SUMMARY: Identification of host genes and pathways that can block cancer cell engraftment and growth could lead to revolutionary new cancer treatment strategies. In metastatic cancer, there are many steps in which cancer cells interact with the host microenvironment: the release of cells from their original location, travel through the circulation, engraftment into a distant location, and growth in the new environment. So-called liquid tumors like acute myeloid leukemia (AML) are not often considered to be metastatic, but leukemic cells disseminate throughout the body and can lead to solid metastasis-like tumors called myeloid sarcomas, interacting with the host microenvironment in similar ways. In the soft-shell clam (Mya arenaria), and other bivalves, fatal AML-like cancer lineages have evolved that metastasize repeatedly—not just from a primary to a secondary site, but from one whole animal to another, over and over again throughout the population for decades or longer. These fatal contagious cancers exert a strong selective pressure in nature to select for clams which can block engraftment and growth of this lineage of cancer cells. We will use this unique bivalve transmissible neoplasia (BTN) system as a model of AML to determine (1) which microenvironments expression patterns correlate with metastatic growth, (2) what genes correlate with resistance to progression, and (3) how different populations have evolved resistance to cancer. This study has the potential to provide an unprecedented understanding of cancer microenvironment and reveal new and important interactions between cancers and their hosts.