APOBEC3A drives deaminase domain-independent chromosomal instability to promote pancreatic cancer metastasis.
Sonja M WörmannAmy ZhangFredrik I ThegeRobert W CowanDhwani N RupaniRunsheng WangSara L ManningChris GatesWeisheng WuRena Levin-KleinKimal I RajapaksheMeifang YuAsha S MultaniYa'an KangCullen M TaniguchiKatharina SchlacherMelena D BellinMatthew H G KatzMichael P KimJason B FlemingSteven GallingerRavikanth MaddipatiReuben Stewart HarrisFaiyaz NottaSusan R RossAnirban MaitraAndrew D RhimPublished in: Nature cancer (2021)
Despite efforts in understanding its underlying mechanisms, the etiology of chromosomal instability (CIN) remains unclear for many tumor types. Here, we identify CIN initiation as a previously undescribed function for APOBEC3A (A3A), a cytidine deaminase upregulated across cancer types. Using genetic mouse models of pancreatic ductal adenocarcinoma (PDA) and genomics analyses in human tumor cells we show that A3A-induced CIN leads to aggressive tumors characterized by enhanced early dissemination and metastasis in a STING-dependent manner and independently of the canonical deaminase functions of A3A. We show that A3A upregulation recapitulates numerous copy number alterations commonly observed in patients with PDA, including co-deletions in DNA repair pathway genes, which in turn render these tumors susceptible to poly (ADP-ribose) polymerase inhibition. Overall, our results demonstrate that A3A plays an unexpected role in PDA as a specific driver of CIN, with significant effects on disease progression and treatment.
Keyphrases
- copy number
- dna repair
- genome wide
- mitochondrial dna
- dna damage
- dna methylation
- endothelial cells
- mouse model
- high glucose
- papillary thyroid
- dna damage response
- gene expression
- poor prognosis
- quality improvement
- squamous cell
- induced pluripotent stem cells
- drug induced
- living cells
- combination therapy
- long non coding rna
- transcription factor
- structural basis
- young adults
- single molecule
- bioinformatics analysis
- lymph node metastasis
- genome wide analysis