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Spindle orientation, asymmetric division and tumour suppression in Drosophila stem cells

Key Points

  • Adult tissues are maintained by the proliferation of tissue stem cells that constitute only a small fraction of the total cell mass. The same applies to some tumours: a small number of cancer stem cells (CSCs) are able to sustain long-term tumour growth.

  • Being immortal, mitotically competent and located in tissues in which tumours appear, stem cells are likely candidates to initiate tumor growth. Consistently, CSCs that are isolated from different tumours have been shown to bear surface markers that are unique to the normal stem cells from the tissues in which the tumours arose.

  • Stem cells can undergo self-renewing asymmetric cell division to produce two unequal daughters; one enters a programme of differentiation, whereas the other retains stem-cell identity.

  • Using Drosophila melanogaster neuroblasts and male germline stem cells (mGSCs) as model stem cells, recent studies have revealed that mutation in any of several genes that are involved in this asymmetric division leads to overgrowth.

  • Proper spindle alignment is key for the correct implementation of the unequal fate of the stem-cell daughters. In both neuroblasts and mGSCs, the two centrosomes are unequal. One is a constitutively active microtubule-organizing centre (MTOC), which remains apical and stays in the stem cell after division; the other is active only during mitosis, when it is localized basally and inherited by the differentiating cell.

  • Consistent with the key role of spindle orientation during stem-cell asymmetric cell division, some mutations that impair spindle orientation in neuroblasts and mGSCs result in overgrowth.

  • Implantation of fly tumours in adult hosts provides a rigorous test to distinguish between hyperplastic, benign and malignant neoplastic growth. It also provides a means to age D. melanogaster tumours over extended periods of time, allowing for complex traits like metastasis and genome instability to appear, thus affording a more realistic model of tumour progression.

  • On the basis of recent data, a new hypothesis is put forward whereby centrosome abnormalities could have a role in tumour development — not by causing aneuploidy, as proposed by the classical Boveri's hypothesis, but through failed cell-fate determination during stem-cell asymmetric division.

  • Some of the issues that remain open for further investigation are: the actual mechanism by which misdetermined cell fate results in overgrowth; how complex traits like metastasis and genome instability appear in these tumours, and the contribution of genome instability to tumour progression; the role of CSCs in fly tumours; the molecular mechanisms that control spindle alignment in stem cells; other possible aspects of functional asymmetry in stem cells; and the extent to which these conclusions apply to tumours in vertebrates.

Abstract

Recent genetic studies in flies have added further support to an increasing body of evidence that suggests that stem cells might be the cell-of-origin of certain tumours. Malfunction of the mechanisms that control the division of stem cells and the developmental fate of the two resulting daughters could be one of the initial events that steers cells into malignant transformation. These studies suggest a role for controlled spindle orientation in suppressing stem-cell overgrowth. In parallel, the machinery that drives asymmetry in stem cells has been further characterized, identifying new components and uncovering the unique, highly sophisticated behaviour of centrosomes in these cells.

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Figure 1: Asymmetric division of neuroblasts and male germline stem cells (mGSC) in Drosophila melanogaster.
Figure 2: Spindle orientation and stem-cell overgrowth in Drosophila melanogaster mutants.

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Acknowledgements

The help received from M. Calleja, E. Castellanos, E. Aguilar, L. Mendizabal and A. Janic, the comments on a first draft from P. Dominguez and J. Janushke, and the input provided by all members of my laboratory are very much appreciated. I am also indebted to A. Martinez-Arias and M. González-Gaitán who provided extensive criticism that contributed significantly to shaping this Review. Research in my laboratory is supported by grants from the European Union, the Spanish Government and the Generalitat de Catalunya.

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Glossary

Spindle alignment

The fixed orientation of the cell-division spindle with respect to certain cell-polarity cues.

Centrosomes

The main microtubule-organizing centre of most animal cells, typically composed of two orthogonally arranged centrioles that are surrounded by a meshwork of pericentriolar material.

Boveri's hypothesis

States that numerical and/or structural centrosome abnormalities that cause chromosome missegregation might be the origin of cancer.

Progenitor cells

Partially committed, undifferentiated cells that retain certain plasticity (or multipotency) and limited self-renewal capability.

Neoplastic transformation

A process by which normal cells start to grow out of control.

Micrometastases

Small colonies of cancerous cells originally derived from cells that migrated away from the primary, much larger tumour.

Transdetermination

An occasional process in which cells of cultured fly imaginal discs switch to a different developmental fate.

Imaginal discs

Disc-shaped structures in holometabolous insects such as Drosophila melanogaster that are set aside during embryogenesis, grow during the larval stages and differentiate to form the adult epidermal structures during metamorphosis.

Mushroom body

A structure of the adult Drosophila melanogaster brain that is required for olfactory learning and memory.

Spindle asters

Star-shaped clusters of microtubules that radiate from the centrosomes during cell division.

Pericentriolar material

The meshwork that surrounds the centrioles and contains the microtubule-nucleating activity of the centrosome.

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Gonzalez, C. Spindle orientation, asymmetric division and tumour suppression in Drosophila stem cells. Nat Rev Genet 8, 462–472 (2007). https://doi.org/10.1038/nrg2103

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