Pancreatic cancer adenocarcinoma (PDAC) is a dire disease with no good treatment and a five-year survival of only 5%. While most PDAC studies focus on cancer initiation and driver mutations, the majority of patients come to the clinic already with a metastatic disease, most frequently with liver metastasis, and most die directly from metastases.
The research group from the Oncology Division Research Lab, led by Dr. Tami Rubinek, head of the lab, Prof. Ido Wolf, head of the Oncology Division and Dr. Shani Journo, a PhD student, aimed to study mechanisms governing development and growth of PDAC liver metastasis.
Through collaboration with Foundation Medicine Inc. they analysed a database of 17,000 PDAC samples and revealed higher prevalence of p15/p16 deletion in liver metastases compared to the local tumors and to other metastatic sites. Further studies showed that deletion of this genes allowed better growth of cells in liver conditions. The liver environment is enriched in ammonia which may be on one hand cytotoxic and on the other may provide building blocks to amino acids and nucleotides. The group found that only PDAC cells expressing p15/p16 cells were affected by exposure to ammonia, and discovered that deletion of p15/p16 rewired cellular metabolic pathways leading to ammonia utilization. Importantly, inhibition of a key gene in this pathway decreased the growth of p15/p16-deleted PDAC cells.
This study revealed a possible vulnerability of PDAC cells that metastasize to the liver, namely. This discovery enables development of novel therapeutic strategies and while this strategy may not be the ultimate panacea that will cure PDAC, it may achieve the more realistic goal of prolonging lives of patients diagnosed with PDAC and liver metastases.