2. Academic Validation
  3. Cancer Manipulates Adjacent Adipose Tissue to Exploit Fatty Acids via HIF-1α/CCL2/PPARα Axis: A Metabolic Circuit to Support Tumor Progression

Cancer Manipulates Adjacent Adipose Tissue to Exploit Fatty Acids via HIF-1α/CCL2/PPARα Axis: A Metabolic Circuit to Support Tumor Progression

  • Adv Sci (Weinh). 2025 Oct 29:e15186. doi: 10.1002/advs.202515186.
Jeong-Eun Yun 1 2,  Jieun Seo 3,  Jiwon Koh 4 5,  Seock-Ah Im 6,  Ki Yong Hong 7,  Yeseon Son 1 2,  Do-Won Jeong 8,  Junji Fukuda 3,  Jong-Wan Park 1 9,  Yang-Sook Chun 1 2 9
Affiliations

Affiliations

  • 1 Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
  • 2 Department of Physiology, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
  • 3 Faculty of Engineering, Yokohama National University, Yokohama, 240-8501, Japan.
  • 4 Department of Pathology, Seoul National University Hospital, Seoul, 03080, Republic of Korea.
  • 5 Cancer Research Institute, Seoul National University, Seoul, 03080, Republic of Korea.
  • 6 Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul National University, Seoul, 03080, Republic of Korea.
  • 7 Department of Plastic and Reconstructive Surgery, Seoul National University Hospital, Seoul, 03080, Republic of Korea.
  • 8 Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA.
  • 9 Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
PMID: 41160815 DOI: 10.1002/advs.202515186
Abstract

Rising obesity rates are closely linked to higher risk of Cancer, yet the underlying mechanisms are not fully understood. It is previously reported that fatty acids (FAs) released from cancer-associated adipose tissue enhance hypoxia-inducible factor-1α (HIF-1α) expression in Cancer cells, promoting tumor progression. Here, it is elucidated that Cancer cells manipulate adjacent adipose tissue by secreting C-C chemokine ligand2 (CCL2) to exploit FAs. Activation of HIF-1α induced by FA influx increases CCL2 expression in Cancer cells, which subsequently leads to lipolysis in nearby adipose tissue by activating Peroxisome Proliferator-activated Receptor alpha (PPARα) signaling. This activation in adipose tissue results in the release of FAs into the tumor microenvironment. The increased lipid supply to tumor reactivates the FA/HIF-1α/CCL2 axis in Cancer cells, further accelerating tumor growth and CCL2 secretion. This establishes a positive feedback loop between tumor and adjacent adipose tissue, which enhances Cancer progression. This crosstalk is validated by using a polydimethylsiloxane-based 3D coculture system and in vivo models. In obese mice, this reciprocal signaling accelerated tumor progression, whereas intra-tumoral injection of CCL2-neutralizing antibody significantly suppressed it. These findings reveal a metabolic circuit for tumor survival and disrupting this interaction may provide promising therapeutic targets, particularly for obese Cancer patients.

Keywords

CCL2; HIF‐1α; PPARα; cancer; obesity.

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