Mitosis-induced Nuclear Adaptation in Cancer Cells under Prolonged Confinement

Core Concepts

Mitosis drives nuclear adaptation in cancer cells under prolonged confinement, regulating volume and tension.

Abstract

Abstract: Mammalian cells face mechanical constraints, with the nucleus playing a key role. Mitosis induces long-term nuclear adaptation to uniaxial confinement in colorectal cancer cells. Mechanism involves cPLA2 and contractility machinery for nuclear tension regulation. Significance Statement: Cell deformation is crucial for cell function, with the nucleus being central. Study reveals mechano-adaptation during mitosis leading to decreased nuclear size. Introduction: Mechanical properties of tumor microenvironment influence cancer cell behavior. Changes in mechanical stress impact cell proliferation and gene expression. Alleviating mechanical stress is considered a therapeutic strategy. Results: Cancer cells adapt to prolonged confinement by altering nuclear volume. Nuclear volume decreases during mitosis under confinement, reaching homeostasis. Mitotic regulation of nuclear volume is crucial for long-term adaptation. Discussion: Mitosis plays a key role in regulating nuclear volume and tension under confinement. Inhibition of cPLA2 or actomyosin contractility prevents nuclear adaptation. Regulation of DNA damage repair mechanism associated with lamin folding and nuclear volume loss. Outlooks: Further investigation into molecular pathways involved in nuclear adaptation is warranted. Role of lamins, p53 mutations, and nucleocytoplasmic transport should be explored for implications in cancer therapy.

Stats

Cells displayed a decrease in cell and nuclear height according to levels of confinement (Fig. 1D-E). Loss of nuclear volume from 20% to 34% observed after 24 h of confinement (Fig. 1H). Nuclei were smaller after first division under confinement, with up to 60% loss in volume (Fig. 2A). No further loss of nuclear volume observed after second division under confinement (Fig. 2B).

Quotes

"Mechanical constraints on mammalian cells highlight the role of the nucleus." "Nuclear adaptation through mitosis crucial for long-term response to confinement."

Key Insights Distilled From

Mitosis sets nuclear homeostasis of cancer cells under confinement

by Mouelhi,M., ... at www.biorxiv.org 05-14-2023

https://www.biorxiv.org/content/10.1101/2023.05.11.540326v2

Deeper Inquiries

How does the regulation of apparent surface area impact cellular responses beyond mitosis?

The regulation of the apparent surface area plays a crucial role in determining cellular responses beyond mitosis. By adjusting the nuclear envelope tension through changes in the apparent surface area, cells can influence various aspects of cell behavior and function. For example: Mechanosensing: The apparent surface area is linked to mechanosensing mechanisms within the cell. Changes in nuclear tension affect how cells respond to mechanical cues from their environment, influencing processes such as migration, proliferation, and differentiation. Gene Expression: Alterations in nuclear volume and tension impact gene expression patterns by modulating chromatin organization and accessibility. Changes in the apparent surface area can therefore regulate transcriptional activity and downstream cellular functions. Cellular Homeostasis: Maintaining a balanced nuclear volume through regulating the apparent surface area is essential for overall cellular homeostasis. Disruptions in this balance can lead to aberrant cell behaviors and potential pathologies. In summary, the regulation of the apparent surface area post-mitosis has far-reaching implications on cellular functions by influencing mechanosensitivity, gene expression profiles, and overall cellular homeostasis.

How might understanding nucleocytoplasmic transport shed light on novel therapeutic strategies against tumor cells?

Understanding nucleocytoplasmic transport provides valuable insights into cancer biology that could inform novel therapeutic strategies against tumor cells: Targeting Nuclear-Cytoplasmic Shuttling: Dysregulation of nucleocytoplasmic transport is common in cancer cells and contributes to oncogenesis. Targeting key molecules involved in this process could disrupt cancer cell proliferation or survival pathways. Modulating Transcription Factor Activity: Many transcription factors are regulated by their shuttling between nucleus and cytoplasm; manipulating these shuttling dynamics could alter gene expression programs critical for tumorigenesis. Drug Delivery Optimization: Nucleocytoplasmic transport influences drug uptake into cancer cells; understanding these mechanisms can help optimize drug delivery strategies for enhanced efficacy. By delving deeper into nucleocytoplasmic transport processes disrupted in cancer cells, researchers may uncover new targets for therapy development aimed at disrupting oncogenic signaling pathways or enhancing drug delivery specifically to tumor sites.

What implications could altered lamins and p53 mutations have on cancer cell response to mechanical stress?

Altered lamins (such as lamin A/C) levels along with p53 mutations can significantly impact how cancer cells respond to mechanical stress: Nuclear Stability: Lamins provide structural support to the nucleus; alterations may weaken nuclear integrity leading to increased susceptibility to deformation under mechanical stress. 2..DNA Damage Response: Mutant p53 impairs DNA damage repair mechanisms which are often activated due to mechanical stress-induced genomic instability resulting from altered lamina structure 3..Metastatic Potential: Changes induced by altered lamins coupled with dysfunctional p53 may enhance invasive properties allowing metastatic spread under conditions like confined microenvironments Overall, these alterations create vulnerabilities that tumors exploit but also present opportunities for targeted therapies aimed at exploiting weaknesses arising from abnormal lamin-p53 interactions under conditions of elevated mechanical forces like those found within solid tumors or during metastatic dissemination