Related Experiment Video
Updated: Jul 12, 2025
Syngeneic Mouse Orthotopic Allografts to Model Pancreatic Cancer
Published on: October 4, 2022
An NFATc1/SMAD3/cJUN Complex Restricted to SMAD4-Deficient Pancreatic Cancer Guides Rational Therapies
Marie C Hasselluhn1, Denise Schlösser2, Lennart Versemann2
1Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, Goettingen, Germany; Department of Medicine, Division of Digestive and Liver Diseases, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York.
Background & Aims:
The highly heterogeneous cellular and molecular makeup of pancreatic ductal adenocarcinoma (PDAC) not only fosters exceptionally aggressive tumor biology, but contradicts the current concept of one-size-fits-all therapeutic strategies to combat PDAC. Therefore, we aimed to exploit the tumor biological implication and therapeutic vulnerabilities of a clinically relevant molecular PDAC subgroup characterized by SMAD4 deficiency and high expression of the nuclear factor of activated T cells (SMAD4-/-/NFATc1High).
Methods:
Transcriptomic and clinical data were analyzed to determine the prognostic relevance of SMAD4-/-/NFATc1High cancers. In vitro and in vivo oncogenic transcription factor complex formation was studied by immunoprecipitation, proximity ligation assays, and validated cross model and species. The impact of SMAD4 status on therapeutically targeting canonical KRAS signaling was mechanistically deciphered and corroborated by genome-wide gene expression analysis and genetic perturbation experiments, respectively. Validation of a novel tailored therapeutic option was conducted in patient-derived organoids and cells and transgenic as well as orthotopic PDAC models.
Results:
Our findings determined the tumor biology of an aggressive and chemotherapy-resistant SMAD4-/-/NFATc1High subgroup. Mechanistically, we identify SMAD4 deficiency as a molecular prerequisite for the formation of an oncogenic NFATc1/SMAD3/cJUN transcription factor complex, which drives the expression of RRM1/2. RRM1/2 replenishes nucleoside pools that directly compete with metabolized gemcitabine for DNA strand incorporation. Disassembly of the NFATc1/SMAD3/cJUN complex by mitogen-activated protein kinase signaling inhibition normalizes RRM1/2 expression and synergizes with gemcitabine treatment in vivo to reduce the proliferative index.
Conclusions:
Our results suggest that PDAC characterized by SMAD4 deficiency and oncogenic NFATc1/SMAD3/cJUN complex formation exposes sensitivity to a mitogen-activated protein kinase signaling inhibition and gemcitabine combination therapy.
Insights
Pancreatic cancer with SMAD4 deficiency and high NFATc1 expression is aggressive. Targeting this subgroup with MEK inhibitors and gemcitabine shows promise in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genomics
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is highly heterogeneous, challenging uniform treatment strategies.
- A specific subgroup, SMAD4-deficient with high nuclear factor of activated T cells (NFATc1) expression (SMAD4-/-/NFATc1High), exhibits aggressive tumor biology.
Purpose of the Study:
- To investigate the tumor biology and therapeutic vulnerabilities of the SMAD4-/-/NFATc1High PDAC subgroup.
- To identify a novel therapeutic strategy for this clinically relevant PDAC subtype.
Main Methods:
- Transcriptomic and clinical data analysis for prognostic relevance.
- In vitro and in vivo studies of transcription factor complex formation (immunoprecipitation, proximity ligation assays).
- Deciphering SMAD4's impact on KRAS signaling, validated by gene expression and genetic perturbations.
- Testing a novel therapeutic option in patient-derived organoids and PDAC models.
Main Results:
- Characterized the aggressive and chemotherapy-resistant SMAD4-/-/NFATc1High PDAC subgroup.
- Identified SMAD4 deficiency as essential for an oncogenic NFATc1/SMAD3/cJUN complex driving RRM1/2 expression.
- RRM1/2 replenishes nucleosides, competing with gemcitabine for DNA incorporation.
- Mitogen-activated protein kinase (MAPK) signaling inhibition disassembled the complex, normalizing RRM1/2 and synergizing with gemcitabine.
Conclusions:
- PDAC with SMAD4 deficiency and the NFATc1/SMAD3/cJUN complex is sensitive to combined MAPK signaling inhibition and gemcitabine therapy.
- This combination therapy offers a potential targeted treatment approach for this aggressive PDAC subgroup.
Related Concept Videos
01:29Chronic Pancreatitis II: Collaborative Care
Assessment:
01:16TGF - β Signaling Pathway
02:23Abnormal Proliferation