Biology subjects

Giangreco, A.

Publications and source records attributed to Giangreco, A..

3 recordsLinked to original sources

bioRxiv2016

Cadm1 regulates airway stem cell growth and differentiation via modulation of Stat3 activity

Airway homeostasis, repair, and regeneration are imperfectly understood processes involving the proliferation and differentiation of endogenous lung stem cells. Here, we establish that epithelial Cell adhesion molecule 1 (Cadm1) regulates the growth and differentiation of airway basal cells, previously identified as lung stem cells. Immunohistochemistry and gene expression analysis reveals that Cadm1 is broadly expressed throughout the murine tracheobronchial epithelium, exhibits transient downregulation concomitant with airway injury, and is subsequently restored during basal cell differentiation. Using Cadm1 null (KO) and keratin 14 (K14)-specific Cadm1 overexpressing transgenic mice, we demonstrate that maintaining Cadm1 expression reduces basal stem cell proliferation after tracheal polidocanol injury, whereas Cadm1 deletion causes increased ciliated cell differentiation and sustained downstream Stat3 signalling. Altogether, this study defines a previously uncharacterised role for Cadm1 in directing airway basal cell homeostasis and repair via modulation of Stat3 activity.

cell biology↗

bioRxiv2016

A comparative microarray analysis identifies a conserved gene expression signature between airway injury and lung cancer

Lung squamous cell carcinoma (SqCC) accounts for 30% of lung cancers, with over 400,000 deaths per year worldwide. Although evidence suggests that chronic lung injury drives carcinogenesis, a comprehensive understanding of this process remains elusive. Here, I used a comparative microarray analysis to identify gene expression differences shared between airway injury and squamous lung cancer. Of the 667 genes that exhibited differential expression following murine polidocanol and SO2 injury, 40.6% were additionally dysregulated in human SqCC. Among these, 150 genes were consistently upregulated and 54 downregulated relative to all controls. Examples included genes associated with increased cell cycling, aberrant cytokinesis and DNA repair, and enhanced tumour cell invasion and metastases. For 88.2% of identified genes, altered expression was associated with increased SqCC progression and patient mortality. These results establish a novel gene expression signature linking airway injury and lung cancer pathogenesis.

bioinformatics↗

bioRxiv2016

A lottery simulation model for predicting cancer risk based on the strength and abundance of individual mutations

Models for predicting an individuals risk of developing cancer are complicated by a lack of well-conserved mutations present in most types of disease. To address this challenge we developed a simple lottery simulation of cancer development based solely on the abundance and relative survival advantage of mutations present within individual stem or progenitor cells. In simulations requiring few mutations or that involve mutations exhibiting a strong survival advantage cancers develop in our simulation in a progressive manner amenable to oncogene-based risk prediction. In contrast, in simulations involving numerous mutations that lack a strong survival advantage, a stochastic process of neutral drift and punctuated equilibrium determines eventual tumour formation. In these situations, the development of cancer is largely attributable to the rate of mutational variability amongst progenitor cells rather than the identity and relative survival advantage of the mutations present at any single time point. These results suggest that measuring rates of stem cell mutational variability represents an important component of predicting an individuals risk of developing cancer.

cancer biology↗