Stem Cell Tumors: Cherub versus brat
How healthy cells become tumors is a question that has interested scientists for decades. Many tumors exhibit genomic instability – that is, increased numbers of DNA mutations and chromosomal rearrangements. However, some tumors – including most childhood cancers – have few mutations and are thought to be driven by mechanisms other than genomic instability (Lee et al., 2012).
Important cancer research in flies has been carried out using neural stem cells called neuroblasts. Normally, a type of neuroblast called a Type II neuroblast divides asymmetrically to form a new neuroblast and a slightly more specialized cell type called an intermediate neural progenitor cell (INP); the new neuroblast is able to repeat this process several times. In parallel, the INP continues to divide to produce a new INP and a neuronal precursor cell in each round (Bello et al., 2008; Boone and Doe, 2008; Bowman et al., 2008, Figure 1A). The neuronal precursor then divides to generate mature neurons. When a tumor suppressor gene called brat is blocked, INPs transform back into tumor neuroblasts that divide indefinitely (Lee et al., 2006). So far, the mechanisms involved have remained unclear.

Misregulation of cherub RNA causes tumor growth.
Neurons develop from neural stem cells called neuroblasts and specialized cells called intermediate neural progenitor (INP) cells. Landskron et al. found that a long non-coding RNA (lncRNA) named cherub has a role in the development of brain tumors. (A) In healthy flies, the protein Staufen (yellow half circle) anchors cherub (red half circle) to the basal part of the neuroblast cell membrane. After the neuroblast divides, cherub is inherited in the INP cell and spreads within it. As neuroblasts mature, they start to produce the protein Syncrip (Syp: green), which reduces the levels of a protein called Imp (blue). (B) In flies that lack the tumor suppressor gene brat, cherub remains at the cell membrane of the INP cells. When Syp is expressed as the neuroblast ages, it also remains anchored to cell membrane of the neuroblast by cherub and Staufen. This prevents Syp from repressing Imp, and some of the INP cells develop into tumor neuroblasts. (C) In flies that lack brat and cherub, cherub can no longer tether Syp; this allows Syp to inhibit Imp, and the neuroblasts are able to mature.
Now, in eLife, Jürgen Knoblich and colleagues at the IMBA in Vienna and the University of Basel – including Lisa Landskron as first author – report that genomic instability is not a driver of neuroblast tumors (Landskron et al., 2018). Landskron et al. compared healthy flies and flies in which the brat gene had been mutated and showed that both groups of flies had the same number of chromosomes. Moreover, they found no additional DNA mutations responsible for tumor development.
However, further analyzes revealed that the tumor cells had increased levels of a previously uncharacterized long non-coding RNA: this is a molecule that is transcribed from DNA but is not usually translated into protein. Landskron et al. found that this specific long non-coding RNA, which they named cherub, was not required for normal development, as mutant flies lacking cherub were healthy and fertile. However, flies with a defect in both the brat gene and the cherub gene had smaller tumors, which suggests that cherub is required for tumor progression.
While other long non-coding RNAs have been implicated in tumor growth, cherub is the first to be discovered that is not uniformly distributed throughout the cell. Rather, cherub is located at the basal end of the neuroblast cell membrane. When healthy neuroblasts divide, cherub is distributed into the INP, which forms on the basal side of the neuroblast, and then diffuses throughout the cell. Thus, with each round of division, cherub levels slowly decrease in the INP (Figure 1A). In brat mutants, however, cherub remains at the cell membrane in both the neuroblast and in the INP. This faulty localization prevents the dilution of cherub and causes the INP to transform back into a tumor neuroblast (Figure 1B).
Why does the incorrect localization of cherub cause tumor growth? In fly neuroblasts, the proteins Imp and Syncrip regulate neuroblast aging (Ren et al., 2017). Normally, these two proteins inhibit each other: Syncrip levels increase as the neuroblasts age, while Imp levels decrease. Both the expression of Syncrip and the absence of Imp are required for neuroblasts to stop dividing (Yang et al., 2017, Figure 1A).
Landskron et al. showed that in flies lacking brat, Syncrip and cherub are inappropriately localized at the tumor neuroblast cell membrane. Moreover, Syncrip and Imp are both expressed. This is presumably because newly-produced Syncrip remains tethered to cherub at the cell membrane, where it is unable to reduce Imp levels (Figure 1B). Thus, the tumors continually produce Imp and do not age. When cherub is not present, Syncrip remains distributed throughout the cell. This reduces the levels of Imp which, in turn, slows the growth of any tumor and improves the life expectancy of brat mutant flies (Figure 1C). How does cherub localize to the cell membrane? The experiments revealed that cherub binds to another protein called Staufen, which attaches to the asymmetric cell division machinery, and thus tethers both cherub and Syncrip to the cell membrane.
This work reinforces the notion that changes to the proteins that regulate asymmetric cell division and cell fate can drive tumor formation. Previous research has shown that Imp levels are also dependent on another protein called Chinmo, and that overexpression of Chinmo causes tumor growth by maintaining inappropriately high Imp levels during the window when Imp is normally expressed (Narbonne-Reveau et al., 2016). Thus, preventing stem cells from maturing and aging appears to fuel tumor development.
This study also highlights the importance of long non-coding RNAs in stem cell development and in tumor formation. While it has been shown that other long non-coding RNAs are involved in stem cell development, this may be one of the first examples where changing the localization of such molecules prevents stem cells from aging, thus driving tumor growth (Guttman et al., 2011). It will be interesting to see whether other long non-coding RNAs use the same mechanisms to drive tumorigenesis.
References
-
Identification of Drosophila type II neuroblast lineages containing transit amplifying ganglion mother cellsDevelopmental Neurobiology 68:1185–1195.https://doi.org/10.1002/dneu.20648
-
A remarkably simple genome underlies highly malignant pediatric rhabdoid cancersJournal of Clinical Investigation 122:2983–2988.https://doi.org/10.1172/JCI64400
Article and author information
Author details
Publication history
Copyright
© 2018, Malin et al.
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 1,480
- views
-
- 120
- downloads
-
- 1
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Cancer Biology
Why does a normal cell possibly harboring genetic mutations in oncogene or tumor suppressor genes becomes malignant and develops a tumor is a subject of intense debate. Various theories have been proposed but their experimental test has been hampered by the unpredictable and improbable malignant transformation of single cells. Here, using an optogenetic approach we permanently turn on an oncogene (KRASG12V) in a single cell of a zebrafish brain that, only in synergy with the transient co-activation of a reprogramming factor (VENTX/NANOG/OCT4), undergoes a deterministic malignant transition and robustly and reproducibly develops within 6 days into a full-blown tumor. The controlled way in which a single cell can thus be manipulated to give rise to cancer lends support to the ‘ground state theory of cancer initiation’ through ‘short-range dispersal’ of the first malignant cells preceding tumor growth.
-
- Cancer Biology
Most human pancreatic ductal adenocarcinoma (PDAC) are not infiltrated with cytotoxic T cells and are highly resistant to immunotherapy. Over 90% of PDAC have oncogenic KRAS mutations, and phosphoinositide 3-kinases (PI3Ks) are direct effectors of KRAS. Our previous study demonstrated that ablation of Pik3ca in KPC (KrasG12D; Trp53R172H; Pdx1-Cre) pancreatic cancer cells induced host T cells to infiltrate and completely eliminate the tumors in a syngeneic orthotopic implantation mouse model. Now, we show that implantation of Pik3ca−/− KPC (named αKO) cancer cells induces clonal enrichment of cytotoxic T cells infiltrating the pancreatic tumors. To identify potential molecules that can regulate the activity of these anti-tumor T cells, we conducted an in vivo genome-wide gene-deletion screen using αKO cells implanted in the mouse pancreas. The result shows that deletion of propionyl-CoA carboxylase subunit B gene (Pccb) in αKO cells (named p-αKO) leads to immune evasion, tumor progression, and death of host mice. Surprisingly, p-αKO tumors are still infiltrated with clonally enriched CD8+ T cells but they are inactive against tumor cells. However, blockade of PD-L1/PD1 interaction reactivated these clonally enriched T cells infiltrating p-αKO tumors, leading to slower tumor progression and improve survival of host mice. These results indicate that Pccb can modulate the activity of cytotoxic T cells infiltrating some pancreatic cancers and this understanding may lead to improvement in immunotherapy for this difficult-to-treat cancer.