Final Report Summary - CANCER&AGEING (COMMOM MECHANISMS UNDERLYING CANCER AND AGEING) Tumour suppressors are genes that can prevent the development of cancer. All our cells have a functional set of these genes. However, despite their efficient protection against cancer, these genes can become defective over time. The affected cells thus become partially unprotected from cancer and, in combination with additional mutations in other genes, can give rise to cancer. Our research group has been working for more than 15 years on the general topic of tumour suppression. During our CANCER&AGEING project, we have continued exploring new pathways and new mouse models of cancer, and we have extended our research to cellular reprogramming and metabolism due to the involvement of tumour suppressors in these two processes.The following are the main achievements of the project:1) Identification of a Barrier for the Generation of induced Pluripotent Stem (iPS) Cells. This has also helped in the understanding of the cellular mechanisms of defence. Artificial iPS cells generation by addition of a defined set of transcription factors is an inefficient process and the motives of the resistance to iPS cells conversion were unknown. We reasoned that since the tumour suppressor genes prevent that normal cells convert into cancer ones, they could also be preventing this other type of cellular “conversion” into iPS cells, and focused on the Ink4/Arf locus of genes, which encodes three potent tumour suppressors. We found that these genes increase their activity during the process of iPS generation and that they were indeed were the cause of the resistance of many cells to become iPS cells thus and that the temporarily blockage of these genes noticeably increases the yield in iPS cells generation. Subsequently, we reported similar findings regarding the tumour suppressor p27.2) Discovery that an Anti-Cancer Gene Also Fights Obesity. We revealed that Pten, one of the main genes protecting against cancer, brings two additional health benefits by boosting longevity and combating obesity, establishing thus a direct link between cancer and metabolism. This has led to the subsequent development of a pharmacological treatment against obesity and metabolic syndrome based on the inhibition of PI3K whose efficacy has been confirmed in mice and monkeys. 3) Discovery of a Relationship Between Cancer Genes and a Reprogramming Gene. We discovered that the tumour suppressor p27 directly regulates the cellular reprogramming gene SOX2 (involved in lung cancer and pituitary cancers), which is also associated with these types of cancer. This new insight helps to understand the origin of p27-linked cancers, and highlight the potential role of adult stem cells in cancer.4) A New Therapeutic Strategy for Non-Small Cell Lung Carcinoma (NSCLC). Lung cancer is one of the most aggressive types of cancer and the most common cause of death from this disease worldwide. We have deciphered one of the molecular pathways behind lung cancer. Using this information, we have identified an experimental drug, which in mice blocks lung cancer growth.5) Discovery of Cell Reprogramming in vivo. We become the first to make adult cells from a living organism step back in their evolutionary development to recover the characteristics of embryonic stem cells bypassing thus the necessity to manipulate cells in vitro. We discovered that in vivo generated iPS cells have a broader capacity for differentiation than those obtained in vitro. Specifically, they have the characteristics of totipotent cells: a primitive state never before obtained in a laboratory. Generating iPS cells within an organism brings iPS cells technology even closer to regenerative medicine. This research was considered to be by the journal Nature Medicine "Achievement of the Year 2013" in the stem cells field6) Discovery that Cellular Senescence Also Plays a Role in Embryo Development. Senescence is one of the main mechanisms the body uses to protect itself against cancer. We discovered that this switching-off mechanism also takes place in embryos, and not as a response to cell damage but as part the normal process of development. We propose that senescence emerged during the course of evolution as an embryonic tissue remodelling process, and that it was subsequently adapted for tissue repair upon damage. 7) Discovery that the Embryonic Pluripotency Factor NANOG Plays a Role in Adult Stratified Epithelia. NANOG is a key pluripotency transcription factor in embryonic stem cells, whose role in adult tissues and cancer was still largely unexplored. We found that it is selectively expressed in stratified epithelia and that its overexpression is oncogenic for various types of human and murine squamous cell carcinomas.
