Metabolic Recycling Enhances Proliferation in MYC‐Transformed Lymphoma B Cells

Abstract

percentage of intact living cancer cells remaining at the tumor site surrounded by dead cancer cell debris. We hypothesize that this dead cell debris creates a microenvironment rich in metabolite and energy sources at the tumor site, promoting growth of the surviving cancer cells in the vicinity of the irradiated, dead cancer cells, thus helping to promote the growth of the remaining living cancer cells beyond their intrinsic fast-growing characteristics.In this study, to mimic a post-therapy microenvironment, MYC-transformed human lymphoma B cells (or P493 MYC-ON cells containing a tetracyclinerepressible MYC construct), [2][3][4][5][6][7] were completely eradicated by UV radiation, and henceforth referred to as dead donor cells. Live, intact P493 cells (receiver cells), were then cultured in this newly created posttherapy environment. After first observing the growth-promoting effect of the posttherapy environment on the receiver cells both in vitro and in vivo, we used stable isotope-resolved metabolomics (SIRM) with labeled 13 C 6 -glucose to investigate how this specific environment increased the proliferation of cancer cells beyond their intrinsic fast-growing characteristics. We discovered that post-therapy dead cancer cells serve as nutritional sources of "off-the-shelf" and precursor metabolites for the live cancer cells to take up and utilize and metabolize.Relapses negatively impact cancer patient survival due to the tumorigenesis ability of surviving cancer cells post-therapy. Efforts are needed to better understand and combat this problem. This study hypothesized that dead cell debris post-radiation therapy creates an advantageous microenvironment rich in metabolic materials promoting the growth of remaining live cancer cells. In this study, live cancer cells are co-cultured with dead cancer cells eradicated by UV radiation to mimic a post-therapy environment. Isotopic labeling metabolomics is used to investigate the metabolic behavior of cancer cells grown in a post-radiation-therapy environment. It is found that post-UV-eradicated dead cancer cells serve as nutritional sources of "off-the-shelf " and precursor metabolites for surviving cancer cells. The surviving cancer cells then take up these metabolites, integrate and upregulate multiple vital metabolic processes, thereby significantly increasing growth in vitro and probably in vivo beyond their intrinsic fast-growing characteristics. Importantly, this active metabolite uptake behavior is only observed in oncogenic but not in non-oncogenic cells, presenting opportunities for therapeutic approaches to interrupt the active uptake process of oncogenic cells without affecting normal cells. The process by which living cancer cells re-use vital metabolites released by dead cancer cells post-therapy is coined in this study as "metabolic recycling" of oncogenic cells.