Metastasis-on-a-chip reveals adipocyte-derived lipids trigger cancer cell migration via HIF-1α activation in cancer cells

Jieun Seo; Kyeong Seog Kim; Jong-Wan Park; Joo-Youn Cho; Hak Chang; Junji Fukuda; Ki Yong Hong; Yang-Sook Chun

doi:10.1016/j.biomaterials.2020.120622

Metastasis-on-a-chip reveals adipocyte-derived lipids trigger cancer cell migration via HIF-1α activation in cancer cells

Biomaterials. 2021 Feb:269:120622. doi: 10.1016/j.biomaterials.2020.120622. Epub 2020 Dec 21.

Authors

Jieun Seo¹, Kyeong Seog Kim², Jong-Wan Park³, Joo-Youn Cho², Hak Chang⁴, Junji Fukuda⁵, Ki Yong Hong⁶, Yang-Sook Chun⁷

Affiliations

¹ Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, South Korea; Department of Physiology, Seoul National University College of Medicine, Seoul, 03080, South Korea.
² Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, South Korea; Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, 03080, South Korea.
³ Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, South Korea; Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, 03080, South Korea.
⁴ Department of Plastic Surgery, Seoul National University Hospital, Seoul, 03080, South Korea.
⁵ Faculty of Engineering, Yokohama National University, Yokohama, 240-8501, Japan.
⁶ Department of Plastic and Reconstructive Surgery, Dongguk University Ilsan Hospital, Dongguk University School of Medicine, Goyang, 10326, South Korea.
⁷ Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, South Korea; Department of Physiology, Seoul National University College of Medicine, Seoul, 03080, South Korea; Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, 03080, South Korea. Electronic address: chunys@snu.ac.kr.

PMID: 33385686
DOI: 10.1016/j.biomaterials.2020.120622

Abstract

Although obesity is a newly considered risk factor for cancer, the mechanisms by which adipocyte-derived metabolites accelerate cancer malignancy have yet to be elucidated. To identify the connection among heterogeneous cell types, conventional methods including Transwell assays or conditioned media (CM) have been used; however, these methods do not fully reflect niche effects in the tumor microenvironment (TME). Here, we established an oxygen permeable polydimethylsiloxane (PDMS)-based three-dimensional (3D) culture system to allow direct attachment between human adipocyte derived stem cells (ADSCs) and cancer cells. By doing so, a physiologically bioactive TME was created, which could be used to reveal further the relationships between different cell types. We found that co-culture of cancer cells with ADSCs resulted in a dispersion phenomenon, and the dispersed spheroid was well matched with the enhanced metastatic potential of cancer cells. Lipid profiling and in vitro migration assays suggested that lipids are the driving force for cancer cell migration via HIF-1α upregulation. In addition, the lipid/HIF-1α axis promoted tumor metastasis in a xenograft mouse model. This study presents an in vitro model of a biomimetic TME and provides new mechanistic insights into the effects of ADSC-released fatty acids on cancer cells as oncometabolites.

Keywords: 3D co-culture; ADSCs; Cancer cell migration; Fatty acids; HIF-1α; Tumor microenvironment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adipocytes*
Animals
Cell Line, Tumor
Cell Movement
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
Lab-On-A-Chip Devices*
Lipids*
Mice
Neoplasms*
Tumor Microenvironment

Substances

Hypoxia-Inducible Factor 1, alpha Subunit
Lipids