Cell competition could be responsible for cancer flare-ups, a study shows

Cell competition could be responsible for cancer flare-ups, a study shows

A normal process called cell competition, in which healthy tissue eliminates unhealthy cells, may be responsible for cancer flare-ups in patients months or years after they are declared cancer-free, according to a new study by researchers at the UT Southwestern Simmons Cancer Center.

The findings, published in Cancer Discovery, could lead to better ways to treat or even prevent metastasis, or the spread of tumors to different parts of the body.

Our results show that cell competition within the primary tumor leads to the displacement of less fit cells into the circulation. But not all of these displaced cells die. Some with metastatic potential survive in the circulation, persist in distal organs, and initiate metastases.”

Srinivas Malladi, Ph.D., principal investigator, assistant professor of pathology at UT Southwestern Medical Center and member of the Harold C. Simmons Comprehensive Cancer Center

Metastases are common in most cancers. In renal clear cell carcinoma (ccRCC), the most common form of kidney cancer, new metastatic lesions often develop long after the primary tumor has been removed, a process called metachronous metastasis. Researchers know that metachronous metastases can appear months or years later, when many patients and their doctors believe they are cancer-free. But how this happens is unknown.

To find out, Dr. Malladi and his colleagues created a mouse model of metachronous metastasis by implanting human ccRCC cells that carried additional genes to make them glow and resist an antibiotic called hygromycin. After four weeks, the researchers surgically removed the primary tumors that had formed at the implantation site and then further monitored the animals for metastases using bioluminescence imaging. Although none of the mice developed metastatic tumors over the next five months, the researchers found live cells in the animals' lungs that glowed and resisted hygromycin.

When the researchers grew these latent metastatic (Lat-M) cells with primary tumor cells in Petri dishes, they found that the primary tumor cells took over the mix and more Lat-M cells entered the culture medium - both signs that the Lat-M cells had "lost" in competition with the primary tumor cells. However, when the researchers implanted the Lat-M cells into mice themselves, tumors effectively grew.

“Although the Lat-M cells were ‘losers’ and were displaced by the primary tumor,” explained Dr. Malladi, “they were ‘winners’ when they grew on their own.” These results indicate that disease progression is not necessarily driven by the dominant aggressive clone, but could be driven by a non-dominant, less fit clone within the primary tumor.

Further investigation identified a gene called SPARC that appeared to play a key role in both the displacement of Lat-M cells and their establishment at distal organs. When SPARC activity decreased in the primary tumor, reduced displacement of Lat-M cells was observed, while depletion of SPARC in Lat-M cells colonizing the lung resulted in increased metastatic burden. Dr. Malladi suggested that other genes waiting to be discovered are also likely important in this process. Ultimately, he said, profiling genes in primary tumors surgically removed from patients could reveal which individuals need to be monitored more closely after surgery for metachronous metastases. Pharmaceuticals could one day act on these genes to prevent Lat-M cells from leaving the primary tumor, a strategy that could prevent metachronous metastases in a range of cancers.

The Malladi Lab focuses on developing preclinical models to provide a conceptual framework to define and target the latent metastatic phase of tumor progression. Her research aims to identify patients harboring latent metastatic cells and provide therapeutic options to eliminate these cells (metastatic seeds) before they trigger overt metastasis.

Other UTSW researchers who contributed to this study include Kangsan Kim, Huocong Huang, Pravat Kumar Parida, Lan He, Mauricio Marquez-Palencia, Tanner C. Resse, Payal Kapur, James Brugarolas and Rolf A. Brekken.

Source:

UT Southwestern Medical Center

Reference:

Kim, K., et al. (2022) Cell competition shapes metastatic latency and relapse. Cancer discovery. doi.org/10.1158/2159-8290.CD-22-0236.

.