Fruit Flies, Flower Power, and Cancer
William Proxmire, a Democrat who represented the state of Wisconsin from 1957 to 1988, was a harsh critic of wasteful government spending. He was particularly well known for issuing “Golden Fleece Awards”, satirical prizes that he bestowed to those government agencies that appeared to squander public monies on silly and trivial grants. Between 1975 and 1988 he conferred 168 such prizes, some to scientific entities like the National Science Foundation, which, in Proixmire’s view, appeared to support worthless research projects. He particularly aimed at studies with ludicrous titles. Some members of the scientific community were dismayed by these awards, claiming, rightly in my opinion, that a funny title doesn’t necessarily mean that the work isn’t worth supporting. The criticism apparently didn’t hurt him. He was reelected repeatedly by huge margins.
Proximire might have conferred a Golden Fleece on Eduardo Moreno of the Champalimaud Centre for the Unknown in Lisbon, Portugal. Moreno and his collaborators have been working for several years on a gene found throughout the animal kingdom that he has nicknamed “Flower”. You can imagine the headlines that accompany reviews of his work. Proxmire might have picked up on them, but the gene and its effects are not laughing matters.
Professor Moreno’s research focuses on a phenomenon that is not widely appreciated. It’s called “cell competition”, and it was first discovered in fruit flies in conjunction with a peculiar set of mutants called “Minutes” (pronounced “my newts”). The first Minute mutation was discovered exactly 100 years ago by Calvin Bridges in Thomas Hunt Morgan’s laboratory in New York City. Flies with two copies of a defective Minute gene die. Flies with one copy have shorter bristles, rough eyes, lower viability, and reduced life span (By convention, in Drosophila the names of dominant mutants, ones that display a phenotype when present in one copy, are capitalized). There are many Minute genes and they’re found all over the Drosophila genome. Molecular analysis later revealed that each of them coded for a different protein component of the ribosome. Since the ribosome is the apparatus that is responsible for synthesizing all the proteins of an organism, defects in one or more of its parts will slow the rate of protein synthesis and thereby result in the Minute phenotype.
Here’s where Moreno comes in. Using a technique that I’ll not describe, he managed to produce mosaic flies with a mixture of normal and Minute cells. As expected, the Minute mutant cells grow somewhat slower than their normal counterparts. What was surprising was that when the normal and mutant cells were next to one another, the Minute cells committed suicide, a phenomenon called “apoptosis”. How was that possible? How could the simple juxtaposition of normal and slower growing cells cause the laggards to kill themselves?
The Flower Gene
The Flower gene appears to be the key to the answer to these questions. The gene encodes a transcript that can be alternatively spliced to yield four different transmembrane proteins that I’ll call Fl1, F2, F3, and F4. Moreno found that when the Flower gene was completely shut down in a human breast cancer cell line there was no effect on cell growth. Similarly, if all four forms of the protein were simultaneously expressed, it also was without effect. However, when cells expressing F1 or F3 were co-cultured with cells expressing either F2 or F4, the F1 or F3 cells killed themselves. At the same time the F2 or F4 cells grew faster. Moreno calls the cells expressing F2 or F4 “winners”, and the F1 or F3 expressing cells “losers”. Winning and losing requires that the two cell types be in contact with one another.
What has all this to do with cancer? In a recent Nature paper emanating from Moreno’s laboratory (“Flower isoforms promote competitive growth in cancer”, Madan et al., Nature 2019 Jul 24. doi: 10.1038/s41586-019-1429-3. [Epub ahead of print]) Moreno examined slides of cells from breast cancer patients. He found that malignant cells were winners, expressing more F2 or F4 than normal cells. Cells surrounding the tumor were high in F1 and F3, and clearly were losers. Their summary: F1, F2, F3, and F4 all are poorly expressed in healthy tissue, F2 and F4 are overexpressed in cancer tissues. And F1 and F3 are found in unusually high concentrations in tissues adjacent to the tumors. Apparently, cancer cells have subverted the Flower gene to become winners. At the same time, as I understand it, the surrounding tissue reacts to its winning neighbors by becoming losers, expressing the F1 and F3 forms of the gene and committing suicide.
These results suggest that the Flower gene might be useful in cancer therapy. Moreno found that interfering with expression of the Flower gene did indeed reduce malignancy. He concludes, “…human [Flower] proteins can have a powerful effect on tumorigenicity" He and his collaborators propose that "therapies targeting these proteins have the potential to impair cancer growth and metastasis.
When I was on the faculty of Johns Hopkins University, one of my more learned colleagues would often shock me by boldly asserting a little known fact about Biology (at least he thought what he was claiming was a fact) that he believed that I wasn’t aware of. One of these statements that was particularly surprising to me was that the scientific community doesn’t know how cancer kills. When challenged, he acknowledged that the assertion wasn’t universally true. For example, some tumors in the intestinal track may physically block digestion. And there are other exceptions. But in most instances, he claimed, we don’t know why people die of cancer.
Moreno’s findings may offer an explanation. It goes like this. Malignant cancers invade tissues. Among other things they subvert normal processes and express winner Flower genes F2 and F4. Surrounding tissues become losers by turning on F1 and F3. The result is that tissues neighboring the tumor commit suicide. Their cell death is the wasting away that often is the basis of a cancer victim’s death.
If that analysis is correct, it has profound implications. By targeting the Flower gene of cancers and surrounding tissues it may be possible to stop the cell death that often accompanies tumorigenesis. That would represent an entirely new way of treating malignancies. It’s amazing. If the therapy proved effective, we would be indebted to a mutant fly with shortened bristles and rough eyes first identified one hundred years ago.