SOX4 Drives a Cancer-Associated Fibroblast-like Transition in Adipose Stromal Cells to Promote Metabolic Disease

Here, we define a pathogenic cancer-associated fibroblast-like (CAF-like) stromal population that accumulates in visceral adipose tissue during obesity under the control of the transcription factor SOX4. Obesity and TGFβ signaling induce SOX4 in mesenchymal stromal cells (MSCs), where it promotes a CAF-like transcriptional program while suppressing adipogenic differentiation.

SOX4 activation in mouse MSCs exacerbated adipose inflammation, fibrosis, and glucose intolerance independently of adiposity. Conversely, Sox4 deletion reduced adipose immune cell accumulation and improved glucose homeostasis during obesity. We further identify the growth factor Midkine (MDK) as a SOX4-regulated paracrine effector of CAF-like cells.