UM-HACC-2A: MYB-NFIB fusion-positive human adenoid cystic carcinoma cell line

Warner, Kristy A.; Oklejas, Alexandra E.; Pearson, Alexander T.; Zhang, Zhaocheng; Wu, Weishing; Divi, Vasu; Rodriguez-Ramirez, Christie; Castilho, Rogerio M.; Polverini, Peter J.

doi:10.1016/j.oraloncology.2018.10.012

Cited by 27 publications

(21 citation statements)

References 47 publications

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“…We additionally predicted the targets of miR-346 using miRWalk2.0 and TargetScan. NFIB, a previously reported tumor promotor in many kinds of cancers [24], shared sequence complementarity in its 3′-UTR with the miR-346 seed sequence, which was confirmed by luciferase report assays. PCR and western blot results showed that overexpression of miR-346 downregulated the expression of NFIB, indicating a negative correlation.…”

Section: Discussionsupporting

confidence: 67%

MicroRNA-346 inhibits the growth of glioma by directly targeting NFIB

Zhang

et al. 2019

Cancer Cell Int

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BackgroundGlioma is considered one of the most common tumors and has a poor prognosis. Recently, microRNAs (miRNAs) have been reported to be strongly linked to various human tumors including glioma. In this study, we investigated a new anticancer miRNA, miR-346, to determine the effects and mechanism of miR-346 and its downstream target gene NFIB on tumors.MethodsLentivirus transfection, real-time PCR, western blotting, immunohistochemistry, cell proliferation assays, and mouse experiments were used to examine the relationship between miR-346 and its regulation of NFIB in glioma cells.ResultsThe expression of miR-346 was downregulated in glioma cells. Overexpression of miR-346 arrested the cell cycle of glioma cells and inhibited their proliferation in vitro and in vivo. NFIB was a direct target of miR-346, whose expression was reduced by the miRNA. Overexpression of NFIB reversed all tested functions of miR-346.ConclusionmiR-346 inhibited the growth of glioma cells by targeting NFIB and may be a new prognostic and diagnostic biomarker for glioma.

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Section: Discussionsupporting

confidence: 67%

MicroRNA-346 inhibits the growth of glioma by directly targeting NFIB

Zhang

et al. 2019

Cancer Cell Int

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“…Finally, Warner et al reported one ACC cell line with retaining MYB‐NFIB fusion genes by adding cytokines, rhEGF, human hydrocortisone and human insulin to conventional medium in 2D culture. To date, only Warner et al successfully established an orthotopic xenograft using their cell line; however, its tumor was only micro‐HLA‐positive cell clusters in the submandibular gland lymph nodes without recapitulating the histological characteristics of original ACC tumor 10 . Overall, it seems that it is difficult for ACC cell lines established in 2D culture to reproduce at least the histological architecture of human salivary ACC.…”

Section: Discussionmentioning

confidence: 99%

“…Salivary ACC is now characterized by frequent representation of MYB‐NFIB/MYBL1‐NFIB fusion gene 5 as well as high MYB expression 6‐9 . The role of these gene fusions on carcinogenesis of ACC has started to be examined widely; however, our understanding of the ACC biology is still incomplete mainly due to limited availability of reliable ACC cell line 10 . The paucity of in vitro and in vivo salivary ACC models is thus hampering the progress of new drug development for patients with these malignancies.…”

Section: Introductionmentioning

confidence: 99%

Establishment of PDX‐derived salivary adenoid cystic carcinoma cell lines using organoid culture method

Takada

Aizawa

Sano

et al. 2020

Intl Journal of Cancer

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To generate a reliable preclinical model system exhibiting the molecular features of salivary adenoid cystic carcinoma (ACC) whose biology is still unclear due to the paucity of stable cell cultures. To develop new in vitro and in vivo models of ACC, the techniques of organoid culture and patient-derived tumor xenograft (PDX), which have attracted attention in other malignancies in recent years, were applied. Tumor specimens from surgically resected salivary ACC were proceeded for the preparation of PDX and organoid culture. The orthotopic transplantation of patient-derived or PDX-derived organoids was demonstrated into submandibular glands of NSG mice and those histology was evaluated. PDX-derived organoid cells were evaluated for the presence of MYB-mediated fusion genes and proceeded for in vitro drug sensitivity assay. Human ACC-derived organoids were successfully generated in three-dimensional culture and confirmed the ability of these cells to form tumors by orthotopic injection. Short-term organoid cell cultures from two individual ACC PDX tumors were also established that maintain the characteristic MYBL1 translocation and histological features of the original parent and PDX tumors. Finally, the establishment of drug sensitivity tests on these short-term cultured cells was confirmed using three different agents. This is the first to report an approach for the generation of human ACC-derived organoids as in vitro and in vivo cancer models, providing insights into understanding of the ACC biology and creating personalized therapy design for patients with ACC. K E Y W O R D S drug sensitivity test, organoid culture, orthotopic transplantation, patient-derived xenograft (PDX) model, salivary adenoid cystic carcinoma 1 | INTRODUCTION Adenoid cystic carcinomas (ACC) is one of the most common types of salivary gland malignancies, representing approximately 1% of all head and neck malignancies and about 10% to 15% of all salivary gland cancers. 1,2 Salivary ACC generally represents as slow growth tumor, however, also

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“…For example, Mitani et al reported that the level of MYB expression in identical histological subtypes of ACC is associated with a shorter survival time. Recently, xenografting and the first MYB‐NFIB‐positive cell line (UM‐HACC‐2A) have been established and represent interesting tools to explore novel therapeutic possibilities . Therapeutically, MYB‐targeted antisense oligodeoxynucleotides (G4460; INX‐3001; LR3001) have not been effective in clinical trials ; however, several lines of evidence suggest that MYB is a promising therapeutic target .…”

Section: Discussionmentioning

confidence: 99%

Clinically Integrated Molecular Diagnostics in Adenoid Cystic Carcinoma

Thierauf

Ramamurthy

et al. 2019

The Oncologist

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Background Adenoid cystic carcinoma (ACC) is an aggressive salivary gland malignancy without effective systemic therapies. Delineation of molecular profiles in ACC has led to an increased number of biomarker‐stratified clinical trials; however, the clinical utility and U.S.‐centric financial sustainability of integrated next‐generation sequencing (NGS) in routine practice has, to our knowledge, not been assessed. Materials and Methods In our practice, NGS genotyping was implemented at the discretion of the primary clinician. We combined NGS‐based mutation and fusion detection, with MYB break‐apart fluorescent in situ hybridization (FISH) and MYB immunohistochemistry. Utility was defined as the fraction of patients with tumors harboring alterations that are potentially amenable to targeted therapies. Financial sustainability was assessed using the fraction of global reimbursement. Results Among 181 consecutive ACC cases (2011–2018), prospective genotyping was performed in 11% (n = 20/181; n = 8 nonresectable). Testing identified 5/20 (25%) NOTCH1 aberrations, 6/20 (30%) MYB‐NFIB fusions (all confirmed by FISH), and 2/20 (10%) MYBL1‐NFIB fusions. Overall, these three alterations (MYB/MYBL1/NOTCH1) made up 65% of patients, and this subset had a more aggressive course with significantly shorter progression‐free survival. In 75% (n = 6/8) of nonresectable patients, we detected potentially actionable alterations. Financial analysis of the global charges, including NGS codes, indicated 63% reimbursement, which is in line with national (U.S.‐based) and international levels of reimbursement. Conclusion Prospective routine clinical genotyping in ACC can identify clinically relevant subsets of patients and is approaching financial sustainability. Demonstrating clinical utility and financial sustainability in an orphan disease (ACC) requires a multiyear and multidimensional program. Implications for Practice Delineation of molecular profiles in adenoid cystic carcinoma (ACC) has been accomplished in the research setting; however, the ability to identify relevant patient subsets in clinical practice has not been assessed. This work presents an approach to perform integrated molecular genotyping of patients with ACC with nonresectable, recurrent, or systemic disease. It was determined that 75% of nonresectable patients harbor potentially actionable alterations and that 63% of charges are reimbursed. This report outlines that orphan diseases such as ACC require a multiyear, multidimensional program to demonstrate utility in clinical practice.

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UM-HACC-2A: MYB-NFIB fusion-positive human adenoid cystic carcinoma cell line

Cited by 27 publications

References 47 publications

MicroRNA-346 inhibits the growth of glioma by directly targeting NFIB

MicroRNA-346 inhibits the growth of glioma by directly targeting NFIB

Establishment of PDX‐derived salivary adenoid cystic carcinoma cell lines using organoid culture method

Clinically Integrated Molecular Diagnostics in Adenoid Cystic Carcinoma

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