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McCloskey, C. W.

Publications and source records attributed to McCloskey, C. W..

2 recordsLinked to original sources
bioRxiv2021

Spatially confined sub-tumor microenvironments orchestrate pancreatic cancer pathobiology

Pancreatic ductal adenocarcinoma (PDAC) remains resistant to most treatments and demonstrates a complex pathobiology. Here, we deconvolute regional heterogeneity in the human PDAC tumor microenvironment (TME), a long-standing obstacle, to define precise stromal contributions to PDAC progression. Large scale integration of histology-guided multiOMICs with clinical data sets and functional in vitro models uncovers two microenvironmental programs in PDAC that were anchored in fibroblast differentiation states. These sub-tumor microenvironments (subTMEs) co-occurred intratumorally and were spatially confined, producing patient-specific cellular and molecular heterogeneity associated with shortened patient survival. Each subTME was uniquely structured to support discrete aspects of tumor biology: reactive regions rich in activated fibroblast communities were immune-hot and promoted aggressive tumor progression while deserted regions enriched in extracellular matrix supported tumor differentiation yet were markedly chemoprotective. In conclusion, PDAC regional heterogeneity derives from biologically distinct reactive and protective TME elements with a defined, active role in PDAC progression. Graphical Abstract & Key findings O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=191 SRC="FIGDIR/small/431890v1_ufig1.gif" ALT="Figure 1"> View larger version (73K): org.highwire.dtl.DTLVardef@17adabdorg.highwire.dtl.DTLVardef@aee778org.highwire.dtl.DTLVardef@deae00org.highwire.dtl.DTLVardef@1718272_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LIPDAC regional heterogeneity originates in sub-tumor microenvironments (subTMEs) C_LIO_LISubTMEs exhibit distinct immune phenotypes and CAF differentiation states C_LIO_LIDifferent subTMEs are either tumor-promoting or chemoprotective C_LIO_LIIntratumoral subTME co-occurrence links stromal heterogeneity to patient outcome C_LI

cancer biology↗
bioRxiv2020

Transcriptional heterogeneity of stemness phenotypes in the ovarian epithelium

The ovarian surface epithelium (OSE) is a monolayer of epithelial cells covering the surface of the ovary. During ovulation, the OSE is ruptured to allow release of the oocyte. This wound is quickly repaired, but mechanisms of this repair are poorly understood. The contribution of tissue-resident stem cells in the homeostasis of several epithelial tissues is widely accepted, such as the intestinal epithelium, airway epithelium, and skin, but their involvement in OSE maintenance is unclear. While putative stem cell populations in the OSE have been described, how they are regulated is poorly defined. We show that traits associated with stem cells (stemness) can be increased in OSE following exposure to the cytokine TGFB1, overexpression of the transcription factor Snai1, or deletion of Brca1. By assessing the gene expression profiles of these populations, we show that stemness is often linked to mesenchymal-associated gene expression and higher activation of ERK signalling, but it is not consistently dependent on their activation. Expression profiles of these populations are extremely context specific, suggesting that stemness may not correspond to a single, distinct population, but rather is a heterogenous state that can possibly emerge from diverse environmental cues. Together, these findings support that the OSE may not require distinct stem cell populations for long-term maintenance, and may achieve this through transient dedifferentiation into a stem-like state.

cell biology↗