Genomic alterations drive metastases formation in pancreatic ductal adenocarcinoma cancer: deciphering the role of CDKN2A and CDKN2B in mediating liver tropism

ABSTRACT: ABSTRACT Metastases are often the direct cause of death of patients with pancreatic ductal adenocarcinoma (PDAC). Yet, the role of genomic alterations in mediating tropism and metastasis formation by pancreatic cancer cells is currently unknown. We aimed to identify genomic alterations predisposing colonization of PDAC cells to distant organs and decipher mechanisms enabling this process. Methods: Frequency of genomic alterations was assessed in 2668 local-biopsied compared to 2840 metastatic PDAC samples. Tumorigenic phenotype and transcriptomic profile of manipulated PDAC cells was assessed. Results: The prevalence of genomic alterations was site dependent, with different profiles observed in samples obtained from the pancreas compared to those obtained from the liver, lungs or lymph nodes. Liver metastases were characterized by deletion of the cyclin dependent kinase inhibitors 2A/2B (CDKN2A/B, encoding p16 and p15, respectively). Studies in PDAC cells indicated enhanced growth under liver conditions following p16/15 deletion. The liver is characterized by high ammonia-low glutamine environment, and a transcriptomic assay revealed modulation of glutamine-ammonia pathway-related genes by p15/p16. Accordingly, p15/p16 deletion promoted growth under high ammonia-low glutamine condition, upregulated glutamate-ammonia ligase (GLUL) and downregulated glutaminase 2 (GLS2). Importantly, GLUL-silencing had a more pronounced effect on proliferation of p15/p16-deleted PDAC cells. Conclusion: These data suggest a unique role for genomic alterations in mediating tropism and metastases formation. Among these alterations, p15/16 loss was identified as a promoter of liver metastases and further studies indicated a novel role for p16/15, namely, regulation of glutamine synthesis. These findings may pave the way for the development of novel therapeutic strategies aiming at the prevention of liver metastases formation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE154492 | GEO | 2023/07/06

REPOSITORIES: GEO