Study Provides New Insights Into Ovarian Cancer
In a new deep analysis of high-grade serous ovarian cancer (HGSOC), researchers have identified a common pathway that could provide a target for new drugs. The analysis also found that the subtypes previously used to classify HGSOC do not reflect the molecular basis of the cancer cells themselves, but rather the surrounding cells, proteins, and other molecules.
HGSOC is the most common type of ovarian cancer. Unfortunately, patients almost always relapse even if they initially respond to therapies. When HGSOC recurs, it is incurable and has a median survival of only about one year. Many patients who relapse develop malignant ascites, a fluid containing cancer cells and other cells, that collects in the abdomen.
In a new study published this week in Nature Medicine, Benjamin Izar, MD, PhD and colleagues performed single-cell RNA sequencing on the malignant ascites fluid to provide a deep analysis of the molecular landscape of HGSOC.
“The idea for this study was that we could collect malignant ascites over time from the same patient, identify the molecular basis of why this fluid contributes to or causes such a poor response to therapy and prognosis for the patient, and understand how this changes over time,” says Dr. Izar, a member of the Tumor Biology and Microenvironment program at the Herbert Irving Comprehensive Cancer Center (HICCC) and assistant professor of medicine at Vagelos College of Physicians & Surgeons (VP&S).
The team collected 22 samples from 11 patients and used single-cell RNA sequencing to describe the cellular and molecular ecosystem of ascites. They found that the fluid was made up of a diverse population of different cell types, with a vast minority of actual cancer cells. One of the cellular sub-types that the team found were cancer-associated fibroblasts (CAFs), whose inflammatory properties may play an important role in the development of ascites and in making cancer cells resistant to certain therapies. Previous studies in pancreatic cancer demonstrated that such inflammatory CAFs promote tumor growth, suggesting that a similar process could be at play across different cancer types.
“We believe that the interaction between CAFs and cancer cells could play an important role in how HGSOC evolves, and could be a potential target for new drugs," says Dr. Izar.
Single-cell profiling of the cancer cells provided deeper insights into the different subclasses of HGSOC that have historically been used to describe and categorize the cancer. Dr. Izar’s analysis demonstrated that these previously described groups are reflective of the tumor microenvironment – the complex signaling pathway that surrounds tumor cells – rather than the cancer cell subtypes themselves.
“This is an important observation, because previous clinical trials used this stratification to stratify patients to certain therapies,” adds Dr. Izar. “I hope that investigators can use our findings to design clinical trials combining therapies that target both the cancer cells as well as dominant cells in the tumor microenvironment.”
In addition to characterizing the differences in the cancer cells, the team interrogated the samples to identify commonalities that could be targeted with therapies. They found that cancer cells across all patients in the cohort shared a very strong expression of a particular pathway, called the JAK/STAT pathway, which is central to inflammatory and immune responses. When the pathway goes haywire, it can also fuel cancer growth.
Armed with this knowledge, Dr. Izar’s team hypothesized that the JAK/STAT pathway is activated by IL-6, a protein expressed by cancer cells and inflammatory CAFS that the team found made up a large proportion of the malignant ascites fluid.
But can the JAK/STAT pathway be targeted to stop cancer growth? The researchers treated cancer cell lines with a JAK/STAT inhibitor and found that it was more effective at killing these cancer cells than other drugs currently used in the clinic, such as chemotherapy or PARP-inhibitors. In mouse models, the drug was also effective in reducing tumor growth and killing existing tumors.
“I believe that our work provides a potential new way to treat HGSOC,” says Dr. Izar, “and I hope that our findings can eventually be translated into helping patients suffering from this disease. Even beyond the analyses presented in our study, I strongly believe that the cancer research community will benefit from using our data as an important resource for further discovery in HGSOC and other cancers.”