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Premalignant pancreatic cells seed stealth metastasis in distant organs in mice


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.

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Fig. 1: Lineage-labeled mouse model of PDAC.
Fig. 2: tdT-positive CAFs surrounding PanIN lesions.
Fig. 3: tdTomato-positive CTCs found in blood from the IVC.
Fig. 4: tdTomato-positive cells in the liver.
Fig. 5: Orthotopic transplantation of tdTomato-positive pancreatic cells.
Fig. 6: tdTomato-positive cells in the bone marrow and lungs.
Fig. 7: A KPCT/TFF1KO mice with abundant CTCs.

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We thank Atsushi Enomoto and Naoya Asai (Department of Pathology, Nagoya University Graduate School of Medicine) for providing us with the LSL-p53R172H and LSL-tdTomato mouse models.


This work was supported by the Japan Society for the Promotion of Science (JSPS) and Grants-in-Aid for Scientific Research (KAKENHI) (grant number 17K10695 and 20H03751).

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Conceptualization, investigation, methodology, visualization, writing, J.Y.; funding acquisition, J.Y., E.T., and T.K.; data curation and supervision, Y.Y. and T.K.; support investigation, Y.O.; and project administration, M.N.

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Correspondence to Junpei Yamaguchi.

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Yamaguchi, J., Kokuryo, T., Yokoyama, Y. et al. Premalignant pancreatic cells seed stealth metastasis in distant organs in mice. Oncogene 40, 2273–2284 (2021).

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