberg, Germany; gDivision of Pediatric Neurooncology, German Cancer Research Center (DKFZ), and German Cancer Research Consortium (DKTK), 69120 Heidelberg, Germany; hDepartment of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, 171 76 Stockholm, Sweden; iDepartment of Clinical Genetics, Karolinska University Hospital, 171 76 Stockholm, Sweden; jInstitute for Research on Cancer and Aging, CNRS UMR 7284, INSERM U1081, University of Nice Sophia Antipolis, Nice, France; kDivision of Neurosurgery, Department of Clinical Sciences, Skane University Hospital, 221 85 Lund, Sweden; lGlioma Immunotherapy Group, Division of Neurosurgery, Department of Clinical Sciences, Lund University, 221 85 Lund, Sweden; and mDepartment of Women’s and Children’s Health, Karolinska Institutet, 171 76 Stockholm, Sweden Edited by Matthew P. Scott, Stanford University, Washington, DC, and approved June 29, 2020 (received for review November 23, 2019) Medulloblastoma is the most common malignant brain tumor in are prone to genetic drift and the molecular diversity and the children. Here we describe a medulloblastoma model using In- tumor heterogeneity seen in the original tumor is seldom reca- duced pluripotent stem (iPS) cell-derived human neuroepithelial pitulated in tumor cell lines (4). To overcome these limitations, stem (NES) cells generated from a Gorlin syndrome patient carry- we took advantage of cellular reprogramming to establish ing a germline mutation in the sonic hedgehog (SHH) receptor healthy neural stem cells carrying a germline mutation known to PTCH1. We found that Gorlin NES cells formed tumors in mouse activate the SHH signaling pathway. Induced pluripotent stem cerebellum mimicking human medulloblastoma. Retransplantation MEDICAL SCIENCES (iPS) cells generated by expression of reprogramming factors in of tumor-isolated NES (tNES) cells resulted in accelerated tumor formation, cells with reduced growth factor dependency, en- skin fibroblasts have demonstrated a pluripotent phenotype hanced neurosphere formation in vitro, and increased sensitivity similar to that of embryonic stem (ES) cells (5), thus patient- to Vismodegib. Using our model, we identified LGALS1 to be a GLI derived iPS cells create a renewable cell source to model human target gene that is up-regulated in both Gorlin tNES cells and SHH- diseases (6). In addition, iPS cells and their derivatives mimic subgroup of medulloblastoma patients. Taken together, we dem- early stages of human development, making them an attractive onstrate that NES cells derived from Gorlin patients can be used as system for studying early onset diseases such as childhood can- a resource to model medulloblastoma initiation and progression cers that are thought to originate in stem or progenitor cells (7). and to identify putative targets. Significance medulloblastoma | neural stem cells | disease model Here we describe and utilize a model of medulloblastoma, a edulloblastoma is the most common malignant childhood malignancy accounting for 20% of all childhood brain cancers. Mbrain tumor. Molecular classification has identified key We used iPS-derived neural stem cells with a familial mutation developmental signaling pathways regulating tumor development causing aberrant SHH signaling. We show that these cells, and segregate medulloblastoma into at least four subgroups: when transplanted into mouse cerebellum, form tumors that wingless (WNT), sonic hedgehog (SHH), group 3, and group 4 mimics SHH-driven medulloblastoma, demonstrating the de- (1). The SHH-subgroup, where SHH-pathway is constitutively velopment of cancer from healthy neural stem cells in vivo. Our active, comprises about 30% of total medulloblastoma. Common results show that reprogramming of somatic cells carrying fa- drivers for this subgroup include mutations or deletions of neg- milial cancer mutations can be used to model the initiation and ative regulators PTCH1 or suppressor of fused (SUFU), as well progression of childhood cancer. as activating mutations of smoothened (SMO), and gene ampli- fications of transcription factors GLI2 and MYCN (2). Author contributions: E.S., F.J.S., A.F., and M.W. designed research; E.S., A.M.N., L.Z., A.S., N.v.B., M.S., M.M., J.T., J.R., V.Z., J.-M.H., H.W., J.W., I.A., A.N., M.K., K.T., A.D., A.F., and Although current treatments have significantly improved sur- M.W. performed research; J.T., T.M., P.S., J.I.J., A.D., F.J.S., A.F., and M.W. contributed new vival of affected children, they often result in devastating side reagents/analytic tools; E.S., A.M.N., L.Z., A.S., N.v.B., M.S., J.R., J.-M.H., H.W., I.A., A.N., effects, such as cognitive deficits, endocrine disorders, and in- M.K., K.T., A.D., F.J.S., A.F., and M.W. analyzed data; and E.S., A.F., and M.W. wrote creased incidence of secondary cancers later in life (3), high- the paper. lighting the importance of developing effective therapies that will The authors declare no competing interest. not harm the healthy brain. To identify and test therapeutic This article is a PNAS Direct Submission. targets against medulloblastoma, we need to develop models that This open access article is distributed under Creative Commons Attribution-NonCommercial- mimic the initiation and progression of the disease. The limita- NoDerivatives License 4.0 (CC BY-NC-ND). tions of disease modeling in nonhuman organisms drive solutions Data deposition: Data has been deposited at Mendeley, DOI: 10.17632/syhdb33jpt.1. RNA sequencing data have been deposited at Gene Expression Omnibus (GEO) with accession that include humanizing animals or creating cellular models that number GSE106718. reliably mimic key processes in healthy and/or diseased humans. 1To whom correspondence may be addressed. Email: [email protected] or anna. However, primary tumor cell lines established from surgically [email protected]. removed tumors represent an end point of tumor development This article contains supporting information online at https://www.pnas.org/lookup/suppl/ when cells are already transformed and genetic rearrangements doi:10.1073/pnas.1920521117/-/DCSupplemental. have taken place. Furthermore, tumor cell lines cultured in vitro First published August 3, 2020. www.pnas.org/cgi/doi/10.1073/pnas.1920521117 PNAS | August 18, 2020 | vol. 117 | no. 33 | 20127–20138 Downloaded by guest on September 27, 2021 The central nervous system develops from a small number of S1B). In addition, we detected both wild-type (WT) and mutant highly plastic progenitors called neuroepithelial cells. These cells PTCH1 alleles in G1 NES, but only WT alleles in control NES have been shown to be competent in generating granule cells, a (Fig. 1D). Western blot analysis shows the presence of both WT major cell population in the cerebellum (8). Long-term self- and truncated (Mut) PTCH1 protein in G1 NES (Fig. 1E). In- renewing neuroepithelial-like stem cells (NES cells) have suc- triguingly, we could not observe any significant up-regulation of cessfully been generated from human ES cells and iPS cells (9), SHH target genes expression in patient cells even though they with similar biological properties and gene expression patterns to express truncated PTCH1 protein (SI Appendix, Fig. S1C). This neuroepithelial stem cells captured from the developing human could indicate that the remaining wild-type allele of PTCH1 is hindbrain that give rise to cerebellum, pons, and medulla still sufficiently blocking SHH signaling, or that the SHH- oblongata (10). NES cells maintain their stem cell properties pathway is not active in proliferating monolayer NES cells. It even after long-term propagation in vitro, and upon removal of has been reported that human iPS cells can acquire dominant- growth factors, these cells differentiate into functional neurons negative p53 mutations during reprogramming and expansion and glial cells with a hindbrain identity (9). We hypothesized that (20). To exclude that p53 mutations have been introduced during NES cells generated from reprogrammed noncancerous somatic reprogramming to iPS cells or NES cell generation, we se- cells carrying a medulloblastoma driver mutation may give rise to quenced exons 4 to 10, where the majority of mutations in the tumors when exposed to a permissive environment. To test this, TP53 gene occur (https://p53.iarc.fr/), and could not detect any we used iPS cell technology to derive a medulloblastoma model mutations (SI Appendix, Fig. S1D). In accordance,
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