Periodic Reporting for period 4 - DENOVOSTEM (DE NOVO GENERATION OF SOMATIC STEM CELLS: REGULATION AND MECHANISMS OF CELL PLASTICITY)
Okres sprawozdawczy: 2020-03-01 do 2021-08-31
In living organs, cells are in intimate contact with each other and with their microenvironment. In this context, 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) in response to signals emanating from their surroundings or to change their behavior in response to tissue needs, as it occurs during wound healing. Healthy tissues can also recognize individual tumor cells, and either eliminate them, or induce them to "normalize" their behavior, as such taming the effect of oncogenic mutations.
These control systems are poorly understood because they represent forms of regulation that are proper of a cellular ensemble in its entirety. Thus, new experimental tools and conceptual paradigms are essential to understand the molecular basis of these tissue-level attributes. Addressing these unknowns has been a main focus of our ERC grant. We believe that understanding how cell communicate with each other and their environment will reveal a “treasure throve” of therapeutic opportunities in regenerative medicine and cancer treatment. This includes new ways to generate stem cells when the natural pool of these cells has been eroded by damage or ageing, and innovative strategies to prevent tumor emergence based on the body own healing capacities.
Our core objective has been to tackle the core question behind these biological events, that is, how normal cells change their fate once the environment is changing. In asking this, our primary perspective has been rooted to the notion that cells are embedded in mechanical signals emanating from their physical touching each other and the extracellular matrix to which they adhere. These signals are potent determinant of cell behavior affecting cells every second of their life. Cells respond to mechanical signals using special mechanosensory proteins, that are the YAP and TAZ transcription factors.
Through this ERC grant, our work revealed a striking overlap between stemness, tissue regeneration and cancer, all sharing features of cell fate plasticity dictated by the activation of YAP/TAZ transcriptional responses. Our insights in cancer biology and cell-cell communication have also with far-reaching implications in the biology of ageing and other human disorders.
These control systems are poorly understood because they represent forms of regulation that are proper of a cellular ensemble in its entirety. Thus, new experimental tools and conceptual paradigms are essential to understand the molecular basis of these tissue-level attributes. Addressing these unknowns has been a main focus of our ERC grant. We believe that understanding how cell communicate with each other and their environment will reveal a “treasure throve” of therapeutic opportunities in regenerative medicine and cancer treatment. This includes new ways to generate stem cells when the natural pool of these cells has been eroded by damage or ageing, and innovative strategies to prevent tumor emergence based on the body own healing capacities.
Our core objective has been to tackle the core question behind these biological events, that is, how normal cells change their fate once the environment is changing. In asking this, our primary perspective has been rooted to the notion that cells are embedded in mechanical signals emanating from their physical touching each other and the extracellular matrix to which they adhere. These signals are potent determinant of cell behavior affecting cells every second of their life. Cells respond to mechanical signals using special mechanosensory proteins, that are the YAP and TAZ transcription factors.
Through this ERC grant, our work revealed a striking overlap between stemness, tissue regeneration and cancer, all sharing features of cell fate plasticity dictated by the activation of YAP/TAZ transcriptional responses. Our insights in cancer biology and cell-cell communication have also with far-reaching implications in the biology of ageing and other human disorders.
Through this ERC grant, we discovered that mechanical signals induce cells to undergo dramatic changes in their differentiation state. We found that 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 discovered 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 identified 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.