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KRAS protein expression becomes progressively restricted during embryogenesis and in adulthood
Marie-Albane Minati1, Mohamad Assi1, Maxime Libert1
1Université catholique de Louvain, de Duve Institute, Liver and Pancreas Differentiation Unit, Brussels, Belgium.
Abstract:
KRAS mutants are common in many cancers and wild-type KRAS is essential in development as its absence causes embryonic lethality. Despite this critical role in development and disease, the normal expression pattern of KRAS protein is still largely unknown at the tissue level due to the lack of valid antibodies. To address this issue, we used the citrine-Kras mouse model in which the Citrine-KRAS (Cit-K) fusion protein functions as a validated surrogate of endogenous KRAS protein that can be detected on tissue sections by immunolabeling with a GFP antibody. In the embryo, we found expression of KRAS protein in a wide range of organs and tissues. This expression tends to decrease near birth, mainly in mesenchymal cells. During transition to the adult stage, the dynamics of KRAS protein expression vary among organs and detection of KRAS becomes restricted to specific cell types. Furthermore, we found that steady state KRAS protein expression is detectable at the cell membrane and in the cytoplasm and that this subcellular partitioning differed among cell types. Our results reveal hitherto unanticipated dynamics in developmental, tissular, cell-specific and subcellular expression of KRAS protein. They provide insight into the reason why specific cell-types are sensitive to KRAS mutations during cancer initiation.
Insights
Understanding KRAS protein expression is key for cancer research. This study reveals KRAS protein dynamics across development and tissues using a novel mouse model, offering insights into cancer initiation.
Area of Science:
- Molecular Biology
- Developmental Biology
- Cancer Biology
Background:
- KRAS mutations are prevalent in human cancers.
- Wild-type KRAS is crucial for embryonic development.
- Normal KRAS protein expression patterns remain largely uncharacterized at the tissue level due to antibody limitations.
Purpose of the Study:
- To investigate the normal expression patterns of KRAS protein during embryonic development and in adult tissues.
- To identify specific cell types and subcellular localizations of KRAS protein.
- To provide a foundation for understanding KRAS-driven oncogenesis.
Main Methods:
- Utilized the citrine-Kras mouse model, where Citrine-KRAS fusion protein serves as a surrogate for endogenous KRAS.
- Employed immunolabeling with a GFP antibody to detect Citrine-KRAS on tissue sections.
- Analyzed KRAS protein expression dynamics during embryonic development, near birth, and in adult tissues.
Main Results:
- Detected KRAS protein expression across a broad spectrum of embryonic organs and tissues.
- Observed a decrease in KRAS expression near birth, particularly in mesenchymal cells.
- Found that KRAS expression becomes restricted to specific cell types in adults, with varying subcellular localization (cell membrane and cytoplasm) across different cell types.
Conclusions:
- Revealed previously unknown developmental, tissular, cell-specific, and subcellular expression dynamics of KRAS protein.
- The findings offer critical insights into why certain cell types are susceptible to KRAS mutations during cancer initiation.
- Establishes a valuable resource for future research on KRAS function and its role in cancer.
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