Three sisters have teamed up to find drivers of uterine corpus endometrial cancer (UCEC), one of the most common, and most deadly, cancers in women. They noted that the Myosin VB gene (Myo5b) had elevated expression levels in UCEC patients, as reported in a study published in PLoS One.
UCEC is one of the most common cancers in women. Whilst early diagnosis typically leads to favourable outcomes, in around 25% of patients the condition goes unnoticed until it is too late for effective treatment. The number of cases has risen significantly over the last three decades, and the disease is prone to reoccurrence.
Following the devastating diagnosis of their mother with breast cancer, the Engevik sisters – from the Medical University of South Carolina and Baylor College of Medicine – set out to pursue a new challenge. All three sisters are primarily gastrointestinal disease researchers. Yet they chose to follow a new path in light of this personal connection. We spoke with lead author, Kristen Engevik, about the work, and the inspiration behind it. “After caring for our mother as she went through chemotherapy, surgery and radiation for breast cancer, we were really motivated to look into drivers of cancers in women,” she stated.
Figure 1: Photo of the Engevik sisters. Photo credit: Medical University of South Carolina.
Myo5b as a driver of UCEC
The sisters scanned publicly available databases to find gene expression changes linked to cancer. They were struck by the high levels of a gene known as Myo5b in UCEC samples and chose to look into this further.
Myo5b is involved in the transport of resources around a cell. As such, elevated Myo5b levels could lead to more efficient growth and development in a cancerous cell. Engevik told us: “In the gut, we know that Myo5b is responsible for delivery of nutrient transporters, such as glucose transporters, to the apical membrane. We think that Myo5b might be doing the same thing in UCEC: delivery transporters that facilitate maximum nutrient absorption. Through increased uptake of nutrients, we think Myo5b is ultimately shifting the metabolism of the UCEC cancer and influencing cell cycle.”
To discover more about how Myo5b is elevated in these tumours, and how this impacts the development of the disease, the researchers looked at mutations in the gene. Shockingly, they discovered that mutations in the Myo5b gene did not affect overall expression of the protein. This led them to believe that there must be an epigenetic modulator of Myo5b that acts in these cancer cells. An analysis of methylation data revealed that Myo5b is under-methylated in UCEC cells, potentially explaining the increased gene expression. Further analysis revealed that this was the case in all tumour grades and stages. The sisters also discovered that the higher the expression level, the worse the prognosis (Figure 2).
Figure 2: Graph showing survival time in days in those who have high or low/medium expression of Myo5b. Survival is significantly reduced in those with higher expression levels. Adapted from Engevik et al., 2023.
Discussing the next stages and the potential clinical applications of the findings, Engevik shared: “There is a commercially available Myo5 inhibitor, MyoVin-1, which we are planning to use in the AN3CA, HEC-1A and RL95-2 cancer cells lines. We hope this inhibitor and the use of CRISPR will allow us to definitely identify how Myo5b influences UCEC cancer. However, we would love to find or design other compounds which could be used in the clinics to combat UCEC.”
It goes without saying that uncovering the mechanisms driving cancer development is crucial to uncovering new treatments. The current study highlights the usefulness of publicly available databases for researchers, tools that allowed the sisters to so easily segue into cancer research. Speaking of the future, and the further potential of the work, Engevik told us: “In addition to UCEC, we also found that Myo5b is hypomethylated and over-expressed in breast invasive adenocarcinoma and we are really interested in tackling this cancer in the future as well. This initial dive into cancer has really captured our interest and we sisters plan to continue examining cell trafficking collaboratively in UCEC and breast cancer.”