Direct cell-to-cell transfer in stressed tumor microenvironment aggravates tumorigenic or metastatic potential in pancreatic cancer

Giyong Jang, Jaeik Oh, Eunsung Jun, Jieun Lee, Jee Young Kwon, Jaesang Kim, Sang Hyuk Lee, Song Cheol Kim, Sung Yup Cho, Charles Lee

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6 Scopus citations

Abstract

Pancreatic cancer exhibits a characteristic tumor microenvironment (TME) due to enhanced fibrosis and hypoxia and is particularly resistant to conventional chemotherapy. However, the molecular mechanisms underlying TME-associated treatment resistance in pancreatic cancer are not fully understood. Here, we developed an in vitro TME mimic system comprising pancreatic cancer cells, fibroblasts and immune cells, and a stress condition, including hypoxia and gemcitabine. Cells with high viability under stress showed evidence of increased direct cell-to-cell transfer of biomolecules. The resulting derivative cells (CD44high/SLC16A1high) were similar to cancer stem cell-like-cells (CSCs) with enhanced anchorage-independent growth or invasiveness and acquired metabolic reprogramming. Furthermore, CD24 was a determinant for transition between the tumorsphere formation or invasive properties. Pancreatic cancer patients with CD44low/SLC16A1low expression exhibited better prognoses compared to other groups. Our results suggest that crosstalk via direct cell-to-cell transfer of cellular components foster chemotherapy-induced tumor evolution and that targeting of CD44 and MCT1(encoded by SLC16A1) may be useful strategy to prevent recurrence of gemcitabine-exposed pancreatic cancers.

Original languageEnglish
Article number63
Journalnpj Genomic Medicine
Volume7
Issue number1
DOIs
StatePublished - Dec 2022

Bibliographical note

Funding Information:
The authors would like to acknowledge grant support from the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (grant number: 2018R1D1A1B07045601 to G.J.); the National Research Foundation of Korea (NRF) grants funded by the Korean government (MSIT) (grant numbers: 2021R1A2C3008021 and 2021R1A4A1029097 to S.-Y.C.); and the International Research & Development Program of the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT (grant number: 2015K1A4A3047851 to J.K.). C.L. was a distinguished Ewha Womans University Professor supported in part by the Ewha Womans University Research grant (2017–2020). The authors thank Kyue-Yim Lee for NTA measurement education, Ms. Jane Cha for the illustration and Dr. Stephen Sampson for careful editing of this manuscript.

Publisher Copyright:
© 2022, The Author(s).

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