TGFB1 and PADI2 identified as key regulators of pancreatic cancer growth
3D organoid profiling reveals that TGFB1 suppresses tumor growth, while PADI2 drives survival in pancreatic cancer
image: (A) Effects of 365 cytokines (65 families) on PANC-1 tumor spheroid formation in Matrigel after 10 d. (B) Representative cytokine families with the strongest inductive or inhibitory effects on tumor spheroid growth. (C) Representative images of PANC-1 tumor spheroids cultured with or without TGFB1 (10 ng/mL) for 5, 7, and 10 d, captured at 4× or 10× magnification. Scale bar, 10 μm. (D–E) Quantification of tumor spheroids number (D) and size (E) in cultures treated with or without TGFB1 (10 ng/mL) for the indicated time points. Data represent mean ± SD from 5 fields of view and were analyzed by 2-way ANOVA with Sidak post hoc test (*P < 0.05, **P < 0.01, ****P < 0.0001). ANOVA = analysis of variance, IL1 = interleukin-1, SD = standard deviation, TGFB1 = transforming growth factor beta 1, VEGF = vascular endothelial growth factor.
Credit: Credit: Daolin Tang and Rui Kang from UT Southwestern Medical Center, Dallas, USA Image source link: http://dx.doi.org/10.1097/JP9.0000000000000248
Pancreatic ductal adenocarcinoma (PDAC) is the most common pancreatic cancer. By 2040, it is projected to become the second leading cause of cancer deaths, driving urgent demand for new therapeutic insights. A novel study published in the Journal of Pancreatology now uncovers key molecular drivers of PDAC growth using physiologically relevant 3D tumor organoid models, challenging findings from traditional 2D cell cultures.
Researchers from UT Southwestern Medical Center systematically evaluated 365 human cytokines for their effects on PDAC cell (PANC-1 and CFPAC-1) growth in 3D Matrigel-based spheroids—models that better mimic the tumor microenvironment (TME) than flat 2D monolayers. The team discovered that transforming growth factor beta 1 (TGFB1), a cytokine with known roles in tumor signaling, strongly suppressed 3D tumor spheroid formation and growth. Notably, this inhibitory effect was completely absent in 2D cultures, highlighting critical differences in cellular responses based on growth environment. The study was published online in the Journal of Pancreatology on November 12, 2026, and in Volume 9, Issue 1, on March 01, 2026.
Transcriptomic profiling further explained these divergent results. In 3D spheroids, TGFB1 regulated pathways linked to PI3K-AKT, WNT, and amebiasis signaling, while 2D cells showed changes in proteoglycan and focal adhesion pathways. Most importantly, the enzyme peptidyl arginine deiminase 2 (PADI2) was selectively upregulated by TGFB1 in 3D spheroids but not in 2D cultures.
Functional experiments confirmed PADI2’s key role: knocking down PADI2 inhibited 3D tumor spheroid growth and amplified TGFB1’s suppressive effect. This indicates PADI2 acts as a survival factor that helps PDAC cells withstand TGFB1-induced stress in 3D environments. Like TGFB1, PADI2 showed no impact on 2D cell proliferation, reinforcing its 3D-specific function.
“Our work demonstrates that 3D tumor spheroid models capture physiological cytokine responses missed by 2D systems,” said corresponding author Dr. Daolin Tang. “TGFB1 acts as a potent growth inhibitor in 3D, while PADI2 serves as a TGFB1-induced survival mechanism. Targeting PADI2 could enhance TGFB1’s tumor-suppressive effects, offering a promising therapeutic strategy for PDAC.”
The study’s limitations include the absence of immune cells, vasculature, and stromal heterogeneity in the 3D models—components critical to the TME. Future research will validate the TGFB1-PADI2 axis in patient-derived organoids and explore combined targeting of both pathways to overcome treatment resistance in PDAC patients.
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Reference
DOI: 10.1097/JP9.0000000000000248