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Profound Reprogramming towards Stemness in Pancreatic Cancer Cells as Adaptation to AKT Inhibition
Hugo Arasanz1,2, Carlos Hernández1, Ana Bocanegra1
1Oncoimmunology, Navarrabiomed-UPNA, Navarra Institute for Health Research (IdiSNA), Irunlarrea 3, 31008 Pamplona, Spain.
Abstract:
Cancer cells acquire resistance to cytotoxic therapies targeting major survival pathways by adapting their metabolism. The AKT pathway is a major regulator of human pancreatic adenocarcinoma progression and a key pharmacological target. The mechanisms of adaptation to long-term silencing of AKT isoforms of human and mouse pancreatic adenocarcinoma cancer cells were studied. Following silencing, cancer cells remained quiescent for long periods of time, after which they recovered proliferative capacities. Adaptation caused profound proteomic changes largely affecting mitochondrial biogenesis, energy metabolism and acquisition of a number of distinct cancer stem cell (CSC) characteristics depending on the AKT isoform that was silenced. The adaptation to AKT1 silencing drove most de-differentiation and acquisition of stemness through C-MYC down-modulation and NANOG upregulation, which were required for survival of adapted CSCs. The changes associated to adaptation sensitized cancer cells to inhibitors targeting regulators of oxidative respiration and mitochondrial biogenesis. In vivo pharmacological co-inhibition of AKT and mitochondrial metabolism effectively controlled pancreatic adenocarcinoma growth in pre-clinical models.
Insights
Pancreatic cancer cells adapt to AKT pathway inhibition by altering metabolism and gaining stem cell traits. Combining AKT and mitochondrial metabolism inhibitors effectively controlled tumor growth in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Metabolic Research
Background:
- The AKT pathway is crucial for pancreatic adenocarcinoma progression and a therapeutic target.
- Cancer cells develop resistance to therapies by adapting their metabolic processes.
Purpose of the Study:
- To investigate the adaptive mechanisms of pancreatic adenocarcinoma cells upon long-term silencing of AKT isoforms.
- To identify proteomic and functional changes associated with AKT pathway adaptation.
- To explore therapeutic strategies targeting adapted cancer cells.
Main Methods:
- Long-term silencing of AKT isoforms in human and mouse pancreatic adenocarcinoma cell lines.
- Proteomic analysis to identify changes in protein expression.
- Assessment of cancer stem cell (CSC) characteristics and metabolic profiles.
- In vivo studies using preclinical models to evaluate combination therapies.
Main Results:
- AKT silencing induced prolonged quiescence followed by recovery of proliferation.
- Adaptation led to significant proteomic alterations, impacting mitochondrial biogenesis and energy metabolism.
- Silencing of specific AKT isoforms resulted in distinct cancer stem cell phenotypes.
- AKT1 silencing promoted dedifferentiation and stemness via C-MYC downregulation and NANOG upregulation.
- Adapted cells showed increased sensitivity to inhibitors of oxidative respiration and mitochondrial biogenesis.
Conclusions:
- Pancreatic cancer cells adapt to AKT inhibition through metabolic reprogramming and acquisition of stem-like properties.
- Targeting both AKT and mitochondrial metabolism simultaneously offers a promising therapeutic strategy for pancreatic adenocarcinoma.
- Understanding these adaptive mechanisms is key to overcoming treatment resistance.
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