Early differential responses elicited by BRAFV600E in adult mouse models

Abstract

The BRAF gene is frequently mutated in cancer. The most common genetic mutation is a single nucleotide transition which gives rise to a constitutively active BRAF kinase (BRAFV600E) which in turn sustains continuous cell proliferation. The study of BRAFV600E murine models has been mainly focused on the role of BRAFV600E in tumor development but little is known on the early molecular impact of BRAFV600E expression in vivo. Here, we study the immediate effects of acute ubiquitous BRAFV600E activation in vivo. We find that BRAFV600E elicits a rapid DNA damage response in the liver, spleen, lungs but not in thyroids. This DNA damage response does not occur at telomeres and is accompanied by activation of the senescence marker p21CIP1 only in lungs but not in liver or spleen. Moreover, in lungs, BRAFV600E provokes an acute inflammatory state with a tissue-specific recruitment of neutrophils in the alveolar parenchyma and macrophages in bronchi/bronchioles, as well as bronchial/bronchiolar epithelium transdifferentiation and development of adenomas. Furthermore, whereas in non-tumor alveolar type II (ATIIs) pneumocytes, acute BRAFV600E induction elicits rapid p53-independent p21CIP1 activation, adenoma ATIIs express p53 without resulting in p21CIP1 gene activation. Conversely, albeit in Club cells BRAFV600E-mediated proliferative cue is more exacerbated compared to that occurring in ATIIs, such oncogenic stimulus culminates with p21CIP1-mediated cell cycle arrest and apoptosis. Our findings indicate that acute BRAFV600E expression drives an immediate induction of DNA damage response in vivo. More importantly, it also results in rapid differential responses of cell cycle and senescence-associated proteins in lung epithelia, thus revealing the early molecular changes emerging in BRAFV600E-challenged cells during tumorigenesis in vivo.

Tissue specificity of oncogenic BRAF targeted to lung and thyroid through a shared lineage factor

“…There are other cellular mechanisms not directly involved in mitogenic signaling pathways that might influence the outcome of Braf mutation. In a recent study comparing immediate effects of ubiquitous BRAF V600E expression in mice, 47 a DNA damage response was evident in several organs including the lungs but not in the thyroid. Although these organ differences were not further investigated, it is possible that cells’ ability to cope with DNA damage on oncogene activation might differentially influence tumorigenesis in lung and thyroid.…”

Distinct senescence mechanisms restrain progression of dysplastic nevi

“…Based on our observations, we conclude that the differences in telomere length in DN are the result of the differential activation of OIS and RS depending on the initiating driver mutation and represent two orthogonal senescence mechanisms limiting the progression of dysplastic nevi. However, an alternative explanation could be that the cell state of the melanocyte in which the driver mutation arises may also affect the fate of the nascent neoplasm and which tumor suppressor mechanisms become engaged, explaining the observed differences in telomere length and p16 accumulation (34,35).…”

Computational High-throughput screening and In vitro approaches identify CB-006-3; A novel PI3K-BRAFV600E dual targeted inhibitor against melanoma

“…Based on computational high-throughput virtual screening followed by in vitro analysis, in this work, we predicted compound CB-006-3 as a dual inhibitor of PI3K/BRAF V600E kinases. Previous studies have shown that a majority of melanoma cancers show BRAF V600E activated mutation, therefore targeting BRAF V600E can control cell proliferation to a significant extent [17]. Since the PI3K pathway is also implicated in a majority of the melanomas, studies have shown that targeting both PI3K and BRAF V600E show improved protection as against the traditional chemotherapy agents [18].…”