Samuel F. Bakhoum is a physician-scientist and cancer biologist at Memorial Sloan Kettering Cancer Center in New York and cofounder of cancer therapeutics company Volastra Therapeutics.
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For more than 50 years, researchers drawn a link between small, DNA-containing structures called micronuclei and cancer. But scientists are only now beginning to understand the role they play in driving cancer progression. Studies have recently shown that micronuclei act as catalysts for chromosomal damage and reorganization, another hallmark of cancer that may promote the chronic inflammation that sustains metastasis
Numerous errors in chromosome segregation during cell division can lead to the formation of micronuclei, even if there isn’t actual mis-segregation of the chromosomes. These events are not mutually exclusive, nor are they independent, as each of these only serves to fuel chromosomal chaos.
When microtubules from each pole of a dividing cell attach to a single centromere, that chromosome lags behind the others and is often encapsulated in a micronucleus, even if it ends up in the intended cell.
If mis-segregation does occur, whether due to an errant microtubule attachment or another reason, the mis-segregated chromosome can similarly get encapsulated. If it doesn’t, the resulting aneuploid cell is at an increased risk of a lagging chromosome and micronucleus formation.
Shortened or broken telomeres can leave chromosomes vulnerable to fusion events that can lead to chromosomes with two centromeres, called dicentric chromosomes. When the cell divides, microtubules attach to both centromeres, often fracturing and separating the dicentric chromosomes into the daughter cells. These broken chromosomes can get sequestered in micronuclei immediately or after a subsequent cell division, due to impaired replication.
Micronuclei have fragile nuclear envelopes that often rupture, causing chromosomes to spill out into the cytoplasm. There, they encounter nucleases that pulverize the DNA into small fragments that can be lost, randomly linked, or looped into circles known as circular extrachromosomal DNA. This process, known as chromo-thripsis, produces complex rearrangements that can drive cancer.
At the same time, the presence of DNA in the cytoplasm triggers the cGAS-STING inflammatory pathway thought to have evolved as a form of immune defense against viral infection. The enzyme cGAS binds DNA from the ruptured micro-nucleus, catalyzing the formation of 2’3′-cyclic GMP-AMP (cGAMP), which subsequently activates STING and downstream inflammation. When chronically activated due to abundant micronuclei in cancer, this inflammation can drive tumor growth and metastasis.
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This article was featured in March 2022, Issue 1 of the digest
Rampant chromosomal abnormalities in tumors could provide new treatment strategies
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