Biology subjects

Colacino, J.

Publications and source records attributed to Colacino, J..

4 recordsLinked to original sources

bioRxiv2018

DNA methylation signature of smoking in lung cancer is enriched for exposure signatures in newborn and adult blood.

BackgroundSmoking impacts DNA methylation genome-wide in blood of both newborns from maternal smoking during pregnancy and adults from personal smoking. Smoking causes lung cancer which involves aberrant methylation. We examined whether DNA methylation smoking signatures identified in blood of newborns and adults are detectable in lung tumors.\n\nMethodsWe compared smoking-related DNA methylation in lung adenocarcinomas (61 never smokers, 91 current smokers, and 238 former smokers) quantified with the Illumina450k BeadArray in The Cancer Genome Atlas with published large consortium meta-analyses of newborn and adult blood. We assessed whether CpG sites related to smoking in blood from newborns and adults were enriched in lung adenocarcinoma.\n\nResultsTesting CpGs differentially methylated by smoke exposure (P<10-4) we identified 296 in lung tumors, while previous meta-analyses (False Discovery Rate (FDR)<0.05) identified 6,073 in newborn blood, and for adult smoking, 18,760 in blood. The lung signals were highly enriched for those seen in newborn (32 overlapping, Penrichment=1.2x10-19) and adult blood (86 overlapping, Penrichment = 9.5x10-49). The 65 genes annotated to CpGs differentially methylated in lung tumors, but not blood, were enriched for RNA processing ontologies.\n\nConclusionsWe found highly significant overlap between smoking-related DNA methylation signals in lung cancer and those seen in blood from newborns, from in utero exposure, or adults, from their own exposure. These results suggest that some epigenetic alterations associated with cigarette smoke exposure are tissue specific, but others are common across tissues. These findings support the value of blood-based methylation biomarkers for assessing exposure effects in target tissues.

cancer biology↗

bioRxiv2018

Novel immune cell subtypes linked to survival among African American women with triple-negative breast cancer

Triple negative breast cancer (TNBC) is an aggressive disease that is twice as likely to be diagnosed in African American (AA) women compared to white women, with poor clinical outcomes. Tumor infiltrating lymphocytes (TILs) are associated with improved survival for TNBC, but the relevance of TILs and immune cell subtypes to survival in AA women with TNBC is unknown. We evaluated histopathologic TIL counts and molecular characteristics among 60 AA women diagnosed with TNBC with linkage to clinical outcomes using data from the Metropolitan Detroit Cancer Surveillance System. We utilized whole genome expression profiling of TN tumors and cell type deconvolution analysis to evaluate the underlying mechanisms and immune cell subtypes associated with survival patterns in the context of TILs. TILs were significantly associated with improved survival [1-10% Hazard Ratio (HR)=0.32, 95% Confidence Interval (CI) 0.12-0.90, p=0.031; >10% HR=0.18, 95% CI 0.05-0.67, 9.9x10-3]. 524 transcripts (326 coding, 198 non-coding) were associated with TIL levels, 34 of which were associated with both TILs and survival (p<0.05). While only naive B cells were associated with survival when considering individual cell types [Median HR=2.43, 95% CI 1.07-5.55, p=0.035], increased naive B cells, plasma cells, and activated NK cells, and decreased resting mast cells, M1 macrophages, and monocytes were associated with transcripts that predicted worse survival. These data provide evidence for novel roles for these immune cells types in TNBC, and further studies are needed to validate these findings and identify determinants of patterns of immune response in TNBC relevant to the AA population.\n\nSummaryWe found that increased naive B cells, plasma cells, and activated natural killer cells, and decreased resting mast cells, M1 macrophages, and monocytes were associated with expression biomarkers of worse survival among African American women with triple negative breast cancer.

epidemiology↗

bioRxiv2017

Cadmium exposure inhibits branching morphogenesis and causes alterations consistent with HIF-1α inhibition in human primary breast organoids

BackgroundDevelopmental cadmium exposure in vivo disrupts mammary gland differentiation, while exposure of breast cell lines to cadmium causes invasion consistent with the epithelial-mesenchymal transition (EMT). The effects of cadmium on normal human breast stem cell development have not been measured.\n\nObjectiveThe objective of this study was to quantify the effects of cadmium exposure on normal breast stem cell proliferation and differentiation.\n\nMethodsWe tested the effects of two physiologically relevant doses of cadmium: 250M and 2.5M on reduction mammoplasty patient-derived breast cells using the mammosphere assay, organoid formation in 3D hydrogels, and tested for molecular alterations using RNA-seq. We functionally validated our RNA-seq findings with a HIF-1 transcription factor activity reporter line and pharmaceutical inhibition of HIF-1 in mammosphere and organoid formation assays.\n\nResults2.5M cadmium reduced primary and secondary mammosphere formation and branching structure organoid formation rates by 33%, 40%, and 83%, respectively. Despite no changes in mammosphere formation, 0.25M cadmium treatment inhibited branching organoid formation in hydrogels by 68%. RNA-seq revealed that cadmium treatment downregulated genes associated with extracellular matrix formation and EMT, while upregulating genes associated with metal response including metallothioneins and zinc transporters. In the RNA-seq data, cadmium treatment also downregulated HIF-1 target genes including LOXL2, ZEB1, and VIM. Cadmium treatment significantly inhibited HIF-1 activity in a luciferase assay, and the HIF-1 inhibitor acriflavine ablated mammosphere and organoid formation.\n\nDiscussionThese findings show that cadmium, at doses relevant to human exposure, inhibited human mammary gland development, potentially through disruption of HIF-1 activity. These findings do not support cadmium being a breast cancer initiator via induction of stem cell proliferation, but instead implicate cadmium as an inhibitor of mammary gland morphogenesis.

pharmacology and toxicology↗

bioRxiv2017

Heterogeneity of normal human breast stem and progenitor cells as revealed by transcriptional profiling

During development and pregnancy, the human mammary gland undergoes extensive remodeling in processes driven by populations of stem and progenitor cells. We recently reported that breast cancers are also hierarchically organized and driven by distinct populations of cancer stem cells characterized as CD44+CD24low/- or by expression of Aldehyde dehydrogenase (ALDH). These sets of markers identify largely non-overlapping mesenchymal and epithelial populations, each of which is capable of tumor initiation when transplanted into immunosuppressed mice. Less is known about these two populations, individually or their overlap, in the normal human mammary gland. The goal of this study was to understand the biology of the ALDH+ and CD44+CD24- populations in the normal human breast, using flow cytometry based sorting paired with functional ex vivo analyses, RNA-sequencing, and single cell RNA expression profiling. ALDH+ cells and ALDH-CD44+CD24- cells, generally, have epithelial-like and mesenchymal-like characteristics, respectively. Despite this, there are substantial similarities in the biological pathways activated in both populations when compared to differentiated cells. Additionally, we found a substantial proportion of cells that simultaneously express ALDH+ and CD44+CD24- whose abundance varies between individuals. At the single cell level, these cells have the greatest mammosphere forming capacity and express high levels of stemness and EMT-associated genes including ID1, SOX2, TWIST1, and ZEB2. Through unbiased analysis of individual ALDH+ cells, we find cells with either epithelial or mesenchymal expression phenotypes. We also identify a subpopulation of cells with a hybrid epithelial/mesenchymal expression phenotype that overexpress genes associated with aggressive triple negative breast cancers. These results highlight the utility of single cell analyses to characterize tissue heterogeneity, even in marker enriched cell populations, and further identifies the genes and pathways that define this heterogeneity.

developmental biology↗