Hyaluronan activated-metabolism phenotype (HAMP) in pancreatic ductal adenocarcinoma

Yuzan Kudo, Shiro Kohi, Keiji Hirata, Michael Goggins, Norihiro Sato

Research output: Contribution to journalArticle

Abstract

Background: The aggressiveness of pancreatic ductal adenocarcinoma (PDAC) is enhanced by its interactions with stromal extracellular matrix, notably with hyaluronan (HA). Our previous studies have demonstrated increased expression of genes involved in HA synthesis and degradation in PDAC, suggesting the presence of an autocrine mechanism which accelerates the production of low-molecular-weight HA. Results: A subset of PDAC (20% of cell lines and 25% of tissues) showed overexpression of multiple genes encoding both HA-synthesizing and HA-degrading enzymes, displaying a phenotype defined as an HA activated-metabolism phenotype (HAMP). Interestingly, HAMP+ cells were more susceptible to the treatment with an HA synthesis inhibitor and HA degradation inhibitor than HAMP- cells. Patients with HAMP+ tumors were significantly associated with shorter survival than those with HAMP- tumors (P = 0.049). Methods: We investigated transcriptional profiling of genes involved in HA synthesis (including HAS2 and HAS3) and degradation (including HYAL1 and KIAA1199) in a panel of PDAC cell lines and primary tissues. Response of PDAC cells to treatment with an HA synthesis inhibitor (4-methylumbelliferone) or HA degradation inhibitor (dextran sulfate) was examined by cell migration assay. Survival was determined by Kaplan–Meier curve and compared by log-rank test. Conclusions: The present study identified a novel phenotype, HAMP, characterized by activation of HA metabolism pathways, in PDAC. HAMP should be further investigated as a prognostic marker as well as a target for personalized medicine.

Original languageEnglish (US)
Pages (from-to)5592-5604
Number of pages13
JournalOncotarget
Volume10
Issue number54
StatePublished - Sep 1 2019

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Keywords

  • Degradation
  • Hyaluronan
  • Pancreatic cancer
  • Prognosis
  • Synthesis

ASJC Scopus subject areas

  • Oncology

Cite this

Kudo, Y., Kohi, S., Hirata, K., Goggins, M., & Sato, N. (2019). Hyaluronan activated-metabolism phenotype (HAMP) in pancreatic ductal adenocarcinoma. Oncotarget, 10(54), 5592-5604.