Biology subjects

Curry, E.

Publications and source records attributed to Curry, E..

3 recordsLinked to original sources

bioRxiv2019

High-throughput propagation of human prostate tissue from induced-pluripotent stem cells

Primary culture of human prostate organoids is slow, inefficient and laborious. To overcome this, we demonstrate a new high-throughput model where rapidly proliferating and easily handled induced pluripotent stem cells, for the first time, enable generation of human prostate tissue in vivo and in vitro. Using a co-culture technique with urogenital sinus mesenchyme, we recapitulated the in situ prostate histology, including the stromal compartment and the full spectrum of epithelial differentiation. This approach overcomes major limitations in primary cultures of human prostate stem, luminal and neuroendocrine cells, as well as the stromal microenvironment. These models provide new opportunities to study prostate development, homeostasis and disease.

developmental biology↗

bioRxiv2019

Amplification of genomic regions harbouring genes with dose-limiting effects provides selection pressure for acquiring aberrant epigenetic silencing in ovarian cancer

High-grade serous ovarian cancer (HGSOC) feature widespread genomic rearrangements that alter the copy number of genes. Genes for which elevated expression is detrimental to growth may be passengers in rearrangements that increase the copy number of strongly selective driver genes. There would then be selection pressure for compensatory epigenetic silencing of such passenger genes, such as through promoter DNA methylation.\n\nWe have used two independent cohorts of primary HGSOC tumour samples to provide evidence of consistent dosage-compensating promoter methylation (DCPM) genome-wide. Mapping CpG methylation to genomic copy number, we show that bias due to variable tumour cellularity of tissue samples results in false positive associations between methylation and copy number. Adjusting for this bias, we found that approximately 5-10% of all measured promoter CpGs with copy number gain showed a statistically significant increase in methylation. DCPM nullifies the association between increased copy number and increased gene expression. We confirmed a functional basis for selective pressure against over-expressing two candidate passenger genes in the 3q12 locus, as overexpressing either gene reduced spheroid formation efficiency in two HGSOC cell lines. DCPM represents a novel class of specific functional interactions between genetic and epigenetic landscapes of cancers.

cancer biology↗

bioRxiv2019

Tumor mutational landscape is a record of the pre-malignant state

Chromatin structure has a major influence on the cell-specific density of somatic mutations along the cancer genome. Here, we present a pan-cancer study in which we searched for the putative cancer cell-of-origin of 2,550 whole genomes, representing 32 cancer types by matching their mutational landscape to the regional patterns of chromatin modifications ascertained in 104 normal tissue types. We found that, in almost all cancer types, the cell-of-origin can be predicted solely from their DNA sequences. Our analysis validated the hypothesis that high-grade serous ovarian cancer originates in the fallopian tube and identified distinct origins of breast cancer subtypes. We also demonstrated that the technique is equally capable of identifying the cell-of-origin for a series of 2,044 metastatic samples from 22 of the tumor types available as primaries. Moreover, cancer drivers, whether inherited or acquired, reside in active chromatin regions in the respective cell-of-origin. Taken together, our findings highlight that many somatic mutations accumulate while the chromatin structure of the cell-of-origin is maintained and that this historical record, captured in the DNA, can be used to identify the often elusive cancer cell-of-origin.

genomics↗