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This study aims to evaluate the acquisition of osteogenic-like features in pancreatic cancer cells and associated molecular changes.

May 26, 2026Open Access

Osteogenic-like Phenotypic Reprogramming Is Associated with Reduced Malignant Behaviors in Pancreatic Cancer Cells Involving MAPK–ERK Signaling

Key Points

This study aims to evaluate the acquisition of osteogenic-like features in pancreatic cancer cells and associated molecular changes.
PDAC cell lines and non-malignant pancreatic epithelial cells were subjected to osteogenic induction.
Mineralization, ALP activity, and osteogenic marker expression were assessed alongside RNA sequencing for transcriptional changes.
Pharmacological inhibition of MEK and RUNX2 knockdown via siRNA were utilized to study the MAPK–ERK signaling pathway.
Osteogenic induction resulted in calcium deposition and increased ALP activity in some PDAC cell lines.
Induced PDAC cells showed reduced migration, invasion, and proliferation compared to control cells.
MEK inhibition led to decreased RUNX2 and ALP expression, indicating their role in the osteogenic-like phenotype.

Abstract

Pancreatic tumors frequently exhibit calcification, suggesting potential osteogenic-related phenotypic plasticity. This study aimed to systematically evaluate whether pancreatic ductal adenocarcinoma (PDAC) cells acquire osteogenic-like features under induction conditions and to assess the associated phenotypic and molecular changes. PDAC cell lines and non-malignant pancreatic epithelial cells were subjected to osteogenic induction. Mineralization, alkaline phosphatase (ALP) activity, osteogenic marker expression, and malignant phenotypes were evaluated. RNA sequencing was performed at defined time points to characterize transcriptional changes. Pharmacological inhibition of MEK and siRNA-mediated knockdown of RUNX2 were applied to examine the involvement of MAPK–ERK signaling and downstream transcriptional regulation. Osteogenic induction led to calcium deposition and increased ALP activity in a subset of PDAC cell lines, accompanied by upregulation of osteogenic-associated markers, including RUNX2 and SPP1. Induced cells exhibited reduced migration, clonogenicity, invasion, and proliferation. Transcriptomic analysis revealed activation of osteogenesis-related and calcium-transport pathways, along with downregulation of cell cycle programs. MAPK–ERK signaling was activated during induction, and MEK inhibition attenuated RUNX2 and ALP expression as well as mineralization-associated changes. Furthermore, RUNX2 knockdown reduced ALP expression and mineralization levels, indicating its contribution to the osteogenic-like phenotype. PDAC cells can acquire osteogenic-like features under defined induction conditions, accompanied by coordinated transcriptional reprogramming and reduced malignant phenotypes. The observed mineralization-associated phenotypes may reflect a combination of active processes and passive calcium deposition. In addition, the MAPK–ERK–RUNX2 axis appears to be involved in this process, although it may reflect a broader adaptive or stress-associated reprogramming rather than lineage commitment. These findings provide insight into the potential relationship between tumor calcification and phenotypic plasticity in PDAC.

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Gong et al. (Sun,) studied this question.

synapsesocial.com/papers/6a1539ccb5d9c58d83e8cd87 https://doi.org/https://doi.org/10.3390/ijms27114725

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