Premalignant pancreatic cells seed stealth metastasis in distant organs in mice

Oncogene. 2021 Mar;40(12):2273-2284. doi: 10.1038/s41388-021-01706-8. Epub 2021 Mar 1.

Abstract

Recent findings suggest that the dissemination of tumor cells occurs at the early stage of breast and pancreatic carcinogenesis, which is known as early dissemination. The evidence of early dissemination has been demonstrated predominantly in the bloodstream and bone marrow; however, limited evidence has revealed the existence and behavior of disseminated cells in distant organs. Here, we show that premalignant pancreatic cells seed distant stealth metastasis that eventually develops into manifest metastasis. By analyzing lineage-labeled pancreatic cancer mouse models (KPCT/TFF1KO; Pdx1-Cre/LSL-KRASG12D/LSL-p53R172H/LSL-tdTomato/TFF1KO), we found that premalignant pancreatic cells, rather than mature malignant cells, were prone to enter the bloodstream and reside in the bone marrow, liver, and lung. While these metastatic cells exhibited the characteristics of the cells of host organs and did not behave as malignant cells, they underwent malignant transformation and formed distinct tumors. Surprisingly, the manifestation of distant metastasis occurred even before tumor development in the primary site. Our data revealed that disseminated premalignant cells reside stealthily in distant organs and evolve in parallel with the progression of the primary tumor. These observations suggest that we must rebuild a therapeutic strategy for metastatic pancreatic cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow / pathology
  • Carcinogenesis / genetics
  • Carcinogenesis / pathology
  • Cell Lineage / genetics
  • Disease Models, Animal
  • Homeodomain Proteins / genetics*
  • Humans
  • Liver / pathology
  • Lung / pathology
  • Mice
  • Neoplasm Metastasis / genetics*
  • Neoplasm Metastasis / pathology
  • Pancreas / metabolism
  • Pancreas / pathology
  • Precancerous Conditions / genetics
  • Precancerous Conditions / pathology
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Trans-Activators / genetics*
  • Trefoil Factor-1 / genetics*
  • Tumor Suppressor Protein p53 / genetics*

Substances

  • Homeodomain Proteins
  • Tff1 protein, mouse
  • Trans-Activators
  • Trefoil Factor-1
  • Trp53 protein, mouse
  • Tumor Suppressor Protein p53
  • pancreatic and duodenal homeobox 1 protein
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)