The motility-proliferation-metabolism interplay during metastatic invasion

Inbal Hecht, Sari Natan, Assaf Zaritsky, Herbert Levine, Ilan Tsarfaty, Eshel Ben-Jacob
2015 Scientific Reports  
Metastasis is the major cause for cancer patients' death, and despite all the recent advances in cancer research it is still mostly incurable. Understanding the mechanisms that are involved in the migration of the cells in a complex environment is a key step towards successful anti-metastatic treatment. Using experimental data-based modeling, we focus on the fundamentals of metastatic invasion: motility, invasion, proliferation and metabolism, and study how they may be combined to maximize the
more » ... ancer's ability to metastasize. The modeled cells' performance is measured by the number of cells that succeed in migration in a maze, which mimics the extracellular environment. We show that co-existence of different cell clones in the tumor, as often found in experiments, optimizes the invasive ability in a frequently-changing environment. We study the role of metabolism and stimulation by growth factors, and show that metabolism plays a crucial role in the metastatic process and should therefore be targeted for successful treatment. Despite impressive advances in cancer research and therapy, cancer metastasis is still mostly incurable and is responsible for most patient deaths 1 . Metastasis is a multistep cascade that encompasses several stages: collective-to-individual cellular transition, migration, intravasation, extravasation and colonization at distant organs 2,3 . During the first stage of the metastatic process, single cells of the primary tumor detach and migrate through the extracellular matrix (ECM) toward the blood vessels. Then they are carried away by the blood stream to other locations, where they may be able to colonize the tissue and establish new, secondary tumors. The early metastatic process can be visualized using an intra-vital confocal analysis of a mouse abdomen with a primary mammary tumor (Fig. 1a, red) , surrounded by blood vessels (green). Higher magnification demonstrates small groups of cells spreading from the primary tumor toward the blood vessels, and a micrometastasis is also seen as a red lump separate from the primary tumor but close to a blood vessel. Blocking metastasis is the key for defeating cancer. In order to reach the blood (or lymph) system, the metastatic tumor cells must adopt a motility phenotype that allows them to move through a tortuous extracellular matrix [4] . Metastatic carcinoma cells exhibit at least two different phenotypes of motility and invasion -amoeboid and mesenchymal 4,5 . Mesenchymal motility is aided by the secretion of matrix metalloproteinases (MMPs) 6 . An example of MMP production by a tumor is presented in Fig. 1b , taken from a mouse mammary tumor. Matrix repatterning by MMP-based degradation is mostly important for massive cellular migration, which typically occurs after "forerunner cells" create small microtracks in the ECM, thus allowing other cells to follow more easily 7,8 . The primary tumor cells undergo Epithelial to Mesenchymal Transition (EMT) to
doi:10.1038/srep13538 pmid:26337223 pmcid:PMC4642550 fatcat:cuohajgclrhbnlfslmf6ps5xsu