Purpose: Metabolic rewiring in malignant transformation is often accompanied by altered expression of metabolic isozymes. Phosphoenolpyruvate carboxykinase-2 (PCK2) catalyzes the rate-limiting step of gluconeogenesis and is the dominant isoform in many cancers including triple-negative breast cancer (TNBC). Our goal was to identify small molecule inhibitors of PCK2 enzyme activity.
View Article and Find Full Text PDFPurpose: We evaluated T- and B-cell receptor (TCR and BCR) repertoire diversity and 38 serum cytokines in pre- and post-treatment peripheral blood of 66 patients with triple-negative breast cancer (TNBC) who received neoadjuvant chemotherapy plus durvalumab and assessed associations with pathologic response and immune-related adverse events (irAEs) during treatment.
Methods: Genomic DNA was isolated from buffy coat for TCR and BCR clonotype profiling using the Immunoseq platform and diversity was quantified with Pielou's evenness index. MILLIPLEX MAP Human Cytokine/Chemokine Magnetic Bead Panel was used to measure serum cytokine levels, which were compared between groups using moderated t-statistic with Benjamini-Hochberg correction for multiple testing.
Differences in the tumor immune microenvironment may result in differences in prognosis and response to treatment in cancer patients. We hypothesized that differences in the tumor immune microenvironment may exist between African American (AA) and NonAA patients, due to ancestry-related or socioeconomic factors, that may partially explain differences in clinical outcomes. We analyzed clinically matched triple-negative breast cancer (TNBC) tissues from self-identified AA and NonAA patients and found that stromal TILs, PD-L1 IHC-positivity, mRNA expression of immune-related pathways, and immunotherapy response predictive signatures were significantly higher in AA samples (p < 0.
View Article and Find Full Text PDFPurpose: We examined gene expression, germline variant, and somatic mutation features associated with pathologic response to neoadjuvant durvalumab plus chemotherapy in basal-like triple-negative breast cancer (bTNBC).
Experimental Design: Germline and somatic whole-exome DNA and RNA sequencing, programmed death ligand 1 (PD-L1) IHC, and stromal tumor-infiltrating lymphocyte scoring were performed on 57 patients. We validated our results using 162 patients from the GeparNuevo randomized trial.
Unlabelled: Metabolic reprogramming is a hallmark of malignant transformation, and loss of isozyme diversity (LID) contributes to this process. Isozymes are distinct proteins that catalyze the same enzymatic reaction but can have different kinetic characteristics, subcellular localization, and tissue specificity. Cancer-dominant isozymes that catalyze rate-limiting reactions in critical metabolic processes represent potential therapeutic targets.
View Article and Find Full Text PDFBackground: The diversity of genomic alterations in cancer poses challenges to fully understanding the etiologies of the disease. Recent interest in infrequent mutations, in genes that reside in the "long tail" of the mutational distribution, uncovered new genes with significant implications in cancer development. The study of cancer-relevant genes often requires integrative approaches pooling together multiple types of biological data.
View Article and Find Full Text PDFCancer cells employ various defense mechanisms against drug-induced cell death. Investigating multi-omics landscapes of cancer cells before and after treatment can reveal resistance mechanisms and inform new therapeutic strategies. We assessed the effects of navitoclax, a BCL2 family inhibitor, on the transcriptome, methylome, chromatin structure, and copy number variations of MDA-MB-231 triple-negative breast cancer (TNBC) cells.
View Article and Find Full Text PDFPatients with epidermodysplasia verruciformis (EV) and biallelic null mutations of (encoding EVER1) or (EVER2) are selectively prone to disseminated skin lesions due to keratinocyte-tropic human β-papillomaviruses (β-HPVs), which lack E5 and E8. We describe EV patients homozygous for null mutations of the gene encoding calcium- and integrin-binding protein-1 (CIB1). CIB1 is strongly expressed in the skin and cultured keratinocytes of controls but not in those of patients.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
July 2017
A natural and permanent transfer of prokaryotic viral sequences to mammals has not been reported by others. Circular "SPHINX" DNAs <5 kb were previously isolated from nuclease-protected cytoplasmic particles in rodent neuronal cell lines and brain. Two of these DNAs were sequenced after Φ29 polymerase amplification, and they revealed significant but imperfect homology to segments of commensal phage viruses.
View Article and Find Full Text PDFHuman papillomaviruses (HPVs) are epithelial tropic viruses that link their productive life cycles to the differentiation of infected host keratinocytes. A subset of the over 200 HPV types, referred to as high-risk, are the causative agents of most anogenital malignancies. HPVs infect cells in the basal layer, but restrict viral genome amplification, late gene expression, and capsid assembly to highly differentiated cells that are active in the cell cycle.
View Article and Find Full Text PDFHuman papillomaviruses infect stratified epithelia and link their productive life cycle to the differentiation state of the host cell. Productive viral replication or amplification is restricted to highly differentiated suprabasal cells and is dependent on the activation of the ATM DNA damage pathway. The ATM pathway has three arms that can act independently of one another.
View Article and Find Full Text PDFCervical cancers, a malignancy associated with oncogenic papilloma viruses, remain a major disease burden in the absence of effective implementation of preventive strategies. CD66(+) cells have previously been identified as a tumor-propagating subset in cervical cancers. We investigated the existence, differentiation state, and neoplastic potential of CD66(+) cells in a precancer cell line harboring HPV31b episomes.
View Article and Find Full Text PDFBased on promising preclinical efficacy associated with the 20S proteasome inhibitor bortezomib in malignant pleural mesothelioma (MPM), two phase II clinical trials have been initiated (EORTC 08052 and ICORG 05-10). However, the potential mechanisms underlying resistance to this targeted drug in MPM are still unknown. Functional genetic analyses were conducted to determine the key mitochondrial apoptotic regulators required for bortezomib sensitivity and to establish how their dysregulation may confer resistance.
View Article and Find Full Text PDFHuman papillomaviruses (HPVs) modulate expression of host microRNAs. Our deep-sequencing analysis of organotypic raft cultures identified microRNA 145 (miR-145) as a differentiation-dependent microRNA that has functionally active target sequences in the HPV-31 E1 and E2 open reading frames. Overexpression of miR-145 in HPV-positive cells resulted in reduced genome amplification and late gene expression, along with decreased levels of cellular transcription factor KLF-4.
View Article and Find Full Text PDFThe liver-enriched transcriptional activator protein (LAP) isoform of CCAAT/enhancer binding protein β (C/EBPβ) is shown to be a major activator of differentiation-dependent human papillomavirus (HPV) late gene expression, while the liver-enriched inhibitory protein (LIP) isoform negatively regulates late expression. In undifferentiated cells, LIPs act as dominant-negative repressors of late expression, and upon differentiation, LIP levels are significantly reduced, allowing LAP-mediated activation of the late promoter. Importantly, knockdown of C/EBPβ isoforms blocks activation of late gene expression from complete viral genomes upon differentiation.
View Article and Find Full Text PDFPolyomavirus enhancer activator 3 protein (Pea3), also known as ETV4, is a member of the Ets-transcription factor family, which promotes metastatic progression in various types of solid cancer. Pea3-driven epithelial-mesenchymal transition (EMT) has been described in lung and ovarian cancers. The mechanisms of Pea3-induced EMT, however, are largely unknown.
View Article and Find Full Text PDFOsteopontin (OPN) is a glycophosphoprotein cytokine that has multiple functions. OPN is expressed and secreted by various cells, and has a role in cell adhesion, chemotaxis, prevention of apoptosis, invasion, migration and anchorage-independent growth of tumor cells. Extensive research has demonstrated the pivotal participation of OPN in the regulation of cell signaling which controls neoplastic and malignant transformation.
View Article and Find Full Text PDF