# Nestin and SOX2 Maintain self-renewal Abilities of Different Pancreatic Cancer Stem Cell Populations

## TL;DR

This study shows that Nestin and SOX2 are important for the self-renewal of different pancreatic cancer cell types, but not for other cancer traits like growth or spread.

## Contribution

The study identifies Nestin and SOX2 as key regulators of self-renewal in mesenchymal and epithelial pancreatic cancer stem cell populations.

## Key findings

- Knockdown of Nestin in mesenchymal cells reduced self-renewal but had little effect on migration or chemotherapy response.
- SOX2 knockdown in epithelial cells similarly impaired self-renewal without major impact on other cancer traits.
- Nestin and SOX2 are crucial for self-renewal in their respective cell types but not for other malignancy features.

## Abstract

Metastasis and therapy resistance are main clinical challenges of pancreatic ductal adenocarcinoma (PDAC) still limiting patient`s prognosis. Both are dependent on tumor cell plasticity, which allows rapid adaptation of tumor cells to changing microenvironmental conditions. Epithelial-Mesenchymal-Transition (EMT), a process by which carcinoma cells acquire invasive abilities, is associated with a gain of cancer stem cell (CSC) properties. Different CSC phenotypes were described in PDAC, whereby high levels of the CSC marker Nestin was identified in CSC clones of mesenchymal Panc1 cells, while CSC clones of epithelial Panc89 cells were characterized by a high SOX2 expression. To investigate the functional impact of these CSC markers in PDAC cells with different EMT phenotypes, expression of either CSC marker was silenced in heterogenous (parental) and CSC PDAC populations to analyze their impact on essential malignancy associated properties.

SiRNA-mediated knockdown (KD) of NES and/or SOX2 in Panc1 and Panc89 cell variants (parental and CSC population), respectively, was successfully achieved. Decreased NES expression in Panc1 cell variants and decreased SOX2 expression in Panc89 cell variants significantly inhibited self-renewing properties, however, only marginally impacted cell growth, EMT marker expression, migration and invasion properties as well as response to chemotherapy. Overall, our data indicate that Nestin and SOX2 are crucial mediators of self-renewal capabilities of mesenchymal and epithelial PDAC cell variants, respectively, but that further factors are required for the maintenance of other malignancy associated properties.

The online version contains supplementary material available at 10.1007/s12015-025-11006-3.