Overview
Cell competition Cell competition was first discovered occurring between normal cells and cells growing more slowly due to mutation of ribosomal protein genes. The mutant cells die by apoptosis when they are next to normal cells, and get replaced by them. Over time, this leads to the progressive replacement of the abnormal cells throughout the tissue. Cell competition also occurs between some other different kinds of cell, and there are even some ‘supercompetitor’ cells that can displace normal cells. Supercompetitor cells often express oncogenes such as myc, suggesting that cell competition may occur in cancer. What are the roles of cell competition during normal development? Could it be exploited to regenerate tissues, eg through the progressive elimination and replacement of diseased or defective cells by corrected replacements? To achieve this, we will need to know the molecular pathways that trigger cell competitiion, and how to manipulate them. How is cell competition involved in diseases such as cancer?
Transcriptional control of cell competition
Because it is a simple multicellular animal that shows cell competition, we used Drosophila in a genetic screen for mutations that interfere with cell competition. Analysis of these mutations defined a previously unknown transcriptional stress response that acts in Rp mutant cells, in cells with other kinds of ribosome assembly defect, and in cells with some other kinds of stress. Unexpectedly, even the reduced translation and growth typical of cells with Rp gene mutations depends mostly on transcriptional mechanisms and not on simply by reducing the number of ribosomes. Cell competition is a consequence of this altered transcriptional state of Rp mutant cells and is prevented by blocking this transcriptional pathway. One current goal is to identify how cell competition recognizes cells that are to be eliminated, by identifying transcriptional targets through mRNA sequencing followed by targeted in vivo expression and knockdown approaches. In this way we will to determine which of the transcriptional differences between Rp mutant and normal cells lead to cell competition. The many possibilities include cell surface differences, extracellular vesicles and particles, and mechanical cell interactions and their consequences. We also plan to investigate what changes occur specifically at competing cell boundaries by single-cell analysis and spatial transcriptomics of tissues within which cell competition is happening. In addition to Drosophila, we will also see whether similar mechanisms occur in mammals by creating similar genetic models.
Cell competition, aneuploidy, and tumor suppression
We have found a function of cell competition in the recognition and elimination of aneuploid cells. Because there are 80 different ribosomal proteins, and they are encoded by genes spread all over the genome, changes in chromosome number usually change the copy number of Rp genes. Ribosome biogenesis stalls whenever a Rp is missing, and this will be true of many ribosomes in aneuploid cells, because of the mismatched Rp gene numbers. Because ribosome biogenesis is the most energy intensive process occurring in the cell, with ribosomal RNA constituting >80% of cellular RNA synthesis, and Rp representing ~25-30% of total protein synthesis, changes in Rp gene dose has large effects on cells, and it seems that Rp gene dose changes, and their cellular consequences, are one the most immediate consequence of aneuploidy. The organism can exploit cell competition as a defense mechanism to recognize and eliminate aneuploid cells, because many have altered Rp gene dose.
In addition to causing birth defects, and representing the major cause of human miscarriage, almost all cancer cells are aneuploid, and aneuploid cells also accumulate in aging tissues. Accordingly, we think that by eliminating aneuploid cells, cell competition provides a defense against cancer, birth defects, and aspects of aging. We will be testing these ideas by characterizing cell competition mechanisms in mammals and evaluating their contributions to cancer, development, and aging, which we will approach using mouse knock-out models and cell culture methods.
Ribosomes and cancer
Do ribosome defects actually contribute to cancer development? We were not initially very interested in ribosomes other than to use ribosomal protein gene mutations as a means to affect cellular growth, but it is possible that ribosomes are mor important in disease than is widely recognized.
Rp gene mutations are present in 43% of human cancers. This very high rate implies that Rp gene mutant cells have a selective advantage in tumors and suggests they contributes to cancer in some way. The human disease Diamond Blackfan Anemia is caused by Rp gene mutations, and patients experience ~5x higher lifetime rates of cancer. How can mutations in Rp genes can contribute to cancer, when ribosomes are required for cell growth including cancer cell growth? Cancer takes years or decades to develop, and much less is known about its early stages than about the mature cancer cells isolated from tumors, which are the end result of a long oncogenic process. We think that Rp gene haploinsufficiency may contribute to early cancer development. Cell competition may help suppress tumor development by eliminating precancerous cells before they can go on to become tumors.
As described above, Rp gene haploinsufficiency is also a common feature of aneuploidy, and almost all cancer cells are aneuploid. It is more than 100 years since Boveri suggested that aneuploidy was the cause of cancer. Surprisingly, it is still not completely clear how aneuploidy contributes to cancer. Rp gene haploinsufficiency may be one way that aneuploidy contributes to cancer, as well as providing a cue to eliminate aneuploid cells.
Another connection between ribosomes and cancer is that cells with ribosome biogenesis defects such as Rp gene mutations activate p53. The molecular mechanisms of this ‘nucleolar stress pathway’ are beginning to be understood, but not why it is useful to activate p53 in these cells. Because p53 is one of the most important human tumor suppressors, we think it is possible that cells with ribosome biogenesis defects activate p53 because they are experiencing an oncogenic stress. If this is the case, then subsequent p53 inactivation might release Rp gene mutant cells to continue developing into cancer. P53 activity also marks mammalisn cells for competition by more normal neighbors, another potential tumor suppressive mechanism. To find out how Rp gene mutations, and other defects in ribosome biogenesis, could promote cancer development, we will be studying all aspects of cells mutated in Rp genes, including their transcriptional , translational, and metabolic defects and their consequences, to see if they play a role early in cancer development.
