New Mechanism Involving NFkappaB Drives Metastasis in Cancer with Chromosomal Instability

By Anthony M Magliocco MD

An interesting and important new study recently published in Nature gives new insights into possible targetable molecular mechanism linking chromosomal instability observed in some cancers and progession and metastasis.

https://www.nature.com/articles/nature25432

A subset of cancers develop chromosomal instability via disjunction errors during mitosis. This can lead to highly aneuploid and abnormal karyotypes more prevalent in certain cancers than other. For example, ovarian cancer is notorious for developing a  disrupted and unstable karyotype.

Metastatic Cancer

It appears that chromosomal instability in itself does not promote metastasis, however, in an intriguing observation it was noted that tumors with chromosomal instability also developed micronuclei when under mechanical stress.

These micronuclei are more prone to cytoplasmic rupture. Free DNA in the cytoplasm triggers a non-canonical NFkappaB cascade which may lead to mesenchymal transformation and a propensity to metastasis.

Interestingly cancers with high aneuploidy do not generally develop a high mutational burden such as cancers like melanoma. Nor do they tend to have targetable driver mutations.

“Cytosolic DNA from micronuclear rupture appears to trigger non-cannonical NFKappaB signaling which could lead to tumor metastasis”

 

DNA in the cytoplasm triggers NFKappaB as part of a host response to viral infection, but cancer may subvert this mechanism. In addition,  NFkappaB non-cannonical activation by cytosolic DNA from ruptured micronuclei may lead to a variety of effects immune activation which could assist with tumor metastasis.

These new insights into the consequences of chromosomal instability create opportunities for developing new therapeutic strategies for these types of cancer that lack specific driver mutations and significant neoantigen loads