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

  • NPJ Genom Med. 2022 Oct 27;7(1):63. doi: 10.1038/s41525-022-00333-w.
Giyong Jang  1  2  3 ,  Jaeik Oh  4  5 ,  Eunsung Jun  6  7  8 ,  Jieun Lee  1  2  9 ,  Jee Young Kwon  1  2  10 ,  Jaesang Kim  1  2 ,  Sang-Hyuk Lee  1  2  11 ,  Song Cheol Kim  6  7  8 ,  Sung-Yup Cho  12  13  14  15 ,  Charles Lee  16  17  18
Affiliations
  • 1. Department of Life Science, Ewha Womans University, Seoul, 03760, Republic of Korea.
  • 2. Ewha-JAX Cancer Immunotherapy Research Center, Ewha Womans University, Seoul, 03760, Republic of Korea.
  • 3. Medical Research Center, Genomic Medicine Institute, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
  • 4. Department of Translational Medicine, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
  • 5. Department of Internal Medicine, Seoul National University Hospital, Seoul, 03080, Republic of Korea.
  • 6. Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea.
  • 7. Asan Medical Institute of Convergence Science and Technology (AMIST), Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea.
  • 8. Department of Convergence Medicine, Asan Institute for Life Sciences, University of Ulsan College of Medicine and Asan Medical Center, Seoul, 05505, Republic of Korea.
  • 9. Department of Surgery, Seoul National University Bundang Hospital, Gyeonggi-do, 13620, Republic of Korea.
  • 10. The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032, USA.
  • 11. Department of Bio-Information Science, Ewha Womans University, Seoul, 03760, Republic of Korea.
  • 12. Medical Research Center, Genomic Medicine Institute, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea. [email protected].
  • 13. Department of Translational Medicine, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea. [email protected].
  • 14. Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea. [email protected].
  • 15. Cancer Research Institute, Seoul National University, Seoul, 03080, Republic of Korea. [email protected].
  • 16. Department of Life Science, Ewha Womans University, Seoul, 03760, Republic of Korea. [email protected].
  • 17. Ewha-JAX Cancer Immunotherapy Research Center, Ewha Womans University, Seoul, 03760, Republic of Korea. [email protected].
  • 18. The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032, USA. [email protected].
PMID: 36302783 DOI: 10.1038/s41525-022-00333-w
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.

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