Mechanisms of Stem Cell Regulation during Tissue Renewal and Cancer Development - Project Summary/Abstract Tissue renewal is essential for long-lived organisms such as humans. Billions of cells are replaced daily in the human body; paradoxically, this constant cellular turnover of aging and damaged cells provides recurrent opportunities for cancer development. Indeed, over 90% of human cancers originate in epithelial tissues that undergo frequent renewal throughout life. However, studying cellular transformation during tissue renewal is challenging as it involves asynchronously different turnover rates (e.g., skin and intestinal epithelia). Tissue turnover is also influenced by complex crosstalk across tissues that impact cellular decisions in the adult body. DNA damage represents one of the earliest manifestations of cellular transformation, and it is a poorly understood hallmark of cancer. In this proposal, we seek to gain fundamental knowledge about the mechanisms underlying the survival of stem cells with DNA damage and the gain of uncontrolled proliferation as they respond to demands of tissue renewal in the adult body. We analyze stem cell behavior in situ and consider the influence of surrounding tissues. We capitalize on an emerging experimental model system based on planarian flatworms. Planarians undergo the constant renewal of tissues fueled by stem cells called neoblasts. DNA double-strand breaks (DSB) are the most dangerous form of DNA damage, and we developed a strategy to induce a cancer phenotype in planarians that evolve in 12 days. This phenotype is based on the functional disruption of an evolutionarily conserved tumor suppressor gene PTEN, the second most inactivated gene in human cancers. Downregulation of PTEN with RNAi in planarians elicits a cancer phenotype resembling the mammalian counterpart. Cellular transformation becomes noticeable within a few hours after PTEN inhibition and evasion of apoptosis, cellular over-proliferation, tissue invasion, and the formation of lethal tumors appear in under two weeks. Strikingly, disrupting neural signals suppress the cancer phenotype offering unprecedented opportunities to learn how to control cancer. We propose using robust genetics and cell biology analyses and cutting-edge genomic studies to integrate information from body regions, neural input, and single cells to reveal multiscale information driving the survival and proliferation of cells with DNA damage during tissue renewal. The information obtained from these experiments is expected to uncover critical mediators connecting adult tissue maintenance and its relationship to cancer progression. Our project addresses fundamental tenets of health and disease by analyzing systemic tissue renewal containing cells that evade apoptosis and divide with genomic instability.
