Stromal Cells Predict Prostate Cancer Metastasis

According to a study done by researchers at Weill Cornell Medicine, non-cancerous cells known as stromal cells found in and around prostate cancers may be beneficial in assessing the tumors’ capacity to spread and may even be targets for future prostate cancer therapies.

Stromal cells, which are distributed throughout the body, help with wound healing, blood vessel creation, and tissue structural support. Scientists understand that cancers frequently co-opt stromal cells to generate a more favorable molecular environment for tumor development and survival. However, their precise involvement in various tumors are only beginning to be understood.

The researchers conducted the most complete investigation of stromal cells in and around prostate tumours to date, as reported in Nature Communications on January 8. They discovered eight subpopulations of stromal cells with unique tumor-associated gene activity patterns after studying prostate tumor mice models and human patient data. They discovered that specific variations in these patterns predicted tumor spread, or metastasis.

The researchers also discovered signaling linkages between stromal cells, tumor cells, and surrounding immune cells, which might be used to prevent metastasis.

“These results illuminate the substantial impact of stromal cells on prostate cancer progression, and point to the possibility of new prognostic and therapeutic strategies,” said study senior author Dr. Massimo Loda, chair of the Department of Pathology and Laboratory Medicine and the David D. Thompson Professor of Pathology at Weill Cornell Medicine and pathologist-in-chief at NewYork-Presbyterian/Weill Cornell Medical Center.

The study’s co-first authors were Hubert Pakula, Mohamed Omar, and Ryan Carelli, all of whom worked in the Department of Pathology and Laboratory Medicine at the time. Omar is presently an assistant professor of research in pathology and laboratory medicine.

Tumor progression is fueled not only by the acquisition of new mutations in malignant cells, but also by tumor-induced (and tumor-supporting) alterations in non-cancerous cells.

Until now, most study on these “tumor microenvironment” cells has been on immune cells, which can be co-opted to reduce natural anti-cancer immunity and prevent the benefits of cancer immunotherapies. Scientists have also been interested in stromal cells’ tumor-supporting actions. In 2017, for example, Loda’s team uncovered a gene activity pattern in prostate cancer stromal cells that looks to promote metastasis and could be useful in forecasting tumor cell spread, which is the leading cause of cancer mortality.

In the new study, the team conducted a detailed investigation of stromal cells in prostate cancer using mouse models representing prostate cancers at various stages of growth as well as human prostate tumor samples.

Using an advanced technology termed single-cell RNA sequencing and AI-based analytical tools, the researchers discovered eight significant subpopulations of tumor-associated stromal cells—in both mouse and human tumors—based on their different patterns of gene activity when a tumor is present.

They discovered that some of these tumor-associated patterns change when cells acquire additional cancer-causing mutations and as tumors spread. Surprisingly, the researchers discovered that stromal cells around prostate cancers frequently create a biochemical environment comparable to bone, basically priming the tumor cells to move to bones—a major destination for prostate cancer metastasis.

The study produced a list of signaling proteins and networks that become abnormally active or inactive during these transitions. Loda suggested that future prostate cancer treatments could target these signaling relationships between tumor cells, stromal cells, and immune cells to prevent metastasis.

In addition to exploring for new therapeutic targets, Loda and his team plan to use their data and future research to create predictive tests on tumor-associated stromal cells that predict the aggressiveness of prostate tumors, allowing clinicians to make better treatment decisions.

“One could even imagine using such a test on biopsy samples where no tumor tissue is found,” said Loda, who is also affiliated with Weill Cornell Medicine’s Sandra and Edward Meyer Cancer Center. “If signs in the stromal cells point to the likely existence of a tumor, maybe an aggressive one, then perhaps you should biopsy again.”

For more information: Distinct mesenchymal cell states mediate prostate cancer progression, Nature Communications, https://dx.doi.org/10.1038/s41467-023-44210-1