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PI3K in stemness regulation: from development to cancer
1UCL Cancer Institute, Paul O'Gorman Building, University College London, 72 Huntley Street, London WC1E 6DD, U.K.
Abstract:
The PI3K/AKT pathway is a key target in oncology where most efforts are focussed on phenotypes such as cell proliferation and survival. Comparatively, little attention has been paid to PI3K in stemness regulation, despite the emerging link between acquisition of stem cell-like features and therapeutic failure in cancer. The aim of this review is to summarise current known and unknowns of PI3K-dependent stemness regulation, by integrating knowledge from the fields of developmental, signalling and cancer biology. Particular attention is given to the role of the PI3K pathway in pluripotent stem cells (PSCs) and the emerging parallels to dedifferentiated cancer cells with stem cell-like features. Compelling evidence suggests that PI3K/AKT signalling forms part of a 'core molecular stemness programme' in both mouse and human PSCs. In cancer, the oncogenic PIK3CAH1047R variant causes constitutive activation of the PI3K pathway and has recently been linked to increased stemness in a dose-dependent manner, similar to observations in mouse PSCs with heterozygous versus homozygous Pten loss. There is also evidence that the stemness phenotype may become 'locked' and thus independent of the original PI3K activation, posing limitations for the success of PI3K monotherapy in cancer. Ongoing therapeutic developments for PI3K-associated cancers may therefore benefit from a better understanding of the pathway's two-layered and highly context-dependent regulation of cell growth versus stemness.
Insights
The PI3K/AKT pathway regulates stemness in both pluripotent stem cells and cancer cells. Understanding this link is crucial for developing effective cancer therapies, as stemness can become treatment-resistant.
Area of Science:
- Oncology
- Developmental Biology
- Cell Signalling
Background:
- The PI3K/AKT pathway is a primary target in cancer, mainly studied for its role in cell proliferation and survival.
- Less attention has been given to the PI3K pathway's role in regulating stemness, despite its connection to therapeutic failure in cancer.
- Acquisition of stem cell-like features in cancer is increasingly linked to poor treatment outcomes.
Purpose of the Study:
- To review the known and unknown aspects of PI3K-dependent stemness regulation.
- To integrate knowledge from developmental, signalling, and cancer biology.
- To explore parallels between pluripotent stem cells (PSCs) and cancer stem cells.
Main Methods:
- Literature review integrating findings from developmental biology, signalling pathways, and cancer research.
- Analysis of the PI3K pathway's role in both mouse and human pluripotent stem cells (PSCs).
- Examination of cancer studies involving PI3K pathway activation and stemness phenotypes.
Main Results:
- PI3K/AKT signalling is integral to a core molecular stemness program in PSCs.
- Constitutive PI3K pathway activation, e.g., via PIK3CAH1047R, increases cancer stemness in a dose-dependent manner.
- Cancer stemness may become "locked" and independent of PI3K activation, limiting monotherapy efficacy.
Conclusions:
- The PI3K pathway plays a critical role in regulating stemness in both normal and cancerous cells.
- Understanding the dual role of PI3K in cell growth and stemness is essential for advancing cancer therapeutics.
- Context-dependent regulation of PI3K is key to overcoming therapeutic resistance driven by cancer stemness.
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