Cep55 overexpression promotes genomic instability and tumorigenesis in mice

Abstract

High expression of centrosomal protein CEP55 has been correlated with clinico-pathological parameters across multiple human cancers. Despite significant in vitro studies and association of aberrantly overexpressed CEP55 with worse prognosis, its causal role in vivo tumorigenesis remains elusive. Here, using a ubiquitously overexpressing transgenic mouse model, we show that Cep55 overexpression causes spontaneous tumorigenesis and accelerates Trp53+/- induced tumours in vivo. At the cellular level, using mouse embryonic fibroblasts (MEFs), we demonstrate that Cep55 overexpression induces proliferation advantage by modulating multiple cellular signalling networks including the PI3K/AKT pathway. Notably, the Cep55 overexpressing MEFs demonstrate high level of mitotic chromosomal instability (CIN) due to stabilized microtubules. Interestingly, Cep55 overexpressing MEFs have a compromised Chk1-dependent S-phase checkpoint, causing increased replication speed and DNA damage, resulting in a prolonged aberrant mitotic division. Importantly, this phenotype was rescued by pharmacological inhibition of Pi3k/Akt or expression of mutant Chk1 (S280A), that is insensitive to regulation by active AKT, in Cep55 overexpressing cell. Collectively, our data demonstrates causative effects of deregulated Cep55 on genome stability and tumorigenesis which have potential implications for tumour initiation and therapy.

Combining genome-wide studies of breast, prostate, ovarian and endometrial cancers maps cross-cancer susceptibility loci and identifies new genetic associations

“…Further, a GTEx look-up for rs5868034 shows that it is associated with the expression of SETD9 in breast (P = 1.9 x 10 -32 ), prostate (P = 8.5 x 10 -18 ), ovarian (P = 9.6 x 10 -12 ), and uterine (P = 1.6 x 10 -11 ) tissues 22 . Lead SNP rs140936696 is ~3kb from CEP55, which encodes a centrosome-and midbody-associated protein that is a major regulator of abscission or the final stage of cytokinesis 51 and of the PI3K/AKT pathway 52 . CEP55 is a member of several common gene expression signatures (such as the "CIN70") that serve as indices of chromosomal instability, cell cycle progression, proliferation, and metastatic potential across multiple cancer types 53 .…”

Extracellular vesicles from genetically unstable, oncogene-driven cancer cells trigger micronuclei formation in endothelial cells

“…To this effect we analyzed the proteome datasets of EVs from oncogene-driven cancer cell lines (RAS-3, U373vIII and GSC83) capable of paracrine induction of endothelial micronuclei 32,36 . Interestingly, this survey revealed the presence of 19 common hits in these EVs, including proteins involved in calcium binding (ANXA1, ANXA2, PDCD6), stem cell phenotype (CD44) and genetic instability (CEP55) 32,37,38 . In contrast, EVs from corresponding cells with no micronuclei inducing capability (IEC-18, U373P) and those that were variable in this regard (e.g.…”