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Pediatric Cancer Biology: Basic and Translational Implications

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Pediatric Oncology".

Deadline for manuscript submissions: closed (25 June 2023) | Viewed by 21884

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Special Issue Editor

Prof. Dr. Atif Ahmed

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Guest Editor

1. Department of Laboratory Medicine & Pathology, University of Washington, Seattle, WA 98195, USA
2. Department of Pathology, Seattle Children's Hospitals, Seattle, WA 98105, USA
Interests: pediatric tumors; pediatric cancer biology; protein expression in cancer; proteome profiling from histologic slides; microRNA expression
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Special Issue Information

Dear Colleagues,

Pediatric cancers are rare and have a complex biology. While a great deal of knowledge exists around adult malignancies, only recently have the molecular, cellular, and genetic properties of pediatric cancers begun to be uncovered. Pediatric cancers are characterized by rapid proliferation, the spectrum of cellular differentiation, and association with developmental genes. Pediatric cancer exhibits a unique genome that is different from that of adult cancers with a smaller mutational burden, fewer single point variants (SNVs), higher prevalence of specific structural variations (e.g., gene fusions and chromosomal rearrangements), and predisposing germline variants. This unique genome translates to a unique morphologic phenotype, tumor microenvironment, and clinical behavior. A better understanding of pediatric cancer biology is needed to reflect its heterogeneity, pathology, and genetics. In this Special Issue, we are pleased to invite potential authors to contribute their latest findings and summarize the current research and open avenues of discussion and collaboration in pediatric cancer. This Special Issue aims to highlight recent research advances in pediatric cancer biology, including pathology, the tumor microenvironment, and cellular and genetic landscape. In this Special Issue, original research articles and reviews are welcome. Research areas may include (but are not limited to) the following:

Developmental biology and cancer predisposition syndromes;
Animal models of pediatric cancer;
Pathobiology of different pediatric cancers including brain tumors, bone cancers, hematologic malignancies, and soft tissue sarcomas;
Translational research;
Molecular prognostic and predictive markers.

We look forward to receiving your contributions.

Dr. Atif Ali Ahmed
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

pediatric cancer
neuroblastoma
Ewing’s sarcoma
rhabdomyosarcoma
leukemias
cancer predisposition syndromes
genetics
omics

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Published Papers (7 papers)

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25 pages, 5455 KiB

Open AccessArticle

Target Genes of c-MYC and MYCN with Prognostic Power in Neuroblastoma Exhibit Different Expressions during Sympathoadrenal Development

by Ye Yuan, Mohammad Alzrigat, Aida Rodriguez-Garcia, Xueyao Wang, Tomas Sjöberg Bexelius, John Inge Johnsen, Marie Arsenian-Henriksson, Judit Liaño-Pons and Oscar C. Bedoya-Reina

Cancers 2023, 15(18), 4599; https://doi.org/10.3390/cancers15184599 - 16 Sep 2023

Viewed by 2126

Abstract

Deregulation of the MYC family of transcription factors c-MYC (encoded by MYC), MYCN, and MYCL is prevalent in most human cancers, with an impact on tumor initiation and progression, as well as response to therapy. In neuroblastoma (NB), amplification of the MYCN oncogene and over-expression of MYC characterize approximately 40% and 10% of all high-risk NB cases, respectively. However, the mechanism and stage of neural crest development in which MYCN and c-MYC contribute to the onset and/or progression of NB are not yet fully understood. Here, we hypothesized that subtle differences in the expression of MYCN and/or c-MYC targets could more accurately stratify NB patients in different risk groups rather than using the expression of either MYC gene alone. We employed an integrative approach using the transcriptome of 498 NB patients from the SEQC cohort and previously defined c-MYC and MYCN target genes to model a multigene transcriptional risk score. Our findings demonstrate that defined sets of c-MYC and MYCN targets with significant prognostic value, effectively stratify NB patients into different groups with varying overall survival probabilities. In particular, patients exhibiting a high-risk signature score present unfavorable clinical parameters, including increased clinical risk, higher INSS stage, MYCN amplification, and disease progression. Notably, target genes with prognostic value differ between c-MYC and MYCN, exhibiting distinct expression patterns in the developing sympathoadrenal system. Genes associated with poor outcomes are mainly found in sympathoblasts rather than in chromaffin cells during the sympathoadrenal development. Full article

(This article belongs to the Special Issue Pediatric Cancer Biology: Basic and Translational Implications)

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12 pages, 1704 KiB

Open AccessArticle

Perinucleolar Compartment (PNC) Prevalence as an Independent Prognostic Factor in Pediatric Ewing Sarcoma: A Multi-Institutional Study

by Elizabeth Gonzalez, Atif A. Ahmed, Laura McCarthy, Katherine Chastain, Sahibu Habeebu, Marta Zapata-Tarres, Rocio Cardenas-Cardos, Liliana Velasco-Hidalgo, Celso Corcuera-Delgado, Rodolfo Rodriguez-Jurado, Lilia García-Rodríguez, Alejandro Parrales, Tomoo Iwakuma, Midhat S. Farooqi, Brian Lee, Scott J. Weir and Terrie G. Flatt

Cancers 2023, 15(8), 2230; https://doi.org/10.3390/cancers15082230 - 10 Apr 2023

Cited by 1 | Viewed by 2321

Abstract

The perinucleolar compartment (PNC) is a small nuclear body that plays important role in tumorigenesis. PNC prevalence correlates with poor prognosis and cancer metastasis. Its expression in pediatric Ewing sarcoma (EWS) has not previously been documented. In this study, we analyzed 40 EWS tumor cases from Caucasian and Hispanic patients for PNC prevalence by immunohistochemical detection of polypyrimidine tract binding protein and correlated the prevalence with dysregulated microRNA profiles. EWS cases showed staining ranging from 0 to 100%, which were categorized as diffuse (≥77%, n = 9, high PNC) or not diffuse (<77%, n = 31) for low PNC. High PNC prevalence was significantly higher in Hispanic patients from the US (n = 6, p = 0.017) and in patients who relapsed with metastatic disease (n = 4; p = 0.011). High PNC was associated with significantly shorter disease-free survival and early recurrence compared to those with low PNC. Using NanoString digital profiling, high PNC tumors revealed upregulation of eight and downregulation of 18 microRNAs. Of these, miR-320d and miR-29c-3p had the most significant differential expression in tumors with high PNC. In conclusion, this is the first study that demonstrates the presence of PNC in EWS, reflecting its utility as a predictive biomarker associated with tumor metastasis, specific microRNA profile, Hispanic ethnic origin, and poor prognosis. Full article

(This article belongs to the Special Issue Pediatric Cancer Biology: Basic and Translational Implications)

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21 pages, 3054 KiB

Open AccessArticle

Drug Resistance in Medulloblastoma Is Driven by YB-1, ABCB1 and a Seven-Gene Drug Signature

by Louisa Taylor, Philippa K. Wade, James E. C. Johnson, Macha Aldighieri, Sonia Morlando, Gianpiero Di Leva, Ian D. Kerr and Beth Coyle

Cancers 2023, 15(4), 1086; https://doi.org/10.3390/cancers15041086 - 8 Feb 2023

Cited by 8 | Viewed by 3117

Abstract

Therapy resistance represents an unmet challenge in the treatment of medulloblastoma. Accordingly, the identification of targets that mark drug-resistant cell populations, or drive the proliferation of resistant cells, may improve treatment strategies. To address this, we undertook a targeted approach focused on the multi-functional transcription factor YB-1. Genetic knockdown of YB-1 in Group 3 medulloblastoma cell lines diminished cell invasion in 3D in vitro assays and increased sensitivity to standard-of-care chemotherapeutic vincristine and anti-cancer agents panobinostat and JQ1. For vincristine, this occurred in part by YB-1-mediated transcriptional regulation of multi-drug resistance gene ABCB1, as determined by chromatin immunoprecipitation. Whole transcriptome sequencing of YB-1 knockdown cells identified a role for YB-1 in the regulation of tumourigenic processes, including lipid metabolism, cell death and survival and MYC and mTOR pathways. Stable cisplatin- and vincristine-tolerant Group 3 and SHH cell lines were generated to identify additional mechanisms driving resistance to standard-of-care medulloblastoma therapy. Next-generation sequencing revealed a vastly different transcriptomic landscape following chronic drug exposure, including a drug-tolerant seven-gene expression signature, common to all sequenced drug-tolerant cell lines, representing therapeutically targetable genes implicated in the acquisition of drug tolerance. Our findings provide significant insight into mechanisms and genes underlying therapy resistance in medulloblastoma. Full article

(This article belongs to the Special Issue Pediatric Cancer Biology: Basic and Translational Implications)

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42 pages, 9984 KiB

Open AccessArticle

Integrative Multi-OMICs Identifies Therapeutic Response Biomarkers and Confirms Fidelity of Clinically Annotated, Serially Passaged Patient-Derived Xenografts Established from Primary and Metastatic Pediatric and AYA Solid Tumors

by Pankita H. Pandya, Asha Jacob Jannu, Khadijeh Bijangi-Vishehsaraei, Erika Dobrota, Barbara J. Bailey, Farinaz Barghi, Harlan E. Shannon, Niknam Riyahi, Nur P. Damayanti, Courtney Young, Rada Malko, Ryli Justice, Eric Albright, George E. Sandusky, L. Daniel Wurtz, Christopher D. Collier, Mark S. Marshall, Rosa I. Gallagher, Julia D. Wulfkuhle, Emanuel F. Petricoin, Kathy Coy, Melissa Trowbridge, Anthony L. Sinn, Jamie L. Renbarger, Michael J. Ferguson, Kun Huang, Jie Zhang, M. Reza Saadatzadeh and Karen E. Pollok Show full author list Hide full author list

Cancers 2023, 15(1), 259; https://doi.org/10.3390/cancers15010259 - 30 Dec 2022

Cited by 5 | Viewed by 3826

Abstract

Establishment of clinically annotated, molecularly characterized, patient-derived xenografts (PDXs) from treatment-naïve and pretreated patients provides a platform to test precision genomics-guided therapies. An integrated multi-OMICS pipeline was developed to identify cancer-associated pathways and evaluate stability of molecular signatures in a panel of pediatric and AYA PDXs following serial passaging in mice. Original solid tumor samples and their corresponding PDXs were evaluated by whole-genome sequencing, RNA-seq, immunoblotting, pathway enrichment analyses, and the drug–gene interaction database to identify as well as cross-validate actionable targets in patients with sarcomas or Wilms tumors. While some divergence between original tumor and the respective PDX was evident, majority of alterations were not functionally impactful, and oncogenic pathway activation was maintained following serial passaging. CDK4/6 and BETs were prioritized as biomarkers of therapeutic response in osteosarcoma PDXs with pertinent molecular signatures. Inhibition of CDK4/6 or BETs decreased osteosarcoma PDX growth (two-way ANOVA, p < 0.05) confirming mechanistic involvement in growth. Linking patient treatment history with molecular and efficacy data in PDX will provide a strong rationale for targeted therapy and improve our understanding of which therapy is most beneficial in patients at diagnosis and in those already exposed to therapy. Full article

(This article belongs to the Special Issue Pediatric Cancer Biology: Basic and Translational Implications)

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11 pages, 2918 KiB

Open AccessArticle

Early Mechanisms of Chemoresistance in Retinoblastoma

by Michelle G. Zhang, Jeffim N. Kuznetsoff, Dawn A. Owens, Ryan A. Gallo, Karthik Kalahasty, Anthony M. Cruz, Stefan Kurtenbach, Zelia M. Correa, Daniel Pelaez and J. William Harbour

Cancers 2022, 14(19), 4966; https://doi.org/10.3390/cancers14194966 - 10 Oct 2022

Cited by 8 | Viewed by 3261

Abstract

Retinoblastoma is the most common eye cancer in children and is fatal if left untreated. Over the past three decades, chemotherapy has become the mainstay of eye-sparing treatment. Nevertheless, chemoresistance continues to represent a major challenge leading to ocular and systemic toxicity, vision loss, and treatment failure. Unfortunately, the mechanisms leading to chemoresistance remain incompletely understood. Here, we engineered low-passage human retinoblastoma cells to study the early molecular mechanisms leading to resistance to carboplatin, one of the most widely used agents for treating retinoblastoma. Using single-cell next-generation RNA sequencing (scRNA-seq) and single-cell barcoding technologies, we found that carboplatin induced rapid transcriptomic reprogramming associated with the upregulation of PI3K-AKT pathway targets, including ABC transporters and metabolic regulators. Several of these targets are amenable to pharmacologic inhibition, which may reduce the emergence of chemoresistance. We provide evidence to support this hypothesis using a third-generation inhibitor of the ABCB1 transporter. Full article

(This article belongs to the Special Issue Pediatric Cancer Biology: Basic and Translational Implications)

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10 pages, 1099 KiB

Open AccessArticle

NanoString Digital Molecular Profiling of Protein and microRNA in Rhabdomyosarcoma

by Atif A. Ahmed, Midhat S. Farooqi, Sultan S. Habeebu, Elizabeth Gonzalez, Terrie G. Flatt, Ashley L. Wilson and Frederic G. Barr

Cancers 2022, 14(3), 522; https://doi.org/10.3390/cancers14030522 - 21 Jan 2022

Cited by 9 | Viewed by 3543

Abstract

Purpose: Rhabdomyosarcoma (RMS) exhibits a complex prognostic algorithm based on histologic, biologic and clinical parameters. The embryonal (ERMS) and spindle cell-sclerosing RMS (SRMS) histologic subtypes warrant further studies due to their heterogenous genetic background and variable clinical behavior. NanoString digital profiling methods have been previously highlighted as robust novel methods to detect protein and microRNA expression in several cancers but not in RMS. Methods/Patients: To identify prognostic biomarkers, we categorized 12 ERMS and SRMS tumor cases into adverse (n = 5) or favorable (n = 7) prognosis groups and analyzed their signaling pathways and microRNA profiles. The digital spatial profiling of protein and microRNA analysis was performed on formalin-fixed, paraffin-embedded (FFPE) tumor tissue using NanoString technology. Results: The detectable expression of several component members of the PI3K/AKT, MAPK and apoptosis signaling pathways was highlighted in RMS, including INPP4B, Pan-AKT, MET, Pan-RAS, EGFR, phospho-p90 RSK, p44/42 ERK1/2, BAD, BCL-XL, cleaved caspase-9, NF1, PARP and p53. Compared to cases with favorable prognosis, the adverse-prognosis tumor samples had significantly increased expression of INPP4B, which was confirmed with traditional immunohistochemistry. The analysis of microRNA profiles revealed that, out of 798 microRNAs assessed, 228 were overexpressed and 134 downregulated in the adverse prognosis group. Significant over-expression of oncogenic/tumor suppressor miR-3144-3p, miR-612, miR-302d-3p, miR-421, miR-548ar-5p and miR-548y (p < 0.05) was noted in the adverse prognosis group. Conclusion: This study highlights the utility of NanoString digital profiling methods in RMS, where it can detect distinct molecular signatures with the expression of signaling pathways and microRNAs from FFPE tumor tissue that may help identify prognostic biomarkers of interest. The overexpression of INPP4B and miR-3144-3p, miR-612, miR-302d-3p, miR-421, miR-548y and miR-548ar-5p may be associated with worse overall survival in ERMS and SRMS. Full article

(This article belongs to the Special Issue Pediatric Cancer Biology: Basic and Translational Implications)

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Review

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24 pages, 783 KiB

Open AccessReview

Synovial Sarcoma Preclinical Modeling: Integrating Transgenic Mouse Models and Patient-Derived Models for Translational Research

by Lorena Landuzzi, Francesca Ruzzi, Pier-Luigi Lollini and Katia Scotlandi

Cancers 2023, 15(3), 588; https://doi.org/10.3390/cancers15030588 - 18 Jan 2023

Cited by 6 | Viewed by 2837

Abstract

Synovial sarcomas (SyS) are rare malignant tumors predominantly affecting children, adolescents, and young adults. The genetic hallmark of SyS is the t(X;18) translocation encoding the SS18-SSX fusion gene. The fusion protein interacts with both the BAF enhancer and polycomb repressor complexes, and either activates or represses target gene transcription, resulting in genome-wide epigenetic perturbations and altered gene expression. Several experimental in in vivo models, including conditional transgenic mouse models expressing the SS18-SSX fusion protein and spontaneously developing SyS, are available. In addition, patient-derived xenografts have been estab-lished in immunodeficient mice, faithfully reproducing the complex clinical heterogeneity. This review focuses on the main molecular features of SyS and the related preclinical in vivo and in vitro models. We will analyze the different conditional SyS mouse models that, after combination with some of the few other recurrent alterations, such as gains in BCL2, Wnt-β-catenin signaling, FGFR family, or loss of PTEN and SMARCB1, have provided additional insight into the mechanisms of synovial sarcomagenesis. The recent advancements in the understanding of SyS biology and improvements in preclinical modeling pave the way to the development of new epigenetic drugs and immunotherapeutic approaches conducive to new treatment options. Full article

(This article belongs to the Special Issue Pediatric Cancer Biology: Basic and Translational Implications)

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