Humanized Stem Cell Models of Pediatric Medulloblastoma Reveal an Oct4/mTOR Axis that Promotes Malignancy

Čančer, Matko; Hutter, Sonja; Holmberg, Karl O.; Rosén, Gunnar; Sundström, Anders; Tailor, Jignesh; Bergström, Tobias; Garancher, Alexandra; Essand, Magnus; Wechsler‐Reya, Robert J.; Falk, Anna; Weishaupt, Holger; Swartling, Fredrik J.

doi:10.1016/j.stem.2019.10.005

Cited by 44 publications

(38 citation statements)

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“…Analysis of the effect of c-MET mutants on glioblastoma formation were also evaluated using c-MET iPSC-derived organoids, which expressed elevated levels of glial fibrillary acidic protein (GFAP) and increased phospho-MET and phospho-STAT3 ( Hwang et al, 2020 ). Activation of the OCT4/mTOR axis via MYCN overexpression was observed in another iPSC model of the Sonic Hedgehog (SHH)-subgroup medulloblastoma ( Cancer et al, 2019 ). A number of genes, including KRAS, have also been activated to induce proliferation via Ras signaling during the generation of hPSCs and organoid models for the investigation of tumorigenesis ( Kim et al, 2013 ; Huang et al, 2015 ).…”

Section: Modeling Cancer Propagation and Dissecting The Genetic Basismentioning

confidence: 97%

Modeling cancer progression using human pluripotent stem cell-derived cells and organoids

et al. 2020

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Conventional cancer cell lines and animal models have been mainstays of cancer research. More recently, human pluripotent stem cells (hPSCs) and hPSC-derived organoid technologies, together with genome engineering approaches, have provided a complementary platform to model cancer progression. Here, we review the application of these technologies in cancer modeling with respect to the cell-of-origin, cancer propagation, and metastasis. We further discuss the benefits and challenges accompanying the use of hPSC models for cancer research and discuss their broad applicability in drug discovery, biomarker identification, decoding molecular mechanisms, and the deconstruction of clonal and intra-tumoral heterogeneity. In summary, hPSC-derived organoids provide powerful models to recapitulate the pathogenic states in cancer and to perform drug discovery.

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Section: Modeling Cancer Propagation and Dissecting The Genetic Basismentioning

confidence: 97%

Modeling cancer progression using human pluripotent stem cell-derived cells and organoids

et al. 2020

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“…MYC and MYCN siblings are similar in structure, and can often substitute each other’s functions ( 51 ). MYC proteins are often redundant in cancer and showing mutually exclusive expression patterns of MYC and MYCN in patient samples ( 52 , 53 ). Repression of target genes by MYC proteins involves another co-factor, MYC interacting zinc finger 1 (MIZ1) that tethers MYC-MAX into a ternary complex to promoter regions of negative cell cycle regulators like CDKN1A or CDKN2B ( 54 , 55 ).…”

Section: Mycn Biology and Regulation In Normal Cellsmentioning

confidence: 99%

“…Similarly, another group identified dual PI3K/mTOR inhibitor, NVP-BEZ235 (Dactolisib), to specifically destabilize MYCN proteins in MYCN-dependent tumors ( 149 ). More recently, our group has proved that many of such second generation mTOR inhibitors are indeed successful in inhibiting MYCN-amplified SHH MB tumor models both in vitro and in vivo ( 52 ). RapaLink-1, a bivalent third generation mTOR inhibitor, which combines rapamycin with INK128 (Sapanisertib) by an inert chemical linker, has also shown great efficacy in MYCN-driven brain tumor models ( 150 ).…”

Section: Direct or Indirect Targeting Of Mycn In Brain Tumorsmentioning

confidence: 99%

“…mTOR is known to promote octamer-binding transcription factor 4 (OCT4) levels in embryonic stem cells ( 155 ). In MYCN-driven human brain tumor models generated from primary embryonic or induced pluripotent stem cell (iPSC)-derived neural stem cells we could show a significant correlation of mTOR pathway activation and OCT4 levels ( 52 ). When we overexpressed OCT4 we further found increased mRNA levels of 4EBP1 gene (EIF4EBP1) as well as elevated phosphorylation of 4EBP1 that marks mTOR pathway activity downstream of mTORC1.…”

Section: Direct or Indirect Targeting Of Mycn In Brain Tumorsmentioning

confidence: 99%

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Targeting MYCN in Molecularly Defined Malignant Brain Tumors

et al. 2021

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Misregulation of MYC genes, causing MYC overexpression or protein stabilization, is frequently found in malignant brain tumors highlighting their important roles as oncogenes. Brain tumors in children are the most lethal of all pediatric malignancies and the most common malignant primary adult brain tumor, glioblastoma, is still practically incurable. MYCN is one of three MYC family members and is crucial for normal brain development. It is associated with poor prognosis in many malignant pediatric brain tumor types and is focally amplified in specific adult brain tumors. Targeting MYCN has proved to be challenging due to its undruggable nature as a transcription factor and for its importance in regulating developmental programs also in healthy cells. In this review, we will discuss efforts made to circumvent the difficulty of targeting MYCN specifically by using direct or indirect measures to treat MYCN-driven brain tumors. We will further consider the mechanism of action of these measures and suggest which molecularly defined brain tumor patients that might benefit from MYCN-directed precision therapies.

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“…Among the variants of human OCT4, only OCT4A, referred to as OCT4 in most reports [ 5 ] and herein, can maintain ESC self-renewal. OCT4 is also expressed in a variety of solid tumors, particularly in small populations (or cancer stem cells) [ 6 ], and is closely related to cancer malignancies [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ]. In addition, a recent Pan-Cancer Atlas project revealed that OCT4 is a crucial factor in constructing a stemness index that quantifies the degree of stemness, which is closely related to cancer metastasis and patient prognosis [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation of OCT4 Serine 236 Inhibits Germ Cell Tumor Growth by Inducing Differentiation

Kim

Song

Han

et al. 2020

Cancers

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Octamer-binding transcription factor 4 (Oct4) plays an important role in maintaining pluripotency in embryonic stem cells and is closely related to the malignancies of various cancers. Although posttranslational modifications of Oct4 have been widely studied, most of these have not yet been fully characterized, especially in cancer. In this study, we investigated the role of phosphorylation of serine 236 of OCT4 [OCT4 (S236)] in human germ cell tumors (GCTs). OCT4 was phosphorylated at S236 in a cell cycle-dependent manner in a patient sample and GCT cell lines. The substitution of endogenous OCT4 by a mimic of phosphorylated OCT4 with a serine-to-aspartate mutation at S236 (S236D) resulted in tumor cell differentiation, growth retardation, and inhibition of tumor sphere formation. GCT cells expressing OCT4 S236D instead of endogenous OCT4 were similar to cells with OCT4 depletion at the mRNA transcript level as well as in the phenotype. OCT4 S236D also induced tumor cell differentiation and growth retardation in mouse xenograft experiments. Inhibition of protein phosphatase 1 by chemicals or short hairpin RNAs increased phosphorylation at OCT4 (S236) and resulted in the differentiation of GCTs. These results reveal the role of OCT4 (S236) phosphorylation in GCTs and suggest a new strategy for suppressing OCT4 in cancer.

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Humanized Stem Cell Models of Pediatric Medulloblastoma Reveal an Oct4/mTOR Axis that Promotes Malignancy

Cited by 44 publications

References 70 publications

Modeling cancer progression using human pluripotent stem cell-derived cells and organoids

Modeling cancer progression using human pluripotent stem cell-derived cells and organoids

Targeting MYCN in Molecularly Defined Malignant Brain Tumors

Phosphorylation of OCT4 Serine 236 Inhibits Germ Cell Tumor Growth by Inducing Differentiation

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