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DE NOVO GENERATION OF SOMATIC STEM CELLS: REGULATION AND MECHANISMS OF CELL PLASTICITY

Periodic Reporting for period 3 - DENOVOSTEM (DE NOVO GENERATION OF SOMATIC STEM CELLS: REGULATION AND MECHANISMS OF CELL PLASTICITY)

Reporting period: 2018-09-01 to 2020-02-29

"In living organs, cells are in intimate contact with each other and with their microenvironment. Within tissues, cells display remarkable, and yet mysterious, “social” behaviors. Prominent examples are the ability of cells to stop proliferating (i.e. of making copies of themselves) when they start touching each other; to change their destiny to accommodate tissue needs; or to self-organize into new tissue during the repair of damaged organs. Healthy tissues can also recognize individual tumor cells and either eliminate them or ""normalize"" their behavior, as such taming the effect of oncogenic mutations.
These tissue-level sensory and control systems are completely subverted in solid tumors, in favor of the expansion of renegade tumor cells. By understanding these overarching control systems, our ultimate goal is to devise strategies to eradicate established tumors and their metastases. We do so by investigating how cells control their function through a set of transcription factors, called YAP and TAZ that operate by regulating the expression of genes.
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Through this ERC grant, we discovered that by physically touching each other and interacting to the material substrate to which they are attached, cells undergo dramatic changes in their differentiation state. We found that, during tissue damage, alteration of the microenvironment induces cells to turn on YAP/TAZ and initiate a reprogramming step by which they shed their more differentiated traits to acquire characteristics that are typical of stem cells of the same tissue. Scientists have long recognized that there is a dark side in tissue repair: the same genetic and cellular programs used by tissue to repair themselves and to make new stem cells are hijacked in tumor cells to initiate tumors and progress them to more and more malignant states. In this ERC program, our investigation of the fundamental mechanisms by which cells perceive themselves and their environment and on the role of YAP/TAZ as cell plasticity factors, is leading the discovery of the very fundamental mechanisms that govern the emergence and maintenance of tumor cells as well as the identification of effective targets for therapeutic intervention and drug discovery.
"We are investigating a completely new form of ""cellular reprogramming"" that, at difference with other reprogramming or transdifferentiation efforts, correspond to a modality of cell plasticity that cells in healthy organs use to respond to tissue needs after tissue damage, or that tumor cells adopt to fuel their expansion and metastastic spread in deranged tissues. Our work aims to identify the basic molecular determinants of the differentiated vs stem cell states and use this knowledge to build new stem cells and device new modalities to predict or combat malignancies."