Constitutive Overexpression of STIL Protein Shortens Lifespan and Suppresses Tumor Formation in Mice

Core Concepts

Constitutive overexpression of the structural centrosome protein STIL induces centrosome amplification, aneuploidy, senescence, and apoptosis, leading to reduced lifespan and suppressed spontaneous and carcinogen-induced tumor formation in mice.

Abstract

The content analyzes the consequences of centrosome amplification induced by overexpression of the structural centrosome protein STIL in transgenic mouse models. Key highlights: STIL overexpression in mouse embryonic fibroblasts (MEFs) leads to centrosome amplification, aneuploidy, impaired proliferation, senescence, and apoptosis in a dose-dependent manner, independent of p53 status. Constitutive, global STIL overexpression in mice causes microcephaly, perinatal lethality, and shortened lifespan, but does not promote spontaneous tumor formation. Inducible, skin-specific STIL overexpression suppresses chemical skin carcinogenesis, an effect not rescued by concomitant p53 inactivation. The tumor-suppressive effects of STIL overexpression are likely due to the deleterious consequences of centrosome amplification and aneuploidy, leading to cell cycle arrest, senescence, and apoptosis. The results suggest that supernumerary centrosomes and the resulting chromosomal instability can impair proliferation and tumor formation in vivo, in contrast to the common association of centrosome amplification with human cancers.

Stats

STIL overexpression induces centrosome amplification in 80% of MEFs. STIL overexpression leads to aneuploidy in over 50% of MEFs. Median survival of CMV-STIL+/- and CMV-STIL+/+ mice is reduced by 15% compared to controls. Spontaneous tumor formation is reduced in CMV-STIL+/- and CMV-STIL+/+ mice compared to controls. Skin papilloma formation is suppressed by 55% in tamoxifen-treated K14CRE-ERT2-STIL+/- mice compared to controls.

Quotes

"Centrosome amplification is associated with a growth disadvantage in cell lines and PLK4-overexpressing MEFs." "High-level centrosome amplification can cause cell death as a consequence of multipolar mitotic divisions in vitro and in vivo, especially in cells with inefficient centrosome clustering mechanisms." "Differences in the extent of supernumerary centrosomes might therefore have contributed to the inconsistent results on tumor formation of the PLK4 mouse models."

Key Insights Distilled From

STIL overexpression shortens lifespan and reduces tumor formation in mice

by Moussa,A. T.... at www.biorxiv.org 12-05-2023

https://www.biorxiv.org/content/10.1101/2023.12.04.569842v1

Deeper Inquiries

How do the tumor-suppressive effects of STIL overexpression compare to the effects of overexpressing other centrosome regulatory proteins, such as PLK4, in mouse models?

STIL overexpression in mouse models leads to centrosome amplification, aneuploidy, senescence, apoptosis, and impaired proliferation, ultimately resulting in reduced lifespan and suppressed tumor formation. This contrasts with the effects of overexpressing PLK4, another centrosome regulatory protein, which has been shown to induce tumorigenesis in some animal models. While PLK4 overexpression can enhance spontaneous tumor formation in various tissues, including skin, STIL overexpression does not promote tumor formation in mice. Additionally, STIL overexpression causes microcephaly, perinatal lethality, and a shortened lifespan, highlighting its distinct effects compared to PLK4 overexpression.

What are the potential mechanisms by which high levels of centrosome amplification and aneuploidy can suppress tumor formation, despite their common association with human cancers?

High levels of centrosome amplification and aneuploidy can suppress tumor formation through several mechanisms. Firstly, these abnormalities can lead to cell death through multipolar mitotic divisions, especially in cells with inefficient centrosome clustering mechanisms. This cell death can act as a tumor-suppressive mechanism, preventing the survival and proliferation of cells with abnormal centrosomes. Additionally, high levels of aneuploidy and chromosomal instability can induce senescence, a state of irreversible cell cycle arrest, which can prevent the uncontrolled growth of cells and inhibit tumor formation. Furthermore, the presence of high levels of aneuploidy and chromosomal instability can lead to impaired proliferation and reduced fitness of cells, further hindering tumor development. Overall, the detrimental effects of centrosome amplification and aneuploidy on cell viability and proliferation contribute to their tumor-suppressive effects, despite their common association with cancer.

Could the insights from this study on the relationship between centrosome amplification, aneuploidy, and tumorigenesis be leveraged for the development of novel cancer therapies targeting centrosome homeostasis?

The insights from this study on the relationship between centrosome amplification, aneuploidy, and tumorigenesis could be valuable for the development of novel cancer therapies targeting centrosome homeostasis. Understanding the mechanisms by which high levels of centrosome amplification and aneuploidy suppress tumor formation can provide insights into potential therapeutic strategies. Targeting pathways involved in inducing cell death or senescence in cells with abnormal centrosomes could be explored as a way to selectively eliminate cancer cells with centrosome abnormalities. Additionally, developing drugs that specifically disrupt centrosome clustering mechanisms or interfere with the survival of cells with supernumerary centrosomes could be a promising approach for cancer therapy. By leveraging the knowledge gained from this study, researchers may be able to design targeted therapies that exploit the vulnerabilities associated with centrosome amplification and aneuploidy in cancer cells.