Scientists have identified a tumor suppressor gene in pancreatic ductal adenocarcinoma (PDA) that they claim may represent a novel therapeutic target and biomarker of disease prognosis. The gene, known as Usp9x, hasn’t previously been linked with PDA or other types of carcinoma in either humans or mouse models.
The discovery is reported by a team led by researchers at Cancer Research U.K.’s Cambridge Research Institute, who used Sleeping Beauty transposon-mediated insertional mutagenesis in a mouse model of pancreatic ductal preneoplasia to identify genes that cooperate with KrasG12D to promote tumorigenesis and cancer progression.
The results of the screen, reported by David A. Tuveson, M.D., and colleagues in Nature, showed that the most commonly mutated gene was the X-linked deubiquitinase Usp9x. In fact, mutations in Usp9x were found in over half of all the murine tumors.
Their in vitro studies further demonstrated that depleting Usp9x in mouse PDA cells using RNA interference significantly increased colony formation in soft agar, and markedly suppressed anoikis. Moreover, conditional deletion of Usp9x was shown to cooperate with KrasG12D to accelerate rapidly pancreatic tumorigenesis in mice, validating the genetic interaction, they note.
A subsequent search for proteins that may be regulated by Usp9x found that Itch protein levels were reduced in Usp9x-deficient mouse and human PDA cells. This indicated that the Usp9x mutation may promote tumorigenesis at least partly by disabling Itch, which is known to promote degradation of proteins relevant to cell proliferation and survival.
Importantly, evaluation of tumors from different human PDA cohorts confirmed that low Usp9x mRNA or protein levels correlated with poor survival after surgery, and metastatic burden. The researchers describe their findings in a paper titled “The deubiquitinase Usp9x suppresses pancreatic ductal adenocarcinoma.”
They say the overall data indicates that Usp9x is a major tumor suppressor gene that may have both prognostic and therapeutic applications in PDA. “Although a recent report implicated Usp9x as a pro-survival gene by stabilizing MCL1, potential inhibitors of Usp9x should be developed with caution as we find that Usp9x has tissue-specific effects including a tumor suppressor role in oncogenic Kras-initiated pancreatic carcinoma,” they conclude.
“Usp9x is probably epigenetically silenced in a subset of PDA, thus explaining why previous DNA sequencing efforts have failed to identify this as a participant in carcinogenesis, and indicating that clinically available epigenome modulators may be beneficial agents in such patients...Itch is a likely mediator of pancreatic tumor suppression by Usp9x, and continued investigation of the Usp9x–Itch pathway is warranted.”