2. Academic Validation
  3. Complement activation at the interface between adipocytes and cancer cells drives tumor progression

Complement activation at the interface between adipocytes and cancer cells drives tumor progression

  • JCI Insight. 2025 Feb 18;10(6):e184935. doi: 10.1172/jci.insight.184935.
Andres Valdivia 1,  Ana Maria Isac 1,  Horacio Cardenas 1,  Guangyuan Zhao 1,  Yaqi Zhang 1,  Hao Huang 1,  Jian-Jun Wei 1 2 3,  Mauricio Cuello-Fredes 4,  Sumie Kato 4,  Fernán Gómez-Valenzuela 4,  Francoise Gourronc 5,  Aloysius Klingelhutz 5,  Daniela Matei 1 2 6
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology.
  • 2 Robert H. Lurie Comprehensive Cancer Center, and.
  • 3 Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
  • 4 Department of Gynecology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
  • 5 Department of Microbiology and Immunology, College of Medicine, The University of Iowa, Iowa City, Iowa, USA.
  • 6 Jesse Brown VA Medical Center, Chicago, Illinois, USA.
PMID: 39964754 DOI: 10.1172/jci.insight.184935
Abstract

The omentum is the primary site of metastasis for ovarian Cancer (OC). Interactions between Cancer cells and adipocytes drive an invasive and prometastatic phenotype. Here we studied Cancer cell-adipocyte crosstalk by using a direct coculture model with immortalized human visceral nondiabetic pre-adipocytes (VNPADs) and OC cells. We demonstrated increased proliferation, invasiveness, and resistance to cisplatin of cocultured compared with monocultured OC cells. RNA Sequencing of OC cells from coculture versus monoculture revealed significant transcriptomic changes, identifying over 200 differentially expressed genes common to OVCAR5 and OVCAR8 cell lines. Enriched pathways included PI3K/Akt and complement activation. Lipid transfer into OC cells from adipocytes induced upregulation of complement C3 and C5 proteins. Inhibiting C3 or C5 reversed the invasive phenotype and C3 knockdown reduced tumor progression in vivo. Increased C3 expression was observed in omental implants compared with primary ovarian tumors and C3 secretion was higher in OC ascites from high-BMI versus low-BMI patients. C3 upregulation in OC cells involved activation of the ATF4-mediated integrated stress response (ISR). Overall, adipocyte-cancer cell interactions promoted invasiveness and tumorigenesis via lipid transfer, activating the ISR, and upregulating complement proteins C3 and C5.

Keywords

Adipose tissue; Cancer; Cell biology; Oncology.

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