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.
Bibliographical noteFunding 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.
© 2022, The Author(s).