Dimensional Priming Reprograms Adipose-Derived Stromal Cells to Promote Pancreatic Cancer Progression

TL;DR

Growing supportive cells in 3D environments makes them promote pancreatic cancer growth, while 2D conditions suppress it.

Contribution

This study shows that physical cues from the environment can reprogram stromal cells to either promote or suppress pancreatic cancer.

Findings

3D-primed stromal cells enhance tumor growth and invasion in animal models.

2D-primed stromal cells suppress tumor expansion and maintain tissue boundaries.

3D-primed cells secrete more IL-6 and TNF-α, promoting a tumor-permissive environment.

Abstract

Pancreatic cancer is difficult to treat in part because tumor cells interact closely with surrounding supportive cells and tissue, known as the tumor microenvironment. These supportive cells can either restrain or promote cancer growth depending on their physical and biological state. In this study, we examined how growing adipose-derived stromal cells under flat (two-dimensional) or three-dimensional conditions changes their behavior and their effects on pancreatic cancer. We found that stromal cells primed in three-dimensional environments promote tumor growth, invasion, and tissue breakdown in animal models, whereas cells primed under flat conditions tend to suppress tumor expansion. These findings highlight how physical cues in the tumor environment can reprogram supportive cells and strongly influence cancer progression. Understanding these interactions may help guide future strategies to target the tumor microenvironment in pancreatic cancer.

Background: The tumor microenvironment (TME) plays a central role in pancreatic ductal adenocarcinoma (PDAC) progression, yet how mechanical cues shape stromal cell behavior remains poorly defined. Here, we investigate how dimensional priming of adipose-derived stromal cells (ADSCs) alters their immunomodulatory functions and subsequent impact on PDAC growth. Methods: ADSCs were cultured under two-dimensional (2D) or three-dimensional (3D) conditions and evaluated using in vitro co-culture systems with PDAC organoids and in vivo xenograft models. Stromal phenotype, cytokine secretion, tumor growth, invasion, and immune cell infiltration were assessed. Results: ADSCs cultured in three-dimensional (3D) hydrogels exhibited reduced Caveolin-1 (CAV-1) expression and reprogramming toward a stress-adapted, CAF-like phenotype compared with two-dimensional (2D) cultures. In vitro, 2D-primed ADSCs constrained PDAC organoid growth, increased MMP-2 activity, and required direct cell–cell contact to suppress tumor viability. By contrast, 3D-primed ADSCs preserved organoid structure but markedly enhanced tumor cell migration through soluble factors, accompanied by increased IL-6 and TNF-α and reduced IL-10 secretion during co-culture. In vivo, 3D-primed ADSCs promoted the largest tumors with aggressive invasion and loss of Col-Tgel containment associated with tumor expansion, whereas 2D-primed ADSCs suppressed tumor growth and maintained gel boundaries. Immunohistochemistry confirmed elevated Ki-67 in tumors containing 3D-primed ADSCs, while macrophage infiltration (F4/80+) was highest in 2D-primed tumors and lowest in 3D-primed tumors. Conclusions: Dimensional priming fundamentally reprograms ADSC phenotype and alters their stromal–immune interactions, generating a tumor-permissive state that accelerates PDAC progression. These findings identify mechanical cues as critical regulators of stromal plasticity and highlight dimensional priming as a potentially targetable axis within the PDAC microenvironment.

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