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Review
. 2022 Aug 3;23(15):8622.
doi: 10.3390/ijms23158622.

Cell Architecture-Dependent Constraints: Critical Safeguards to Carcinogenesis

Komal Khalil  1   2   3 , Alice Eon  1   2   4 , Florence Janody  1   2
Affiliations
Review

Cell Architecture-Dependent Constraints: Critical Safeguards to Carcinogenesis

Komal Khalil et al. Int J Mol Sci. .

Abstract

Animal cells display great diversity in their shape. These morphological characteristics result from crosstalk between the plasma membrane and the force-generating capacities of the cytoskeleton macromolecules. Changes in cell shape are not merely byproducts of cell fate determinants, they also actively drive cell fate decisions, including proliferation and differentiation. Global and local changes in cell shape alter the transcriptional program by a multitude of mechanisms, including the regulation of physical links between the plasma membrane and the nuclear envelope and the mechanical modulation of cation channels and signalling molecules. It is therefore not surprising that anomalies in cell shape contribute to several diseases, including cancer. In this review, we discuss the possibility that the constraints imposed by cell shape determine the behaviour of normal and pro-tumour cells by organizing the whole interconnected regulatory network. In turn, cell behaviour might stabilize cells into discrete shapes. However, to progress towards a fully transformed phenotype and to acquire plasticity properties, pro-tumour cells might need to escape these cell shape restrictions. Thus, robust controls of the cell shape machinery may represent a critical safeguard against carcinogenesis.

Keywords: Waddington’s landscape; carcinogenesis; cell fate; cell shape; cell-intrinsic forces; cytoskeleton macromolecules; signalling networks.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the writing of the manuscript or in the decision to publish this review.

Figures

Figure 1
Figure 1
Examples of mechanisms by which cell shape regulates gene transcription. (a) Forces transmitted from the cell surface to the nuclear envelope through MFs, MTs or IFs can alter chromatin organization, the accessibility of transcription and other chromatin regulatory factors, as well as stretch nuclear pores to facilitate the transport of molecules. (b) Alteration of surface tension, bending of the membrane or forces applied on F-actin beneath the plasma membrane can mechanically activate calcium channels. (c) Stretching of the membrane can also induce tension on actomyosin, which can unfold proteins, exposing their substrate sites and induce signalling to the nucleus. (d) Cell shape-dependent alterations of the membrane and of the actin cytoskeleton can alter lipid raft micro-domains within the plasma membrane and activate signalling pathways. (e) Shape-dependent alteration of cell surface tension can activate signalling pathways by stimulating the rate of endocytosis.
Figure 2
Figure 2
Schematic inspired by Waddington’s epigenetic landscape depicting how cell shape could act as an attractor to control the fate of normal and cancer cells. (Middle landscape) Each ball moving into the valleys represents a cell defined by its specific shape and network state represented in the boxes on the left and right of the landscape. The blue balls on the left are normal cells. The pink balls on the right are cancer cells. (Left) The shape of normal cells determines which valley will be taken by the cell (black arrows) to reach specific basins of attraction. Cell shape 1 and 2 control specific regulatory interaction networks, which trigger phenotype 1 and 2, respectively. Each regulatory network also stabilizes cell shapes 1 and 2, respectively (pink arrows). Changes in cell shape could trigger cell reprogramming by which a cell climbs up on the landscape and falls down into another basin of attraction (plain blue arrows). These cell shape-dependent phenotypic reversions could rely on the climbing distance and depth of the initial basin of attraction. If it is modest, reversion will be easily attainable (plain blue arrows). However, if it is important, reversion would be less likely (dashed blue arrows). (Right) Cells suffering anomalies in their shape (cell shape 3 and 4) and/or acquiring mutations in oncogenic signalling components (pink spots) could climb up the hill and fall down into other basins of attraction (plain green arrow), for example by reacquiring proliferative abilities. To attain basins of attraction that require higher distances to climb up, cells may need to acquire additional cellular alterations (dashed green arrows). During cancer progression, alterations of the regulatory network could inhibit the cell shape-dependent control (pink inhibitions in the upper right box). By escaping the restrictions imposed by cell shape, cells could reach new attractors not attained by normal cells (pink arrows).
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