Biology subjects

Meltzer, P. S.

Publications and source records attributed to Meltzer, P. S..

6 recordsLinked to original sources

bioRxiv2026

TCF4 and CtBP1 Repress LEF1 to Maintain a TCF4-centric Transcriptional Program in Colon Cancer.

Abstract The canonical WNT signaling pathway guides cell growth throughout the human lifespan. In adults, WNT plays an essential role in tissue homeostasis by maintaining tissue stem cells. In the intestine, the WNT transcription factor, TCF4, is necessary for stem cell maintenance. Aberrant activation of WNT signaling is generally accepted as an initiating event in colon cancer, leading to constitutive TCF4 activity. To investigate the role of this key transcription factor in global gene regulation, we abrogated TCF4 expression in colon cancer cells. Loss of TCF4 function resulted in the over-expression of the WNT transcription factor, LEF1. LEF1 was transcriptionally competent and over-compensated for TCF4 (TCF7L2) silencing in a WNT reporter assay. TCF4 enlisted the transcriptional repressor CtBP1, and bound the LEF1 promoter, indicative of direct repression. TCF4 and LEF1 drove different transcriptional programs, with TCF4 favoring MYC and cell cycle progression, while LEF1 favored immune-related gene signatures. TCF4 was the primary regulator of MYC expression, yet also the mediator of LEF1 repression, suggestive of competition centered on TCF4 transcriptional output despite the {beta}-catenin saturated colon cancer nucleus. We conclude that TCF4 has dual activator-repressor activity in colon cancer.

cell biology↗

bioRxiv2024

Telomere interactions and structural variants in ALT cells revealed with TelSPRITE

Acquisition of a telomere maintenance mechanism is essential for cancer cells. In a minority of tumors, telomeres are lengthened via Alternative Maintenance of Telomeres (ALT), a telomerase-independent pathway based on homologous recombination. ALT tumors have heavily rearranged genomes with many structural variants containing telomere repeats. To better understand the genetic evolution of these tumors, we seek to determine if certain genomic loci tend to spatially associate with telomeres in ALT and are especially liable to experience telomere recombination events as a result. Assays that reveal close spatial associations between genomic loci, such as SPRITE and Hi-C, have enabled extensive exploration of genomic spatial organization. However, as analysis pipelines for these next-generation sequencing-based assays typically discard reads aligning to repetitive elements, little is known about the spatial arrangement of telomeres and other repetitive loci in the nucleus. Here, we present TelSPRITE, a novel approach to extracting telomere contact frequencies from SPRITE data. We identify reads containing telomere repeats and sort them into a single bin, quantifying spatial contacts between the telomere bin and the rest of the genome. Our analysis reveals a strong dependency of telomere contact frequency on chromosomal distance from the telomere, consistent with the known effect of linear distance on 3-dimensional spatial contacts. Telomere contacts are also strongly enriched near centromeres, a phenomenon that may be reflective of spatial clustering of heterochromatic regions. ALT cell lines are globally enriched for telomere content and display distinctive intrachromosomal spikes in telomere contact frequency. Our customized analysis of long read sequencing data suggests that loci with high telomere contact frequencies represent structural variants containing telomere repeats in ALT cells. Collectively, our results demonstrate general principles of telomeric spatial organization while also profiling the spectrum of genomic rearrangements in ALT cells.

genomics↗

bioRxiv2024

Cancer-associated DAXX mutations reveal a critical role for ATRX localization in ALT suppression

To maintain genome stability, proliferating cells must enact a program of telomere maintenance. While most tumors maintain telomeres through the action of telomerase, a subset of tumors utilize a DNA-templated process termed Alternative Lengthening of Telomeres or ALT. ALT is associated with mutations in the ATRX/DAXX/H3.3 histone chaperone complex, which is responsible for deposition of non-replicative histone variant H3.3 at heterochromatic regions of the genome including telomeres. We wished to better understand the role DAXX plays in ALT suppression, and to determine which disease-associated DAXX mutations are unable to suppress ALT. To answer this question, we have leveraged the G292 cell line, in which ATRX is wild type but DAXX has undergone a fusion event with the non-canonical kinesin KIFC3. Restoration of wild-type DAXX in G292 localizes ATRX and abrogates ALT. Using this model system, we tested the ability of a panel of disease-associated DAXX missense variants to suppress ALT. Missense mutations in the ATRX binding domain, the histone binding domain, and the C-terminal SUMO interaction motif reduce the ability of DAXX to suppress ALT. Unexpectedly, we find that mutations in the DAXX histone binding domain lead to failure of ATRX localization. We conclude that a key function of DAXX in ALT suppression is the localization of ATRX to nuclear foci.

cancer biology↗

bioRxiv2020

SCLC_CellMiner: Integrated Genomics and Therapeutics Predictors of Small Cell Lung Cancer Cell Lines based on their genomic signatures

Model systems are necessary to understand the biology of SCLC and develop new therapies against this recalcitrant disease. Here we provide the first online resource, CellMiner-SCLC (https://discover.nci.nih.gov/SclcCellMinerCDB) incorporating 118 individual SCLC cell lines and extensive omics and drug sensitivity datasets, including high resolution methylome performed for the purpose of the current study. We demonstrate the reproducibility of the cell lines and genomic data across the CCLE, GDSC, CTRP, NCI and UTSW datasets. We validate the SCLC classification based on four master transcription factors: NEUROD1, ASCL1, POU2F3 and YAP1 (NAPY classification) and show transcription networks connecting each them with their downstream and upstream regulators as well as with the NOTCH and HIPPO pathways and the MYC genes (MYC, MYCL1 and MYCN). We find that each of the 4 subsets express specific surface markers for antibody-targeted therapies. The SCLC-Y cell lines differ from the other subsets by expressing the NOTCH pathway and the antigen-presenting machinery (APM), and responding to mTOR and AKT inhibitors. Our analyses suggest the potential value of NOTCH activators, YAP1 inhibitors and immune checkpoint inhibitors in SCLC-Y tumors that can now be independently validated. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=151 SRC="FIGDIR/small/980623v2_ufig1.gif" ALT="Figure 1"> View larger version (65K): org.highwire.dtl.DTLVardef@10930e7org.highwire.dtl.DTLVardef@699d9corg.highwire.dtl.DTLVardef@1ea773corg.highwire.dtl.DTLVardef@3a1589_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LISCLC-CellMiner provides the most extensive SCLC resource in terms of number of cell lines (118 cell lines), extensive omics data (exome, microarray, RNA-seq, copy number, methylomes and microRNA) and drug sensitivity testing. C_LIO_LIWe find evidence of distinct epigenetic profile of SCLC cell lines (global hypomethylation and histone gene methylation), which is consistent with their plasticity. C_LIO_LITranscriptome analyses demonstrate the coherent transcriptional networks associated with the 4 main genomic subgroups (NEUROD1, ASCL1, POU2F3 & YAP1 = NAPY classification) and their connection with the NOTCH and HIPPO signaling pathways. C_LIO_LISCLC-CellMiner provides a conceptual framework for the selection of therapies for SCLC in a personalized fashion allowing putative biomarkers according molecular classifications and molecular characteristics. C_LIO_LISCLC-Y cell lines differ from the other cancer cell lines; their transcriptome resemble NSCLC cell lines. YAP1 cell lines while being the most resistant to standard of care treatments (etoposide, cisplatin and topotecan) respond to mTOR and AKT inhibitors and present native immune predisposition suggesting sensitivity to immune checkpoint inhibitors. C_LI

cancer biology↗

bioRxiv2019

Melanoblast transcriptome analysis reveals novel pathways promoting melanoma metastasis

Cutaneous malignant melanoma is an aggressive cancer of melanocytes with a strong propensity to metastasize. We posited that melanoma cells acquire metastatic capability by adopting an embryonic-like phenotype, and that a lineage approach would uncover novel metastatic melanoma biology. We used a genetically engineered mouse model to generate a rich melanoblast transcriptome dataset, identified melanoblast-specific genes whose expression contributed to metastatic competence, and derived a 43-gene signature that predicted patient survival. We identified a melanoblast gene, KDELR3, whose loss impaired experimental metastasis. In contrast, KDELR1 deficiency enhanced metastasis, providing the first example of different disease etiologies within the KDELR-family of retrograde transporters. We show that KDELR3 regulates the metastasis suppressor, KAI1, and report an interaction with the E3 ubiquitin-protein ligase gp78, a regulator of KAI1 degradation. Our work demonstrates that the melanoblast transcriptome can be mined to uncover novel targetable pathways for melanoma therapy.

cancer biology↗

bioRxiv2018

Microbiome-TP53 Gene Interaction in Human Lung Cancer

BackgroundLung cancer is the leading cancer diagnosis worldwide and the number one cause of cancer deaths. Exposure to cigarette smoke, the primary risk factor in lung cancer, reduces epithelial barrier integrity and increases susceptibility to infections. Herein, we hypothesized that somatic mutations together with cigarette smoke generate a dysbiotic microbiota that is associated with lung carcinogenesis. Using lung tissue from controls (n=33) and cancer cases (n=143), we conducted 16S rRNA bacterial gene sequencing, with RNA-seq data from lung cancer cases in The Cancer Genome Atlas (n=1112) serving as the validation cohort.\n\nResultsOverall, we demonstrate a lower alpha diversity in normal lung as compared to non-tumor adjacent or tumor tissue. In squamous cell carcinoma (SCC) specifically, a separate group of taxa were identified, in which Acidovorax was enriched in smokers (P =0.0013). Acidovorax temporans was identified by fluorescent in situ hybridization within tumor sections, and confirmed by two separate 16S rRNA strategies. Further, these taxa, including Acidovorax, exhibited higher abundance among the subset of SCC cases with TP53 mutations, an association not seen in adenocarcinomas (AD).\n\nConclusionsThe results of this comprehensive study show both a microbiome-gene and microbiome-exposure interactions in SCC lung cancer tissue. Specifically, tumors harboring TP53 mutations, which can damage epithelial function, have a unique bacterial consortia which is higher in relative abundance in smoking-associated SCC. Given the significant need for clinical diagnostic tools in lung cancer, this study may provide novel biomarkers for early detection.

cancer biology↗