Abstract
Cell invasion is defined by the capability of cells to migrate across compartment boundaries established by basement membranes (BMs). The development of complex organs involves regulated cell growth and regrouping of different cell types, which are enabled by controlled cell proliferation and cell invasion. Moreover, when a malignant tumor takes control over the body, cancer cells evolve to become invasive, allowing them to spread to distant sites and form metastases. At the core of the switch between proliferation and invasion are changes in cellular morphology driven by remodeling of the cytoskeleton. Proliferative cells utilize their actomyosin network to assemble a contractile ring during cytokinesis, while invasive cells form actin-rich protrusions, called invadopodia that allow them to breach the BMs. Studies of developmental cell invasion as well as of malignant tumors revealed that cell invasion and proliferation are two mutually exclusive states. In particular, anchor cell (AC) invasion during Caenorhabditis elegans larval development is an excellent model to study the transition from cell proliferation to cell invasion under physiological conditions. This mini-review discusses recent insights from the C. elegans AC invasion model into how G1 cell-cycle arrest is coordinated with the activation of the signaling networks required for BM breaching. Many regulators of the proliferation-invasion network are conserved between C. elegans and mammals. Therefore, the worm may provide important clues to better understand cell invasion and metastasis formation in humans.
Highlights
anchor cell (AC) invasion in Caenorhabditis elegans is an excellent model to investigate the various checkpoints regulating developmental cell invasion, including G1 cell cycle arrest required for basement membranes (BMs) breaching (Matus et al, 2015; Deng et al, 2020; Medwig-Kinney et al, 2020)
While egl-43 and hlh-2 are important for the AC/ventral uterine (VU) fate decisions, they later play a central role in inducing the invasive AC fate by enabling G1 cell cycle arrest and activating the expression of pro-invasive genes, which are controlled by the C. elegans ortholog of human FOS fos-1 (Sherwood et al, 2005) (Figure 2)
The C. elegans AC is an excellent model to investigate the various aspects underlying the complex process of cell invasion using an integrated approach by simultaneously examining: (1) cell fate acquisition, (2) establishment and maintenance of cell cycle arrest, (3) epigenetic and transcription factor networks that induce a pro-invasive gene expression pattern, (4) generation of extracellular cues that guide invading cells, (5) formation of invasive protrusions and (6) BM breaching
Summary
AC invasion in Caenorhabditis elegans is an excellent model to investigate the various checkpoints regulating developmental cell invasion, including G1 cell cycle arrest required for BM breaching (Matus et al, 2015; Deng et al, 2020; Medwig-Kinney et al, 2020). While egl-43 and hlh-2 are important for the AC/VU fate decisions, they later play a central role in inducing the invasive AC fate by enabling G1 cell cycle arrest and activating the expression of pro-invasive genes, which are controlled by the C. elegans ortholog of human FOS fos-1 (Sherwood et al, 2005) (Figure 2). Two distinct mechanisms ensure G1 arrest of the AC; EGL-43 inhibits S-phase entry by repressing Notch signaling, while NHR-67 maintains the G1 arrest of the AC by activating CKI-1 expression This double authentication system established by NHR-67 and EGL-43-mediated cell cycle inhibition may add the developmental robustness necessary for the AC to adopt a stable invasive fate. Hlh-2 might integrate developmental timing with spatial cues to program the AC for the G1-arrested invasive state
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