Cell Cooperation and Competition Within the Tumor Micro Environment

Speaker

Carlos Carmona-Fontaine
Assistant Professor
Department of Biology, New York University

Abstract

Most cancer and cell biologists are familiar with the fact that mammalian cells grow poorly when cultured at low densities. The usual explanation for this density-dependent effect, is that secreted growth factors increase cell growth in a paracrine manner. I will present evidence for a novel cooperative mechanism that is growth factor-independent and essential for the survival of cancer cells under nutrient deprived conditions usually found in the tumor microenvironment. Our results in lung, breast, colon, and pancreatic tumor cells show that these cells can collectively scavenge extracellular peptides when extracellular amino acids levels are scarce. Surprisingly, these peptides are not catabolized inside cells but are cleaved by membrane-associated aminopeptidases (MAAPs) outside the cell, resulting in a shared pool of extracellular amino acids. While dense populations benefit from this mechanism, in low density populations amino acids do not accumulate to meaningful levels and thus cell growth stalls and cells eventually die. In vivo, MAAP gene copy numbers, mRNA expression, and protein levels are increased in multiple tumors, including lung adenocarcinomas. High MAAP levels also correlate with poor patient prognosis. Our data show a previously unrecognized mechanism by which mammalian cells cope with amino acid starvation. In contrast to other known mechanisms such as transporter-mediated amino acid uptake and macropinocytosis followed by lysosomal catabolism of proteins, this is a non-cell autonomous process. This mechanism is a previously unrecognized form of amino acid scavenging in mammalian cells and one of the first examples of growth factor-independent cell cooperation with potential implications for tumor ecology and evolution. We propose that this mechanism is a critical adaptation to amino acid starvation during tumor progression and potentially a novel therapeutic target.

Biography

Carlos Carmona-Fontaine is an Assistant Professor of Biology and member of the Center for Genomics and Systems Biology at New York University. He holds a Ph.D. in Cell and Developmental Biology from University College London, UK and a B.Sc. in Biological Sciences from PUC (Chile). The main interest of his laboratory is to understand how cells organize to form multicellular structures and to coordinate in collective processes. M Prior to joining the faculty at NYU, Carlos was an independent research fellow at the Computational Biology Program at the Memorial Sloan Kettering Cancer Center.