TY - JOUR
T1 - C/EBPδ Suppresses Motility-Associated Gene Signatures and Reduces PDAC Cell Migration
AU - Hartl, Leonie
AU - Maarschalkerweerd, Pien A. F.
AU - Butler, Joe M.
AU - Manz, Xue D.
AU - Thijssen, Victor L. J. L.
AU - Bijlsma, Maarten F.
AU - Duitman, JanWillem
AU - Spek, C. Arnold
N1 - Funding Information: M.F.B. has received research funding from Celgene and Lead Pharma, and has acted as a consultant for Servier. None were involved in the design of this study or drafting of the manuscript. All other authors declare no conflict of interest. Publisher Copyright: © 2022 by the authors.
PY - 2022/11/1
Y1 - 2022/11/1
N2 - Pancreatic Ductal Adenocarcinoma (PDAC) is among the most aggressive human cancers and occurs globally at an increasing incidence. Metastases are the primary cause of cancer-related death and, in the majority of cases, PDAC is accompanied by metastatic disease at the time of diagnosis, making it a particularly lethal cancer. Regrettably, to date, no curative treatment has been developed for patients with metastatic disease, resulting in a 5-year survival rate of only 11%. We previously found that the protein expression of the transcription factor CCAAT/Enhancer-Binding Protein Delta (C/EBPδ) negatively correlates with lymph node involvement in PDAC patients. To better comprehend the etiology of metastatic PDAC, we explored the role of C/EBPδ at different steps of the metastatic cascade, using established in vitro models. We found that C/EBPδ has a major impact on cell motility, an important prerequisite for tumor cells to leave the primary tumor and to reach distant sites. Our data suggest that C/EBPδ induces downstream pathways that modulate actin cytoskeleton dynamics to reduce cell migration and to induce a more epithelial-like cellular phenotype. Understanding the mechanisms dictating epithelial and mesenchymal features holds great promise for improving the treatment of PDAC.
AB - Pancreatic Ductal Adenocarcinoma (PDAC) is among the most aggressive human cancers and occurs globally at an increasing incidence. Metastases are the primary cause of cancer-related death and, in the majority of cases, PDAC is accompanied by metastatic disease at the time of diagnosis, making it a particularly lethal cancer. Regrettably, to date, no curative treatment has been developed for patients with metastatic disease, resulting in a 5-year survival rate of only 11%. We previously found that the protein expression of the transcription factor CCAAT/Enhancer-Binding Protein Delta (C/EBPδ) negatively correlates with lymph node involvement in PDAC patients. To better comprehend the etiology of metastatic PDAC, we explored the role of C/EBPδ at different steps of the metastatic cascade, using established in vitro models. We found that C/EBPδ has a major impact on cell motility, an important prerequisite for tumor cells to leave the primary tumor and to reach distant sites. Our data suggest that C/EBPδ induces downstream pathways that modulate actin cytoskeleton dynamics to reduce cell migration and to induce a more epithelial-like cellular phenotype. Understanding the mechanisms dictating epithelial and mesenchymal features holds great promise for improving the treatment of PDAC.
KW - CCAAT/enhancer-binding protein delta
KW - cytoskeleton
KW - metastases
KW - migration
KW - pancreatic ductal adenocarcinoma
UR - http://www.scopus.com/inward/record.url?scp=85141556910&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/cells11213334
DO - https://doi.org/10.3390/cells11213334
M3 - Article
C2 - 36359732
SN - 2073-4409
VL - 11
JO - Cells
JF - Cells
IS - 21
M1 - 3334
ER -