The molecular landscape of the University of Michigan laryngeal squamous cell carcinoma cell line panel

BackgroundLaryngeal squamous cell carcinomas (LSCCs) have a high risk of recurrence and poor prognosis. Patient‐derived cancer cell lines remain important preclinical models for advancement of new therapeutic strategies, and comprehensive characterization of these models is vital in the precision medicine era.MethodsWe performed exome and transcriptome sequencing as well as copy number analysis of a panel of LSCC‐derived cell lines that were established at the University of Michigan and are used in laboratories worldwide.ResultsWe observed a complex array of alterations consistent with those reported in The Cancer Genome Atlas head and neck squamous cell carcinoma project, including aberrations in PIK3CA, EGFR, CDKN2A, TP53, and NOTCH family and FAT1 genes. A detailed analysis of FAT family genes and associated pathways showed disruptions to these genes in most cell lines.ConclusionsThe molecular profiles we have generated indicate that as a whole, this panel recapitulates the molecular diversity observed in patients and will serve as useful guides in selecting cell lines for preclinical modeling.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151290/1/hed25803.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151290/2/hed25803_am.pd

Future research directions on the "elusive" white shark

White sharks, Carcharodon carcharias, are often described as elusive, with little information available due to the logistical difficulties of studying large marine predators that make long-distance migrations across ocean basins. Increased understanding of aggregation patterns, combined with recent advances in technology have, however, facilitated a new breadth of studies revealing fresh insights into the biology and ecology of white sharks. Although we may no longer be able to refer to the white shark as a little-known, elusive species, there remain numerous key questions that warrant investigation and research focus. Although white sharks have separate populations, they seemingly share similar biological and ecological traits across their global distribution. Yet, white shark’s behavior and migratory patterns can widely differ, which makes formalizing similarities across its distribution challenging. Prioritization of research questions is important to maximize limited resources because white sharks are naturally low in abundance and play important regulatory roles in the ecosystem. Here, we consulted 43 white shark experts to identify these issues. The questions listed and developed here provide a global road map for future research on white sharks to advance progress toward key goals that are informed by the needs of the research community and resource managers

The molecular landscape of the University of Michigan laryngeal squamous cell carcinoma cell line panel

BackgroundLaryngeal squamous cell carcinomas (LSCCs) have a high risk of recurrence and poor prognosis. Patient‐derived cancer cell lines remain important preclinical models for advancement of new therapeutic strategies, and comprehensive characterization of these models is vital in the precision medicine era.MethodsWe performed exome and transcriptome sequencing as well as copy number analysis of a panel of LSCC‐derived cell lines that were established at the University of Michigan and are used in laboratories worldwide.ResultsWe observed a complex array of alterations consistent with those reported in The Cancer Genome Atlas head and neck squamous cell carcinoma project, including aberrations in PIK3CA, EGFR, CDKN2A, TP53, and NOTCH family and FAT1 genes. A detailed analysis of FAT family genes and associated pathways showed disruptions to these genes in most cell lines.ConclusionsThe molecular profiles we have generated indicate that as a whole, this panel recapitulates the molecular diversity observed in patients and will serve as useful guides in selecting cell lines for preclinical modeling.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151290/1/hed25803.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151290/2/hed25803_am.pd

Genetic analysis of sinonasal undifferentiated carcinoma discovers recurrent SWI/SNF alterations and a novel PGAP3-SRPK1 fusion gene

Abstract Background Sinonasal Undifferentiated Carcinoma (SNUC) is a rare and aggressive skull base tumor with poor survival and limited treatment options. To date, targeted sequencing studies have identified IDH2 and SMARCB1 as potential driver alterations, but the molecular alterations found in SMARCB1 wild type tumors are unknown. Methods We evaluated survival outcomes in a cohort of 46 SNUC patients treated at an NCI designated cancer center and identify clinical and disease variables associated with survival on Kaplan-Meier and Cox multivariate survival analysis. We performed exome sequencing to characterize a series of SNUC tumors (n = 5) and cell line (MDA8788–6) to identify high confidence mutations, copy number alterations, microsatellite instability, and fusions. Knockdown studies using siRNA were utilized for validation of a novel PGAP3-SRPK1 gene fusion. Results Overall survival analysis revealed no significant difference in outcomes between patients treated with surgery +/− CRT and CRT alone. Tobacco use was the only significant predictor of survival. We also confirmed previously published findings on IDH and SMARC family mutations and identified novel recurrent aberrations in the JAK/STAT and PI3K pathways. We also validated a novel PGAP3-SRPK1 gene fusion in the SNUC cell line, and show that knockdown of the fusion is negatively associated with EGFR, E2F and MYC signaling. Conclusion Collectively, these data demonstrate recurrent alterations in the SWI/SNF family as well as IDH, JAK/STAT, and PI3K pathways and discover a novel fusion gene (PGAP3-SRPK1). These data aim to improve understanding of possible driver mutations and guide future therapeutic strategies for this disease.http://deepblue.lib.umich.edu/bitstream/2027.42/173540/1/12885_2021_Article_8370.pd

The genomic landscape of UM-SCC oral cavity squamous cell carcinoma cell lines

ObjectivesWe sought to describe the genetic complexity of 14 UM-SCC oral cavity cancer cell lines that have remained uncharacterized despite being used as model systems for decades.Materials and methodsWe performed exome sequencing on 14 oral cavity UM-SCC cell lines and denote the mutational profile of each line. We used a SNP array to profile the multiple copy number variations of each cell line and use immunoblotting to compare alterations to protein expression of commonly amplified genes (EGFR, PIK3CA, etc.). RNA sequencing was performed to characterize the expression of genes with copy number alterations.ResultsThe cell lines displayed a highly complex network of genetic aberrations that was consistent with alterations identified in the HNSCC TCGA project including PIK3CA amplification, CDKN2A deletion, as well as TP53 and CASP8 mutations, enabling genetic stratification of each cell line in the panel. Copy number FISH and spectral karyotyping analysis demonstrate that cell lines retain chromosomal heterogeneity.ConclusionsCollectively, we developed an important resource for future oral cavity HNSCC cell line studies and highlight the complexity of genomic aberrations in cell lines

Small molecule profiling to define synergistic EGFR inhibitor combinations in head and neck squamous cell carcinoma.

BackgroundHead and neck squamous cell carcinoma (HNSCC) is a debilitating disease with poor survival. Although epidermal growth factor receptor (EGFR)-targeting antibody cetuximab improves survival in some settings, responses are limited suggesting that alternative approaches are needed.MethodsWe performed a high throughput drug screen to identify EGFR inhibitor-based synergistic combinations of clinically advanced inhibitors in models resistant to EGFR inhibitor monotherapies, and then performed downstream validation experiments on prioritized synergistic combinations.ResultsFrom our screen, we re-discovered known synergistic EGFR inhibitor combinations with FGFR or IGF-1R inhibitors that were broadly effective and also discovered novel synergistic combinations with XIAP inhibitor and DNMT inhibitors that were effective in only a subset of models.ConclusionsConceptually, our data identify novel synergistic combinations that warrant evaluation in future studies, and suggest that some combinations, although highly synergistic, will require parallel companion diagnostic development to be effectively advanced in patients

Supplementary Tables 1-8 from Adipose Triglyceride Lipase Is a Therapeutic Target in Advanced Prostate Cancer That Promotes Metabolic Plasticity

Supplementary Tables 1-8 to accompany the main text and, in particular, the materials and methods.</p

\u3ci\u3eDrosophila\u3c/i\u3e Muller F Elements Maintain a Distinct Set of Genomic Properties Over 40 Million Years of Evolution

The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25–50%) than euchromatic reference regions (3–11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11–27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4–3.6 vs. 8.4–8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu