Abstract C02: Ecological movement paradigms to understand the dynamics of metastasis
Authors: Amend Sarah R. , Roy Sounak , Brown Joel S. , Pienta Kenneth J. 
Published: October 2016

The process by which PCa (PCa) cells non-randomly disseminate to the bone to form lethal metastases remains unknown. Metastasis is the consequence of the long-range dispersal of a cancer cell from the primary tumor to a distant secondary site. Movement ecology provides a framework for a deeper understanding of metastasis. This paradigm describes four interacting components: (1) the microenvironmental pressures on the cancer cell that directly influences (2) the intrinsic motivation to disperse, (3) the biomechanical requirements of movement, and (4) the capacity of an individual to spatially direct migration.

Malignant cells are inherently programmed to proliferate. Under constrained circumstances of overcrowding and subsequent resource limitation of the tumor microenvironment, however, the risk of death in the primary tumor eventually outweighs the risks associated with dispersal. This phase-shift in population density, resource allocation, and, therefore risk assessment, alters the cancer cell's intrinsic motivation from one of stationary growth (“grow”) to one capable of adaptive movement (“go”). The tumor cells that are successful dispersers will invade a favorable high-resource low-population secondary site and the intrinsic motivation for movement of the cancer cell will shift back to a goal of low-migration and local resource use.

Prior to dispersal a cell must acquire the phenotypic traits necessary to move. The genetic clonal architecture of cancer cells suggests that most cancer cells have the capacity to metastasize, highlighting the necessity of phenotypic adaptation. The complex transmogrification of the cancer cell between the proliferative epithelial and migratory mesenchymal phenotypes is not well understood. In ecology, such a phenotypic transformation between morphs typically occurs through a non-reversible developmental epigenetic trigger in the organism's offspring instigated by high population density and low resources rather than through individual phenotypic plasticity. It is unclear by which mechanism a cancer cell undergoes a transmogrification to gain movement ability. We hypothesize that cell division will be necessary for epithelial-to-mesenchymal transition (EMT). To test this, we will halt cell division in epithelial PCa cells (PC3-Epi) and culture the cells under EMT-inducing conditions. We anticipate that cells unable to divide will fail to undergo an EMT. Answering this question will provide insight of how a cancer cell actively metastasizes and has important implications the development of therapeutic interventions.

The preferential homing of PCa to bone implies that dispersal of cancer cells from the primary tumor cannot be entirely undirected. Unintentional chaperoning by a highly migratory species to assist the dispersal of another species is a common ecological phenomenon. It is likely that a similar mechanism of directed dispersal contributes to the non-random PCa homing to bone. A component of the physiologic function of many bone marrow cells is to enter the circulation to surveil for inflammation. Our data show that tumor cells from PCa patients circulate in complex with host white blood cells. We hypothesize that bone marrow cells may unwittingly carry information or physically chaperone cancer cells to the bone marrow niche as they continue their path through the circulation and back to the bone marrow. Work is underway to identify the cell type of the bone marrow chaperones.

Just because a cancer cell acquires the physical machinery to move does not mean that it will. Determining the combination of environmental and cellular cues that endow a cell to become an active and successful emigrant remains a high priority for the cancer field. A deeper understanding of each of the components of the movement ecology of cancer will lead to the development of novel therapeutics targeted to interrupt previously unidentified steps of metastasis.

Citation Format: Sarah R. Amend, Sounak Roy, Joel S. Brown, Kenneth J. Pienta. Ecological movement paradigms to understand the dynamics of metastasis. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr C02.