Thread by @FaltasLab

Pre-print alert 🚨 New story from my lab "The cytidine deaminase APOBEC3G drives cancer mutagenesis and clonal evolution in bladder cancer" This is one of the first projects in my lab, so I am thrilled to see it come to fruition 🐁🧪 🔬 #bladdercancer #biology @OncoAlert

Led by postdoc @weisi_liu w amazing contributions by @knewtrophil @FKhaniPath @DrLaMontBarlow @DuyDNguyen1 L. Gu K. Eng @BhavneetBhinder @MDUppal92 @ChRecapet @asbonerw S. Ross @ElementoLab @ChelicoUSASK

We previously showed that bladder cancer is characterized by extensive and early divergent evolution.
We also showed that the APOBEC3-like mutational signatures were enriched in chemotherapy-resistant urothelial cancers nature.com/articles/ng.36… @NatureGenet

We and others have been working on experimentally linking individual APOBEC3 cytidine deaminases to mutational signatures and cancer evolution. We previously hypothesized that the APOBEC3 enzymes drive the evolution of #bladdercancer nature.com/articles/s4157… @NatureRevCancer

We can model this in mice because of evolution! mice have a single Apobec3 (mA3) gene, and humans have 7 orthologs. Knocking out the mouse Apobec3 provides a null “clean” mutational background for transgenic expression of any of the seven human APOBEC3 proteins.

We bred mice that express the human APOBEC3G (hA3G) transgene on the mA3-null background (hA3G(+) mA3(-/-). We used the chemical carcinogen called BBN to initiate carcinogenesis.

Strikingly, the hA3G mice had more advanced cancers and significantly shorter survival compared to the KO littermates.

APOBEC3G promotes mutagenesis, genomic instability, and kataegis and acts as "mutagenic fuel" that increases the clonal diversity of bladder cancers thus driving divergent cancer evolution.

We characterize the single base substitution signature induced by APOBEC3G in vivo, showing the induction of a mutational signature distinct from that caused by APOBEC3A and APOBEC3B.

Analysis of thousands of human cancers reveals the contribution of APOBEC3G to the mutational profiles of multiple cancer types, including bladder cancer. Interestingly, in #bladdercancer, this APOBEC3G signature is associated with WORSE survival consistent with the mouse model.

We used IF and confocal microscopy of GFP-tagged APOBEC3G to show that it is present in the nuclear compartment which is a prerequisite for mutagenesis

We were glad to see other reports showing that APOBEC3G causes DNA damage and promotes genomic instability in other cancer types conistent with our findings.nature.com/articles/s4140…

Grateful for @HarrisLabUTHSA @CharlesSwanton @DmitryYeast L. Alexandrov @adrpdaclab @abbygreenlab @J_Maciejowski @prokuninaolsson @MPetljak @HarmitMalik S. Roberts, M. Weizman @TimFenton10 and many others whose work advanced our understanding of APOBEC3 mutagenesis in cancer

Grateful for the support from the Starr Cancer Consortium, my @WCMGUcancer colleagues @DrScottTagawa @DrAnaMolina @cnsternberg @DrJonesNauseef @DrDavidNanus
@mdmanishshah @DrMhidalgo @wolchokj @WCM_MeyerCancer

If you are interested in working on understanding the principles of cancer evolution using #bladdercancer as a model of APOBEC3-induced mutagenesis, check out our postdoc openings jobrxiv.org/job/weill-corn… Spread the word #research #science #bladdercancer

biorxiv.org/content/10.110…