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조회214

서울대학교 의과대학

Adv. Sci., Oct 29 2025, | https://doi.org/10.1002/advs.202515186 Cancer Manipulates Adjacent Adipose Tissue to Exploit Fatty Acids via HIF-1α/CCL2/PPARα Axis: A Metabolic Circuit to Support Tumor Progression

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 *}

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

^*Corresponding author: correspondence to Yang-Sook Chun

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.

논문정보

형식Research article
게재일2025년 10월 (BRIC 등록일 2025-11-05)
연구진국내(교신)+국외 연구진
분야 의약학 > 종양의학

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