Chronic Obstructive Pulmonary Disease is a generally smoking-linked major cause of morbidity and mortality. Genome-wide Association Studies identified a locus including a non-synonymous single nucleotide polymorphism in CHRNA5, rs16969968, encoding the nicotinic acetylcholine receptor α5 subunit, predisposing to both smoking and Chronic Obstructive Pulmonary Disease. Here we report that nasal polyps from rs16969968 non-smoking carriers exhibit airway epithelium remodeling and inflammation. These hallmarks of Chronic Obstructive Pulmonary Disease occur spontaneously in mice expressing human rs16969968. They are significantly amplified after exposure to porcine pancreatic elastase, an emphysema model, and to oxidative stress with a polymorphism-dependent alteration of lung function. Targeted rs16969968 expression in epithelial cells leads to airway remodeling in vivo, increased proliferation and production of pro-inflammatory cytokines through decreased calcium entry and increased adenylyl-cyclase activity. We show that rs16969968 directly contributes to Chronic Obstructive Pulmonary Disease-like lesions, sensitizing the lung to the action of oxidative stress and injury, and represents a therapeutic target.
Despite its efficacy in solid tumours, in particular HER2+ breast cancer, HER2‐targeted therapy has given rise to disappointing results in non‐small cell lung cancer (NSCLC). With the aim of refining the target population for anti‐HER2 therapies in NSCLC, we investigated the relationships between HER2 and the tumour suppressor fragile histidine triad (FHIT) in lung tumour cells. First, we observed a negative correlation between FHIT expression and the activated form of HER2 (pHER2) in NSCLC samples and in lung tumour cell lines. Moreover, the silencing or overexpression of FHIT in lung cell lines led to an increase or decrease of HER2 activity, respectively. We also demonstrated that two anti‐HER2 drugs, irbinitinib and trastuzumab, restore a more epithelial phenotype and counteract cell invasiveness and growth of FHIT‐silenced tumour cell lines. Finally, we showed that the FHITlow/pHER2high phenotype predicts sensitivity to an anti‐HER2 therapy in primary tumour cells from NSCLC patients. Our results show that FHIT regulates the activity of HER2 in lung tumour cells and that FHIT‐inactivated tumour cells are sensitive to HER2 inhibitors. A new subclass of patients with NSCLC may be eligible for an anti‐HER2 therapy. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
The tumor microenvironnement consists of cells, soluble factors, signaling molecules, extracellular matrix (EM), and mechanical cues that can promote neoplastic transformation, support tumor growth and invasion, and foster therapeutic resistance. In addition to provide a physical barrier against invasion, type I collagen, the most abundant protein in EM, is also known to play a role in tumor cell proliferation (1). DeClerck et al. (2) has reported a direct inhibitory effect of fibrillar type I collagen on tumor cell proliferation when compared to the monomeric one. Type I collagen is a life-long protein (half-life 15 yrs) susceptible to undergo non enzymatic post-translational modifications such as production of Advanced Glycation End Products (AGEs). These modifications are able to influence the behavior of tumor cells. Here, we investigated whether regulation of HT-1080 cell proliferation is a consequence of type I collagen aging in terms of fibrillar state of the protein (2,3), or of the level of AGEs, also known to stimulate cell proliferation (4). Rat tail type I collagen were prepared from adult (2 months) and old (2 years) animals. A significant increase in AGEs has been observed in collagen extracted from old rats, compared to the adult. Under 3D growth condition, HT-1080 cells proliferate rapidly in old type I collagen relative to the adult one. This effect was not observed in 2D coating culture. The low rate of proliferation in adult collagen is accompanied by a downregulation of ERK1/2 activation, and an upregulation of p21, the inhibitor of cell cycle progression. This age-dependent cell proliferation regulatory effect does not involve α2β1 integrins. Neither Pi3K/Akt nor JNK pathways were involved in this process. Accumulating evidence suggest that Discoidin Domain Receptor 2 (DDR2) is a Receptor Tyrosine Kinase (RTK) with the unique ability among RTKs to respond to fibrillar collagen (5). To determine whether a similar response is elicited by DDR2 in both collagens, DDR2 was immunoprecipitated from cell lysates, and phosphorylated DDR2 was detected by immunoblotting. High level of DDR2 phosphorylation was observed after 3 days culture in adult collagen compared to the old one, whereas DDR2 expression remains unchanged in the presence of both collagens. Moreover, the DDR2 kinase function inhibitor, nilotinib, restored cell proliferation in adult collagen to a level similar to that observed in the old one. Taken together, these data establish a role for DDR2 in critical events during restriction of tumor cell proliferation induced by adult type I collagen. References: (1) Lukashev ME et al. Trends Cell Biol. 1998;8(11):437, (2) Wall SJ et al. J Biol Chem. 2005;280(48):40187, (3) Wilson SL et al. FASEB J. 2013; (accepted), (4) Ishihara K et al. FEBS Lett. 2003;28;550(1-3):107, (5) Rajeshwari R et al. Cancer Metastasis Rev. 2012;31(1-2):295 Citation Format: Charles Saby, Hassan El Btaouri, Julie Routhier, Céline Charpentier, Laurence Van-Gulick, Marie Pierre Courageot, Pierre Jeannesson, Hamid Morjani. Age of type I collagen is critical for regulation of HT-1080 cell proliferation in 3D matrices. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1154. doi:10.1158/1538-7445.AM2014-1154
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