Incorrect number of chromosomes, gene-dosage imbalance and cancer

Marco Milán & Ángel R. Nebreda – Institut de Recerca Biomèdica (IRB Barcelona)

Genomic instability was originally proposed to cause cancer over 100 years ago and it has been observed in most solid tumors. There are various forms of genomic instability and the most common in cancer is chromosomal instability (CIN), which refers to the high rate by which chromosome structure and number changes over time in cancer cells compared to normal cells. While CIN contributes to the gain or loss of chromosomes carrying oncogene or tumor-suppressor genes, respectively, errors in chromosome segregation cause DNA damage and chromosomal rearrangements, and the resulting aneuploidy, defined as an abnormal number of chromosomes or parts of them, compromises cell fitness.

Marco Milán and colleagues have used the wing primordia of Drosophila to molecularly dissect the cellular and tissue-wide effects of CIN-induced aneuploidy. These wing primordia grow from 20 to 30,000 cells in 4 days and provide the advantage that individual cells can be tracked and the tissue can be manipulated genetically in a temporal and spatial manner. Previous work from the lab has shown that CIN-induced aneuploid cells are removed from the tissue by JNK-dependent apoptosis. When highly aneuploid cells are prevented from entering apoptosis, JNK drives the expression of mitogenic molecules and matrix-metalloproteases and induces tumor-like tissues that grow extensively, cause malignancy to the host and metastasize when transplanted into the abdomen of adult hosts.

Authors have now made use of the inherent aneuploidy in male flies to unravel a role of chromosome-wide gene dosage imbalance to the effects of CIN in vivo. Authors also identify several mechanisms that buffer the deleterious effects of CIN in proliferative tissues, including activation of the DNA-damage response pathway, induction of p38 MAPK signaling to protect against reactive oxygen species (ROS), and expression of mitogenic cytokines to promote compensatory cell proliferation and restore tissue loss. Compromising the activity of these buffering mechanisms enhances the deleterious and pro-tumorigenic effects of CIN.

Reference

Clemente-Ruiz M, Murillo-Maldonado JM, Benhra N, Barrio L, Pérez L, Quiroga G, Nebreda AR & Milán M 2016, ‘Gene dosage imbalance contributes to chromosomal instability-induced tumorigenesis’, Developmental Cell, vol. 36, issue 3, pp. 290–302.

Chromosomal instability – as a consequence of the incorrect segregation of chromosomes during mitosis- leads to aneuploidy, an altered number of chromosomes. Aneuploidy induces the elimination of the cell from the epithelium by a process of delamination and activation of the apoptotic pathway. When aneuploid cells are maintained in the tissue by apoptosis inhibition, a tumor is being induced. Marco Milán and colleagues are characterizing the molecular mechanisms underlying these two cellular behaviors in Drosophila epitheila.