To understand this spread, the Penn researchers developed a mouse model that uses multiple fluorescent proteins to tag and track different pancreatic cancer cells as they enter the bloodstream and spread to distant organs. In this mouse model, mutations in Kras and p53 genes resulted in the formation of individual tumor cell populations that were labeled with different colors. Similar to humans, the mice developed tumors at secondary sites including the liver, lung, peritoneum, and diaphragm. They observed that these metastases were often made of cells from at least two different colors of tumor cell populations. To understand how these multi-colored lesions originated they examined blood from these mice and found that tumor cells in circulation frequently occurred as clusters comprised of different colored cancer cells.
What's more, they also found that once these multi-colored clusters arrived at the secondary sites, the exact characteristics of subsequent growth was heavily dependent on the organ in which they now resided. During cell expansion in the peritoneum and diaphragm the lesions remained multi-colored, whereas in the lung and liver only a single color population was able to grow out. This suggested that specific factors in each organ may also influence the evolution of metastases.
"These results provide an unprecedented window into the cellular dynamics of tumor evolution and suggest that interactions between subpopulations of tumor cell types contribute to metastatic progression from initial tumors," Stanger said. "The finding that metastases are frequently polyclonal and that subsequent cellular behavior is site-dependent also gives us insight into the origins and evolution of clonal diversity in metastatic disease."
"If cells do cooperate during metastasis, what is the molecular basis for their communication, and can we hit that?," Stanger asked. The work also reinforces the importance of finding tumor cell clusters in the blood as a mechanism of detecting cancer metastasis earlier.
Maddipati R and Stanger BZ. Pancreatic cancer metastases harbor evidence of polyclonality. Cancer Discovery. 2015; doi: 10.1158/2159-8290.CD-15-0120 [Abstract]