Are Micro RNAs the Key to Stopping Lung Cancer?
Cancer metastasis is a complex, multistep process characterized by dissociation of cancer cells from primary tumors, invasion of those cancer cells into neighboring tissues and entry into circulation, exit of cancer cells from circulation, entry of cancer cells into new tissues and proliferation at distal sites to form secondary tumors. Although genes that participate in particular steps of metastasis are known, the mechanisms by which tumors progress to become metastatic are not. Such knowledge is important for developing effective strategies for treating lung cancer as 90% of patients die of metastasis.
MicroRNAs (miRNAs) are molecules that regulate the activity of genes that can either promote or inhibit metastasis. An emerging hypothesis is that miRNAs involved in cancer progression are selectively secreted from tumor cells into circulating body fluids, travel to distant sites and influence the function of cells at their new locations. To test this hypothesis, The Jackson Laboratory has generated a population of patient derived xenograft (PDX) mice implanted with human lung tumors. The goal of this pilot proposal is to validate PDX mice as a model for studying the role of circulating miRNAs in cancer progression by:
- identifying miRNAs that are expressed by and retained within lung tumors
- identifying miRNAs that are secreted from lung tumors into the bloodstream
Lung cancer is the leading cause of cancer deaths worldwide and 90% of patients die of metastasis. Metastasis is a complex process that involves loss of tumor cell adhesion, invasion of tumor cells into neighboring tissues and into circulation, survival of tumor cells while in transit, exit of tumor cells from circulation and entry into new tissues and, finally, proliferation of tumor cells at distal sites to form secondary tumors. While recent studies have discovered many of the genes that govern specific steps of metastasis, such as the transition of cancer cells from an epithelial to a mesenchymal morphology (EMT), the mechanisms of cancer progression are largely unknown.
We will address this gap in knowledge by generating and characterizing a patient derived xenograft (PDX) mouse resource for the long-range goal of identifying the microRNAs (miRNAs) that represent upstream regulators of genes that facilitate lung cancer progression. The goal of this pilot proposal is to validate our PDX mouse model by identifying miRNAs expressed in engrafted lung tumors, identifying miRNAs present in the bloodstream and the origin (tumor or host) of circulating miRNAs. Several recent studies suggest that miRNAs are selectively secreted from specific tumor cell populations into circulating body fluids and that these miRNAs may play vital roles in metastasis. Alternatively, circulating miRNAs could be nonspecifically released into circulation from dead/dying cells or from a host immune response. Successful completion of this proposal will validate our PDX model for future studies to elucidate the mechanisms by which miRNAs influence lung cancer progression and acquired therapeutic drug resistance.