image: Mesothelial cell-cell junctions (β-Catenin immunostaining using a secondary antibody shown in magenta and cell nuclei shown in blue). Areas of disrupted junctional assembly are highlighted with punctuated instead of continuous staining. Cancer cells can squeeze through these weak spots to invade into the surrounding tissue. view more
Credit: University of Pittsburgh Swanson School of Engineering
Most women diagnosed with metastatic ovarian cancer have a less than five year survival rate. Researchers at the University of Pittsburgh Swanson School of Engineering are working to change that.
Ioannis Zervantonakis, assistant professor of bioengineering at Pitt, and his team received $792,000 for four years from the American Cancer Society to understand the biology behind cell interactions that cause ovarian cancer to metastasize to other parts of the body.
To stop ovarian cancer from spreading throughout the abdomen, patients are treated with a combination of surgery and chemotherapy; however, the prognosis is still bleak.
“Because ovarian cancer is diagnosed at a late stage, patients usually don’t respond to chemotherapy,” explained Zervantonakis. “There is an urgent need to understand how ovarian cancer progresses and develop better bioengineered models that can help researchers discover novel therapeutic targets.”
Ovarian cancer becomes metastatic when tumors are formed by an attachment and growth on mesothelial cells, or cells that cover the outer surface of internal organs in the abdominal cavity. In most cases, these attachments lead to a full invasion of host tissue, significantly lowering the patient’s chance of surviving past treatment.
Cancer cells secrete IGFBP2, a protein associated with a worse prognosis for patients. When IGFBP2 binds to mesothelial cells, it results in activation of the SRC pathway, which supports metastatic progression. The team believes that by targeting this IGFBP2-SRC interaction between cancer cells and mesothelial cells, ovarian cancer metastasis can be stopped.
By developing new three-dimensional models using microfluidic technology (a manipulation of fluid movement at the micron scale), the team will be able to study how production of IGFBP2 by cancer cells impacts mesothelial cell biology and pro-metastatic functions.
“Most of our experiments will be done in 3D microfluidics or mouse models to really give us a good idea of what is actually happening when cells talk to each other through the production of IGFBP2,” said Dorota Jazwinska, a Pitt graduate student leading the experimental work at the Zervantonakis Lab on the project.
Because this project is targeting mesothelial cells in the abdominal cavity, it will eventually be applicable to other types of cancer that colonize abdominal organs.
The grant is expected to begin January 2023. In another project on ovarian cancer metastasis, Zervantonakis received $160,000 from the Elsa Pardee Foundation in 2020 to study the role of macrophages in metastatic ovarian cancer.