Wistar Science Highlights: Advances in Ovarian Cancer Research and the Impact of p53 Genetic Variant on Iron Accumulation in African Americans

The TP53 gene is the most frequently mutated gene in human cancer. In addition to mutations, this gene comes in numerous variations in the human population. Some of these variations alter the function of the p53 protein. 

A collaborative study from the Dotiwala and Murphy laboratories discovered that a rare, African-specific variant of TP53 called P47S causes iron accumulation in macrophages and other cell types and is associated with poorer response to bacterial infections, along with markers of iron overload in African Americans.  

According to the study, published online in Nature Communications, macrophage iron accumulation disrupts their function, resulting in more severe bacterial infections. It also causes macrophages to have antinflammatory properties.

Interestingly, the P47S variant improved response to malaria in mice. Researchers injected them with the malaria toxin and observed a less severe disease than in mice that carry the common p53 variant. Acute malaria is a highly inflammatory disease, therefore the antinflammatory activity of P47S macrophages limits disease severity in mice. The authors hypothesize that this effect of the P47S p53 variant could help people survive in malaria-endemic regions. 

This study may help understand the connection between the P47S TP53 gene variant and iron overload disorders as well as the increased occurrence of certain bacterial infections and cancers found in African Americans.

     The Zhang laboratory continues to make strides in ovarian cancer research. In a paper published in Cancer Cell the team described a novel therapeutic strategy based on combining EZH2 inhibition and PARP1 inhibition. 

PARP inhibitors are used as a maintenance treatment in women who carry genetic mutations that cause impaired DNA repair ability. Therefore, tumors with functional DNA damage repair do not typically respond to this therapy.

The lab researched a strategy to expand the use of PARP inhibitors to benefit a larger group of women whose tumors don’t have defects in DNA repair. They found that another class of inhibitors called EZH2 inhibitors render cancer cells vulnerable to PARP inhibitors in ovarian cancers with overexpression of the CARM1 oncogene. The study suggests that PARP inhibitors and EZH2 inhibitors may be used in combination as a precision treatment strategy for ovarian cancer.

In a second study, published in Nature Communications, Zhang and colleagues discovered a novel pathway involved in cellular senescence that controls inflammation and response to cancer immunotherapy.

Cellular senescence is a natural tumor suppression means that stably halts proliferation of damaged or premalignant cells, for example after chemotherapy. Senescent cells also produce an array of inflammatory molecules that trigger inflammation and immune reaction.
 
The newly discovered pathway enables detection of DNA in the cytoplasm, which is a signal of DNA damage, and controls inflammation and cellular senescence. This pathway may be targeted to affect cancer cell response to checkpoint inhibitors during chemotherapy.