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NOTCH and AKT Signalling Interact to Drive Mammary Tumour Heterogeneity
Liliana Ordonez1, Giusy Tornillo1, Howard Kendrick1
1The European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff CF24 4HQ, UK.
Abstract:
A better understanding of the mechanisms generating tumour heterogeneity will allow better targeting of current therapies, identify potential resistance mechanisms and highlight new approaches for therapy. We have previously shown that in genetically modified mouse models carrying conditional oncogenic alleles, mammary tumour histotype varies depending on the combination of alleles, the cell type to which they are targeted and, in some cases, reproductive history. This suggests that tumour heterogeneity is not a purely stochastic process; rather, differential activation of signalling pathways leads to reproducible differences in tumour histotype. We propose the NOTCH signalling pathway as one such pathway. Here, we have crossed conditional knockout Notch1 or Notch2 alleles into an established mouse mammary tumour model. Notch1/2 deletion had no effect on tumour-specific survival; however, loss of Notch alleles resulted in a dose-dependent increase in metaplastic adenosquamous carcinomas (ASQCs). ASQCs and adenomyoepitheliomas (AMEs) also demonstrated a significant increase in AKT signalling independent of Notch status. Therefore, the NOTCH pathway is a suppressor of the ASQC phenotype, while increased PI3K/AKT signalling is associated with ASQC and AME tumours. We propose a model in which PI3K/AKT and NOTCH signalling act interact to determine mouse mammary tumour histotype.
Insights
The NOTCH pathway suppresses metaplastic adenosquamous carcinomas (ASQCs) in mouse mammary tumors. Loss of NOTCH1/2 alleles increases ASQCs, suggesting PI3K/AKT and NOTCH signaling interactions influence tumor type.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Tumor heterogeneity influences therapeutic strategies and resistance mechanisms.
- Mammary tumor histotype in mouse models depends on oncogenic alleles, cell type, and reproductive history, suggesting non-stochastic origins.
- Signaling pathways play a critical role in determining reproducible differences in tumor histotype.
Purpose of the Study:
- To investigate the role of the NOTCH signaling pathway in regulating mouse mammary tumor heterogeneity.
- To determine the effect of NOTCH1 and NOTCH2 deletion on mammary tumor development and histotype.
- To explore the relationship between NOTCH signaling, PI3K/AKT signaling, and the development of metaplastic adenosquamous carcinomas (ASQCs) and adenomyoepitheliomas (AMEs).
Main Methods:
- Utilized genetically modified mouse models with conditional knockout alleles for Notch1 or Notch2.
- Crossed these conditional knockout alleles into an established mouse mammary tumor model.
- Analyzed tumor histotype, tumor-specific survival, and AKT signaling activation in the presence and absence of NOTCH alleles.
Main Results:
- Deletion of Notch1/2 alleles did not impact tumor-specific survival.
- Loss of NOTCH alleles led to a dose-dependent increase in metaplastic adenosquamous carcinomas (ASQCs).
- ASQCs and adenomyoepitheliomas (AMEs) showed increased AKT signaling, irrespective of NOTCH status.
Conclusions:
- The NOTCH pathway acts as a suppressor of the ASQC phenotype in mouse mammary tumors.
- Increased PI3K/AKT signaling is significantly associated with ASQC and AME tumor development.
- A model is proposed where PI3K/AKT and NOTCH signaling pathways interact to determine mouse mammary tumor histotype.
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