• Humans
• Rhabdoid Tumor/diagnosis
• Rhabdoid Tumor/pathology
• Rhabdoid Tumor/genetics
• Rhabdoid Tumor/metabolism
• Proto-Oncogene Proteins c-kit/genetics
• Proto-Oncogene Proteins c-kit/metabolism
• Transcription Factors/genetics
• Transcription Factors/metabolism
• Child, Preschool
• Biomarkers, Tumor/metabolism
• Biomarkers, Tumor/genetics
• Male
• Pelvic Neoplasms/diagnosis
• Pelvic Neoplasms/pathology
• Pelvic Neoplasms/genetics
• Pelvic Neoplasms/metabolism
• Immunohistochemistry

• Children and infant
• Malignant rhabdoid tumor
• Sarcoma
• Solid tumor
• Systematic review and meta-analysis
• Urology oncology

• Child
• Humans
• Infant
• Kidney Neoplasms/therapy
• Kidney Neoplasms/diagnosis
• Kidney Neoplasms/genetics
• Lung Neoplasms
• Retrospective Studies
• Rhabdoid Tumor/diagnosis
• Rhabdoid Tumor/therapy
• Rhabdoid Tumor/genetics
• Soft Tissue Neoplasms
• Child, Preschool

• 2022J01437 Natural Science Foundation of Fujian Province

• NUT
• SMARCA4
• carcinoma
• rhabdoid

• Humans
• Transcription Factors/genetics
• Nuclear Proteins/genetics
• DNA Helicases/genetics
• Biomarkers, Tumor
• Carcinoma/diagnosis
• Carcinoma/pathology
• Thoracic Neoplasms/diagnosis
• Thoracic Neoplasms/genetics
• Thoracic Neoplasms/pathology

• JP21K06919 Japan Society for the Promotion of Science

• embryonal neoplasms
• cns cancer

• Humans
• Rhabdoid Tumor/genetics
• Multiomics
• SMARCB1 Protein/genetics
• Transcription Factors/genetics
• Brain Neoplasms/genetics
• Diagnostic Imaging
• Teratoma/pathology
• Hedgehog Proteins/genetics

• alpha-fetoprotein (AFP)
• atypical teratoid rhabdoid tumor (ATRT)
• cancer biomarkers
• cancer vaccines
• immunotherapy
• malignant rhabdoid tumor antigens
• matrix metalloproteinases (MMPs)
• mesothelin (MSLN)
• mucin-16 (MUC16/CA125)
• osteopontin (OPN)
• therapeutic targets

• 9LA01 Florida Department of Health

Pediatric non-Wilms renal tumors (NWRTs), which comprise a small proportion of renal tumors, are a heterogeneous group of neoplasms with variable malignant potential, mortality, and response to treatment. We performed this study to determine the clinical characteristics, management and prognosis of children with Pediatric NWRTs.

Medical records of all patients (n = 139) treated for NWRTs over a 12-year period (2008.01–2019.10) at a single center were reviewed retrospectively.

The histopathological groups of NWRTs included malignant rhabdoid tumor of the kidney (MRTK) (n: 30, 21.6%), renal cell cancer (RCC) (n: 26,18.7%), clear cell sarcoma of the kidney (CCSK) (n: 24,17.3%), congenital mesoblastic nephroma (CMN) (n: 21,15.1%), cystic nephroma (CN) (n: 16,11.5%), metanephric tumors (n: 12, 8.6%), renal angiomyoliporma (RAML) (n: 3, 2.2%), renal primitive neuroectodermal tumor (n: 2, 1.4%), renal hemangioma (n: 2, 1.4%), inflammatory myofibroblastic tumor (n: 2, 1.4%), ossifying renal tumor of infancy (ORTI) (n: 1, 0.7%). The distribution of all malignant NWRTs, including MRTK, CCSK, RCC and PNET, according to stage was as follows: stages I (n = 26), II (n = 16), III (n = 29), and IV (n = 11). The summary table shows the treatment offered to children with NWRTs. A total of 123 children were followed up for an average of 42 months. Sixteen children were lost to follow-up. Tumor-free survival was observed in 94 children. One patient who suffered from RCC is currently receiving targeted therapy and survives with the tumor. Twenty-eight children (22.8%) died.

Pediatric NWRTs comprise 19.1% of all renal tumors in our single center. Most NWRTs can readily be distinguished using a range of immunohistochemical markers. Molecular genetic profiling has allowed much progress in the understanding of this group of tumors, making diagnosis and classification less difficult. The mainstay treatment of malignant NWRTs, including MRTK, CCSK, RCC and PNET, is comprehensive treatment. The mainstay treatment of benign NWRTs, including RAML, CN, ORTI, CMN, metanephric tumors, and renal hemangioma, is surgical resection alone and when the tumor diameter is smaller than 7 cm and the tumor locates in one pole, NSS can be performed.

• Children
• Management
• Non-Wilms' renal tumors

Atypical teratoid rhabdoid tumour (ATRT) is an aggressive undifferentiated malignancy of the central nervous system in children. A defining feature of ATRT is the loss of the SMARCB1 gene that is essential for regulating gene expression required for normal developmental processes. We show that treatment of human ATRT cell models with the histone deacetylate inhibitor, panobinostat, inhibits tumour growth, reactivates the expression of developmental genes, and drives neuronal differentiation. These results demonstrate the therapeutic potential of panobinostat for the treatment of ATRT.

Atypical teratoid rhabdoid tumour (ATRT) is a rare but highly aggressive undifferentiated solid tumour arising in the central nervous system and predominantly affecting infants and young children. ATRT is exclusively characterized by the inactivation of SMARCB1, a member of the SWI/SNF chromatin remodelling complex that is essential for the regulation of large sets of genes required for normal development and differentiation. Histone deacetylase inhibitors (HDACi) are a promising anticancer therapy and are able to mimic the normal acetylation functions of SMARCB1 in SMARCB1-deficient cells and drive multilineage differentiation in extracranial rhabdoid tumours. However, the potential efficacy of HDACi in ATRT is unknown. Here, we show that human ATRT cells are highly responsive to the HDACi panobinostat and that sustained treatment leads to growth arrest, increased cell senescence, decreased clonogenicity and induction of a neurogenesis gene-expression profile. Furthermore, in an orthotopic ATRT xenograft model, continuous panobinostat treatment inhibits tumour growth, increases survival and drives neuronal differentiation as shown by the expression of the neuronal marker, TUJ1. Collectively, this preclinical study supports the therapeutic potential of panobinostat-mediated differentiation therapy for ATRT.

• HDACi
• atypical teratoid rhabdoid tumour
• differentiation
• panobinostat

• SMARCB1/INI1
• brachyury
• epithelioid sarcoma

• Brain tumors
• Embryonal tumor with multilayered rosettes
• Ependymoblastoma
• Medulloepithelioma

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.

• Cancer propagation
• Cell-of-origin
• Drug discovery
• Human pluripotent stem cells
• Metastasis
• Organoids

• ESC-like signature
• SMARCB1
• atypical teratoid/rhabdoid tumor
• dedifferentiation
• embryonic stem cell
• induced pluripotent stem cell
• pediatric tumor
• pluripotency

Cancer stem cell (CSC) identification relies on transplantation assays of cell subpopulations sorted from fresh tumor samples. Here, we attempt to bypass limitations of abundant tumor source and predetermined immune selection by in vivo propagating patient-derived xenografts (PDX) from human malignant rhabdoid tumor (MRT), a rare and lethal pediatric neoplasm, to an advanced state in which most cells behave as CSCs. Stemness is then probed by comparative transcriptomics of serial PDXs generating a gene signature of epithelial to mesenchymal transition, invasion/motility, metastasis, and self-renewal, pinpointing putative MRT CSC markers. The relevance of these putative CSC molecules is analyzed by sorting tumorigenic fractions from early-passaged PDX according to one such molecule, deciphering expression in archived primary tumors, and testing the effects of CSC molecule inhibition on MRT growth. Using this platform, we identify ALDH1 and lysyl oxidase (LOX) as relevant targets and provide a larger framework for target and drug discovery in rare pediatric cancers.

•

Human malignant rhabdoid tumor (MRT) can be propagated in vivo as tumor xenografts

• ALDH1
• LOX inhibition
• MRT
• PDX
• cancer stem cells
• stem cells
• targeted therapy

Wnt is a complex signaling pathway involved in the regulation of crucial biological functions such as development, proliferation, differentiation and migration of cells, mainly stem cells, which are virtually present in all embryonic and adult tissues. Conversely, dysregulation of Wnt signal is implicated in development/progression/invasiveness of different kinds of tumors, wherein a certain number of multipotent cells, namely “cancer stem cells”, are characterized by high self-renewal and aggressiveness. Hence, the pharmacological modulation of Wnt pathway could be of particular interest, especially in tumors for which the current standard therapy results to be unsuccessful. This might be the case of glioblastoma multiforme (GBM), one of the most lethal, aggressive and recurrent brain cancers, probably due to the presence of highly malignant GBM stem cells (GSCs) as well as to a dysregulation of Wnt system. By examining the most recent literature, here we point out several factors in the Wnt pathway that are altered in human GBM and derived GSCs, as well as new molecular strategies or experimental drugs able to modulate/inhibit aberrant Wnt signal. Altogether, these aspects serve to emphasize the existence of alternative pharmacological targets that may be useful to develop novel therapies for GBM.

• Wnt signal pathway
• drugs targeting Wnt pathway
• epithelial-to-mesenchymal transition
• glioblastoma multiforme

Germline mutations of the SMARCB1 gene predispose to two distinct tumor syndromes: rhabdoid tumor predisposition syndrome, with malignant pediatric tumors mostly developing in brain and kidney, and familial schwannomatosis, with adulthood benign tumors involving cranial and peripheral nerves. The mechanisms by which SMARCB1 germline mutations predispose to rhabdoid tumors versus schwannomas are still unknown. Here, to understand the origin of these two types of SMARCB1-associated tumors, we generated different tissue- and developmental stage-specific conditional knockout mice carrying Smarcb1 and/or Nf2 deletion. Smarcb1 loss in early neural crest was necessary to initiate tumorigenesis in the cranial nerves and meninges with typical histological features and molecular profiles of human rhabdoid tumors. By inducing Smarcb1 loss at later developmental stage in the Schwann cell lineage, in addition to biallelic Nf2 gene inactivation, we generated the first mouse model developing schwannomas with the same underlying gene mutations found in schwannomatosis patients.

SMARCB1 mutations predispose to rhabdoid tumors and schwannomas but the mechanisms underlying the tumor type specificity are unknown. Here the authors present new mouse models and show that early Smarcb1 loss causes rhabdoid tumors whereas loss at later stages combined with Nf2 gene inactivation causes shwannomas.

Atypical teratoid rhabdoid tumor (AT/RT) is among the most fatal of all pediatric brain tumors. Aside from loss of function mutations in the SMARCB1 (BAF47/INI1/SNF5) chromatin remodeling gene, little is known of other molecular drivers of AT/RT. LIN28A and LIN28B are stem cell factors that regulate thousands of RNAs and are expressed in aggressive cancers. We identified high-levels of LIN28A and LIN28B in AT/RT primary tumors and cell lines, with corresponding low levels of the LIN28-regulated microRNAs of the let-7 family. Knockdown of LIN28A by lentiviral shRNA in the AT/RT cell lines CHLA-06-ATRT and BT37 inhibited growth, cell proliferation and colony formation and induced apoptosis. Suppression of LIN28A in orthotopic xenograft models led to a more than doubling of median survival compared to empty vector controls (48 vs 115 days). LIN28A knockdown led to increased expression of let-7b and let-7g microRNAs and a down-regulation of KRAS mRNA. AT/RT primary tumors expressed increased mitogen activated protein (MAP) kinase pathway activity, and the MEK inhibitor selumetinib (AZD6244) decreased AT/RT growth and increased apoptosis. These data implicate LIN28/RAS/MAP kinase as key drivers of AT/RT tumorigenesis and indicate that targeting this pathway may be a therapeutic option in this aggressive pediatric malignancy.

• Cell Line, Tumor
• Chromosomal Proteins, Non-Histone/genetics
• DNA Methylation/genetics
• DNA-Binding Proteins/genetics
• Gene Expression/genetics
• Gene Expression Regulation, Developmental/genetics
• Histones/genetics
• Humans
• MicroRNAs/genetics
• Rhabdoid Tumor/genetics
• SMARCB1 Protein
• Transcription Factors/genetics
• Transcriptome/genetics

• P30 CA060553 NCI NIH HHS
• CIHR-262119 CIHR
• N01CO12400 NCI NIH HHS
• FDN-143288 CIHR
• N01-CO-12400 NCI NIH HHS
• HHSN261200800001E NCI NIH HHS

• Oncofetal protein
• SALL4

• atypical teratoid /rhabdoid tumor
• brain tumors
• diagnosis
• immunohistochemistry
• prognosis

• Immunohistochemistry (IHC)
• Lung cancer biopsy and tissue microarray (TMA)
• Metastatic NSCLC
• Non-small cell lung cancer (NSCLC)
• Transcription factor SALL4 and OCT4

• CD34
• INI1
• SALL4
• epithelioid sarcoma
• malignant rhabdoid tumour

• FISH
• INI1
• Rhabdoid tumor
• SMARCB1
• conventional cytogenetic
• sequential G-banded FISH

• Brain Neoplasms/genetics
• Brain Neoplasms/metabolism
• Brain Neoplasms/pathology
• Female
• Humans
• Male
• MicroRNAs/genetics
• Neoplasms, Germ Cell and Embryonal/metabolism
• Neoplasms, Germ Cell and Embryonal/pathology
• Neuroectodermal Tumors, Primitive/genetics
• Neuroectodermal Tumors, Primitive/metabolism
• Neuroectodermal Tumors, Primitive/pathology
• RNA-Binding Proteins/metabolism

• Adolescent
• Age of Onset
• Brain Neoplasms/diagnosis
• Brain Neoplasms/genetics
• Brain Neoplasms/metabolism
• Brain Neoplasms/therapy
• Cell Line, Tumor
• Child
• Child, Preschool
• DNA (Cytosine-5-)-Methyltransferases/metabolism
• DNA Methylation
• Diagnosis, Differential
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Infant
• Male
• MicroRNAs/genetics
• Multigene Family
• Neuroectodermal Tumors, Primitive/diagnosis
• Neuroectodermal Tumors, Primitive/genetics
• Neuroectodermal Tumors, Primitive/metabolism
• Neuroectodermal Tumors, Primitive/therapy
• RNA-Binding Proteins/metabolism
• DNA Methyltransferase 3B

• 13457 Cancer Research UK
• P50 CA097257 NCI NIH HHS
• R01 CA109467 NCI NIH HHS
• R01 CA163737 NCI NIH HHS
• R01 CA148621 NCI NIH HHS
• P30 CA014236 NCI NIH HHS
• 102684 CIHR