Macrophage adipocyte crosstalk as a node of intervention for pancreatic cancer-associated weight loss

Introduction: Up to 85% of pancreatic ductal adenocarcinoma (PDAC) patients are afflicted with cachexia – a metabolic syndrome characterized by loss of skeletal muscle mass and adipose tissue (AT) wasting. Cachexia worsens the already reduced quality of life of PDAC patients, their ability to tolerate therapeutic interventions, and, ultimately, their survival. Drawing insights from obesity research, where local changes in the adipose tissue play a crucial role in the pathophysiology, we explore adipose tissue in the context of PDAC cachexia at single-cell resolution.

Methods: We established a workflow for the characterization of human AT by single nucleus sequencing, which we applied to a representative cohort of surgical patients from Heidelberg University Hospital, grouped (1) PDAC with cachexia (2) PDAC without cachexia and (3) patients without a history of malignancy. In order to validate factors directly affecting glycerol release from adipocytes, we developed an in vitro murine co-culture system. This robust platform allowed us to examine the effect of macrophages, a central immune cell type in the AT, on adipocyte lipolysis by measuring the amount of released glycerol from adipocytes following a 6h-incubation in macrophage supernatant. Metabolomics analysis was applied to investigate metabolite abundance in the macrophage supernatants.

Results: Our analysis of 280,000+cells reveal distinct subpopulations of adipocytes, adipose stem and progenitor cells, mesothelial and immune cells. Our data identify cachexia-associated immune signatures and highlight changes at the immunometabolic junction, linking specific cell types to an increased risk of PDAC-associated cachexia. Additionally, we outline a framework of cellular interactions within the adipose niche in the context of cachexia. The biggest phenotypic shifts were observed in macrophages and adipocytes which showed signs of oxidative stress and altered metabolism. Accordingly, macrophage conditioned media significantly elevated lipid release from murine adipocytes, demonstrating that macrophages may play a role in cancer-associated adipose wasting.

Conclusion: With the largest single-nucleus RNA dataset present to date, we offer a detailed view of the human adipose tissue microenvironment in PDAC-associated cachexia. This dataset serves as a crucial resource for understanding the cellular mechanisms underlying cachexia and may help identify novel therapeutic targets.

Publication History

Article published online:
04 September 2025