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Review
. 2024 Jun 8;13(6):425.
doi: 10.3390/biology13060425.

C. elegans Germline as Three Distinct Tumor Models

Mariah Jones  1 , Mina Norman  1 , Alex Minh Tiet  2   3 , Jiwoo Lee  3 , Myon Hee Lee  1   3
Affiliations
Review

C. elegans Germline as Three Distinct Tumor Models

Mariah Jones et al. Biology (Basel). .

Abstract

Tumor cells display abnormal growth and division, avoiding the natural process of cell death. These cells can be benign (non-cancerous growth) or malignant (cancerous growth). Over the past few decades, numerous in vitro or in vivo tumor models have been employed to understand the molecular mechanisms associated with tumorigenesis in diverse regards. However, our comprehension of how non-tumor cells transform into tumor cells at molecular and cellular levels remains incomplete. The nematode C. elegans has emerged as an excellent model organism for exploring various phenomena, including tumorigenesis. Although C. elegans does not naturally develop cancer, it serves as a valuable platform for identifying oncogenes and the underlying mechanisms within a live organism. In this review, we describe three distinct germline tumor models in C. elegans, highlighting their associated mechanisms and related regulators: (1) ectopic proliferation due to aberrant activation of GLP-1/Notch signaling, (2) meiotic entry failure resulting from the loss of GLD-1/STAR RNA-binding protein, (3) spermatogenic dedifferentiation caused by the loss of PUF-8/PUF RNA-binding protein. Each model requires the mutations of specific genes (glp-1, gld-1, and puf-8) and operates through distinct molecular mechanisms. Despite these differences in the origins of tumorigenesis, the internal regulatory networks within each tumor model display shared features. Given the conservation of many of the regulators implicated in C. elegans tumorigenesis, it is proposed that these unique models hold significant potential for enhancing our comprehension of the broader control mechanisms governing tumorigenesis.

Keywords: C. elegans germline; GLD-1; GLP-1/Notch signaling; PUF-8; RNA-binding proteins; tumorigenesis.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
C. elegans germline and three distinct tumor models. (A) Schematics of adult C. elegans and its germline. Germ cells at the distal end of the germline, including GSCs, divide mitotically (yellow). As germ cells move proximally, they enter meiosis (green) and differentiate into either oocytes (pink) or sperm (blue). (B) Schematics of normal hermaphrodite germline and three tumor germline models resulting from glp-1 gain-of-function (gf), gld-1 loss-of-function (lf), or puf-8 loss-of-function mutation (lf). (C,D) Normal and tumor germlines. Wild-type (N2) and tumor germlines were stained with anti-HIM-3 (meiosis marker) antibodies and DAPI (DNA marker).
Figure 2
Figure 2
Notch signaling and its regulators. (A) Conserved Notch signaling pathways. Upon signaling, cleaved NICD translocates from the membrane to the nucleus. In the nucleus, NICD forms a tertiary complex with CSL and a co-activator (MSML, Mastermind-like protein), activating the expression of target genes. (B) C. elegans GLP-1/Notch signaling pathways. The DTC expresses GLP-1/Notch ligands (e.g., LAG-2) and employs GLP-1/Notch signaling to promote continued mitotic division of GSCs. (C) Positive and negative regulators of GLP-1/Notch signaling.
Figure 3
Figure 3
GLD-1 translational repressor and its regulators. (A) Schematic of GLD-1 binding to the regulatory element(s) (gray boxes) on the 5′ or 3′ UTRs of target mRNAs (a black line). GLD-1 generally represses the translation of target mRNAs. A predicted GLD-1 3D protein structure was generated using the AlphaFold Protein Structure Data Base [57]. (B) Positive and negative regulators of GLD-1.
Figure 4
Figure 4
PUF-8 translational repressor and its regulators. (A) Schematic of PUF-8 binding to the regulatory element(s) (a gray box) on the 3′ UTR of target mRNAs (a black line). PUF-8 generally represses the translation of target mRNAs. A predicted PUF-8 3D protein structure was generated using the AlphaFold Protein Structure Data Base [57]. (B) The PUF protein family is widely distributed throughout eukaryotes. (C) Role of PUF-8 and its genetic partners in differentiation/dedifferentiation decisions.
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