Hypoxia Abrogates Tumor-Suppressive Activities of C/EBPδ in Pancreatic Cancer
Leonie Hartl1,2, Marieke S Ten Brink3, Hella L Aberson1,2
1Center for Experimental and Molecular Medicine, Laboratory for Experimental Oncology and Radiobiology, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease with a low 5-year survival rate of only 13%. Despite intense research efforts, PDAC remains insufficiently understood. In part, this is attributed to opposing effects of key players being unraveled, including the stroma but also molecules that act in a context-dependent manner. One such molecule is the transcription factor C/EBPδ, where we recently showed that C/EBPδ exerts tumor-suppressive effects in PDAC cells in vitro. To better understand the role of C/EBPδ in different contexts and the development of PDAC, we here build on these findings and assess the effect of C/EBPδ in a PDAC model in mice. We establish that the lack of oxygen in vivo-hypoxia-counteracts the tumor-suppressive effects of C/EBPδ, and identify a reciprocal feedback loop between C/EBPδ and HIF-1α. RNA sequencing of C/EBPδ-induced cells under hypoxia also suggests that the growth-limiting effects of C/EBPδ decrease with oxygen tension. Consequently, in vitro proliferation assays reveal that the tumor-suppressive activities of C/EBPδ are abrogated due to hypoxia. This study demonstrates the importance of considering major physiological parameters in preclinical approaches.
Insights
Hypoxia counteracts the tumor-suppressive effects of C/EBPδ in pancreatic cancer. This study reveals a feedback loop with HIF-1α, highlighting the importance of oxygen levels in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with a 5-year survival rate of 13%.
- The role of key molecules in PDAC development is context-dependent, complicating research.
- Transcription factor C/EBPδ exhibits tumor-suppressive effects in vitro in PDAC cells.
Purpose of the Study:
- To investigate the role of C/EBPδ in a mouse model of PDAC.
- To understand how physiological conditions, specifically hypoxia, affect C/EBPδ function in PDAC.
- To elucidate the interaction between C/EBPδ and hypoxia-inducible factor 1-alpha (HIF-1α).
Main Methods:
- In vivo assessment of C/EBPδ in a mouse PDAC model.
- RNA sequencing of C/EBPδ-induced cells under hypoxic conditions.
- In vitro proliferation assays to evaluate C/EBPδ activity under varying oxygen tensions.
Main Results:
- Hypoxia in vivo counteracts the tumor-suppressive effects of C/EBPδ.
- A reciprocal feedback loop between C/EBPδ and HIF-1α was identified.
- The growth-limiting effects of C/EBPδ diminish with decreasing oxygen levels, abrogating its tumor-suppressive activity in vitro.
Conclusions:
- Physiological parameters like hypoxia significantly influence the function of tumor-associated molecules in PDAC.
- Preclinical models must account for in vivo conditions, such as oxygen tension, for accurate results.
- Understanding context-dependent molecular roles is crucial for developing effective PDAC therapies.
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