Periodic Reporting for period 2 - EGFRtoMITO (EGFR signalling talks to mitochondria through contact sites)
Période du rapport: 2023-01-01 au 2024-06-30
Cells have receptors on their surface which act like antennas, receiving signals from the outside world. When a receptor binds to an external signal molecule, it triggers a cascade of chemical reactions inside the cell that eventually reach the nucleus, the cell's control centre. Here, instructions are received and processed to generate a cellular response, such as to replicate or move elsewhere. Until recently, it was believed that this ‘long-range’ communication from the cell surface to the nucleus was the only way cells respond to an external stimulus. However, alternative communication routes are now being discovered, revealing the existence of a much more complex and sophisticated communication network inside the cell that involves many different cellular components or organelles working together to generate appropriate biological responses.
Research by our group has revealed that a particular group of receptors, known as growth factor receptors, can communicate directly with certain organelles in the cell. Growth factors are messengers that cells use to communicate with each other. They are important for coordinating the activities of cells in our bodies, playing a crucial role in processes like growth, development, and wound healing. When a growth factor binds to its receptor, it can induce a multitude of cellular responses:
• growth and division to produce more cells,
• differentiation, where cells become more specialized for a specific function,
• migration to a different location,
• survival,
• metabolic changes affecting how cells utilize energy and nutrients,
• changes in gene or protein expression which are needed to support specific functions.
How a cell interprets the signal from the growth factor and chooses the appropriate cellular response for a given circumstance is still unclear.
Our hypothesis is that activated receptors can utilize different communication routes inside the cell, leading to various cellular responses. These responses depend on specific conditions such as the type of cell and the level and duration of growth factor stimulation. In essence, different conditions trigger the selection of distinct communication routes downstream of the receptor, resulting in diverse cellular outcomes.
The aim of this project is to explore the organelle communication network used by a particular growth factor receptor that is involved in many essential biological functions, such as proliferation, survival, migration and differentiation, but also in diseases, such as cancer. Our project seeks to understand precisely how this communication occurs, by trying to answer the following questions:
• How are signals passed from one organelle to another to produce a specific cellular response?
• Which proteins mediate the physical interaction between organelles?
• How do these interactions influence the cell’s behaviour?
The results of this research will not only increase our understanding of how cells respond to their environment, but can also give clues to how this process can go wrong in disease. The dysregulation of growth factor signalling is a common feature of diseases such as cancer or developmental disorders. The characterization of the different communications routes used by growth factor receptors could lead to the development of new therapies that can interfere with these routes and block the unwanted cellular response.
Research by our group has revealed that a particular group of receptors, known as growth factor receptors, can communicate directly with certain organelles in the cell. Growth factors are messengers that cells use to communicate with each other. They are important for coordinating the activities of cells in our bodies, playing a crucial role in processes like growth, development, and wound healing. When a growth factor binds to its receptor, it can induce a multitude of cellular responses:
• growth and division to produce more cells,
• differentiation, where cells become more specialized for a specific function,
• migration to a different location,
• survival,
• metabolic changes affecting how cells utilize energy and nutrients,
• changes in gene or protein expression which are needed to support specific functions.
How a cell interprets the signal from the growth factor and chooses the appropriate cellular response for a given circumstance is still unclear.
Our hypothesis is that activated receptors can utilize different communication routes inside the cell, leading to various cellular responses. These responses depend on specific conditions such as the type of cell and the level and duration of growth factor stimulation. In essence, different conditions trigger the selection of distinct communication routes downstream of the receptor, resulting in diverse cellular outcomes.
The aim of this project is to explore the organelle communication network used by a particular growth factor receptor that is involved in many essential biological functions, such as proliferation, survival, migration and differentiation, but also in diseases, such as cancer. Our project seeks to understand precisely how this communication occurs, by trying to answer the following questions:
• How are signals passed from one organelle to another to produce a specific cellular response?
• Which proteins mediate the physical interaction between organelles?
• How do these interactions influence the cell’s behaviour?
The results of this research will not only increase our understanding of how cells respond to their environment, but can also give clues to how this process can go wrong in disease. The dysregulation of growth factor signalling is a common feature of diseases such as cancer or developmental disorders. The characterization of the different communications routes used by growth factor receptors could lead to the development of new therapies that can interfere with these routes and block the unwanted cellular response.
Our research has shown that when a particular growth factor receptor is activated by high levels of growth factor, organelles inside the cell, such as the endoplasmic reticulum and mitochondria, move closer the cell surface (or plasma membrane) where the activated receptors are located. The endoplasmic reticulum is an organelle that produces proteins and acts as a store of calcium, a crucial chemical messenger in the cell, while mitochondria are responsible for the cell’s energy production. Notably, this organelle ‘platform’ is not formed when low levels of growth factor are present suggesting that it could be involved in activating specific cellular responses to high levels of receptor activation.
We found that, through this organelle platform, the activated receptors can interact with the endoplasmic reticulum and mitochondria, influencing their function. First, the receptor transmits a signal to the nearby endoplasmic reticulum causing it to release calcium. We have identified the different proteins and precise biochemical reactions that are involved in the transmission of this signal. The released calcium is then sensed by neighbouring mitochondria causing them to increase their production of the cell’s energy molecule, called ATP. ATP works like a tiny battery storing and supplying energy for all the processes occurring inside the cell. This increased ATP production in the vicinity of activated receptors has a dual purpose. On the one hand, it powers the internalization of activated receptors and their trafficking to a compartment (the lysosomes) inside the cell where they are degraded. This results in a dampening down of growth signals from the receptor. On the other hand, the ATP is used to power the cellular machinery responsible for cell movement, i.e. the actin cytoskeleton. The actin cytoskeleton is made up of tiny fibres called actin filaments, which crisscross throughout the cell. The filaments act like dynamic scaffolding, which, by changing shape, helps cells move. Therefore, the inter-organelle communication network appears to be important in ensuring the correct cellular response to high levels of growth factor, i.e. suppressing the cell growth while promoting cell movement.
Importantly, we have identified proteins involved in keeping the activated receptors, the endoplasmic reticulum, and mitochondria close together. Some of these proteins play a role in the exchange of lipids, the building blocks of membranes, across different organelles. Each organelle, as well as the cell itself, is surrounded by a membrane, which acts as a flexible barrier controlling what goes in and out. Different kinds of lipids are found in membranes, which influence the membranes’ properties and help regulate what molecules can pass through. In this way, the lipids help maintain the internal environment while allowing communication with the surroundings. Since we found that many of the proteins involved in bringing the activated receptors and organelles together are also involved in exchanging lipids between membranes, this means that growth factor signalling could directly influence organelle function through regulating the lipid composition of their membrane. This finding highlights another potential mechanism by which growth factors can regulate cell function.
In summary, our research, has characterized a novel route of transmitting signals from the external environment to inside cells, involving different proteins, chemical messengers, and organelles, which work together to generate a coherent cellular response. The identification of this communication route specifically involved in growth factor signalling could lead to the development of novel pharmaceuticals for the treatment of diseases such as cancer.
We found that, through this organelle platform, the activated receptors can interact with the endoplasmic reticulum and mitochondria, influencing their function. First, the receptor transmits a signal to the nearby endoplasmic reticulum causing it to release calcium. We have identified the different proteins and precise biochemical reactions that are involved in the transmission of this signal. The released calcium is then sensed by neighbouring mitochondria causing them to increase their production of the cell’s energy molecule, called ATP. ATP works like a tiny battery storing and supplying energy for all the processes occurring inside the cell. This increased ATP production in the vicinity of activated receptors has a dual purpose. On the one hand, it powers the internalization of activated receptors and their trafficking to a compartment (the lysosomes) inside the cell where they are degraded. This results in a dampening down of growth signals from the receptor. On the other hand, the ATP is used to power the cellular machinery responsible for cell movement, i.e. the actin cytoskeleton. The actin cytoskeleton is made up of tiny fibres called actin filaments, which crisscross throughout the cell. The filaments act like dynamic scaffolding, which, by changing shape, helps cells move. Therefore, the inter-organelle communication network appears to be important in ensuring the correct cellular response to high levels of growth factor, i.e. suppressing the cell growth while promoting cell movement.
Importantly, we have identified proteins involved in keeping the activated receptors, the endoplasmic reticulum, and mitochondria close together. Some of these proteins play a role in the exchange of lipids, the building blocks of membranes, across different organelles. Each organelle, as well as the cell itself, is surrounded by a membrane, which acts as a flexible barrier controlling what goes in and out. Different kinds of lipids are found in membranes, which influence the membranes’ properties and help regulate what molecules can pass through. In this way, the lipids help maintain the internal environment while allowing communication with the surroundings. Since we found that many of the proteins involved in bringing the activated receptors and organelles together are also involved in exchanging lipids between membranes, this means that growth factor signalling could directly influence organelle function through regulating the lipid composition of their membrane. This finding highlights another potential mechanism by which growth factors can regulate cell function.
In summary, our research, has characterized a novel route of transmitting signals from the external environment to inside cells, involving different proteins, chemical messengers, and organelles, which work together to generate a coherent cellular response. The identification of this communication route specifically involved in growth factor signalling could lead to the development of novel pharmaceuticals for the treatment of diseases such as cancer.
We have discovered a novel route by which growth factor receptors can transmit their signal inside the cell and generate cellular responses. This communication network does not involve the nucleus or changes in gene expression, but instead involves the interaction of three essential organelles: the plasma membrane (where the activated receptor is located), the endoplasmic reticulum, and the mitochondria. The interaction between these organelles influences their functions and ultimately leads to a biological output, i.e. cell migration.
Currently, we are exploring the relevance of this inter-organelle communication route to the normal functioning of the body. To do this, we are investigating whether this communication route is active in different cell types and organs. These experiments require sophisticated laboratory models that can be easily manipulated and analysed.
To study different types of normal cells, we are using an immortal stem cell model that can differentiate into distinct cell types, such as:
• heart muscle cells (cardiomyocytes),
• liver cells (hepatocytes),
• skin cells that also line the internal organs (epithelial cells),
• specialized skin cells that play a crucial role in maintaining the integrity and strength of the skin (keratinocytes),
• connective tissue cells which provide structure and support to tissues and help them to heal after injury (fibroblasts).
To study organs, we are using organoids, miniaturized versions of organs that can be grown in the lab. Organoids are made from stem cells, which, under the right conditions, can produce the different types of cells found in an organ. These cells self-organize to mimic the structure and function of real organs. Using an inhibitor to the block the activity of the growth factor receptor that we are studying, the growth of organoids derived from the mammary gland and the intestine was inhibited. These results indicate a central role of this receptor in the development and growth of these organs.
We are now using these laboratory models to investigate whether the inter-organelle communication network is present and, if so, how it is regulated. We also want to understand what the effects of inhibiting this communication route are on cell/organoid function. These experiments will provide insights into the normal function and regulation of the inter-organelle communication network and possibly how its deregulation could contribute to diseases such as cancer.
Currently, we are exploring the relevance of this inter-organelle communication route to the normal functioning of the body. To do this, we are investigating whether this communication route is active in different cell types and organs. These experiments require sophisticated laboratory models that can be easily manipulated and analysed.
To study different types of normal cells, we are using an immortal stem cell model that can differentiate into distinct cell types, such as:
• heart muscle cells (cardiomyocytes),
• liver cells (hepatocytes),
• skin cells that also line the internal organs (epithelial cells),
• specialized skin cells that play a crucial role in maintaining the integrity and strength of the skin (keratinocytes),
• connective tissue cells which provide structure and support to tissues and help them to heal after injury (fibroblasts).
To study organs, we are using organoids, miniaturized versions of organs that can be grown in the lab. Organoids are made from stem cells, which, under the right conditions, can produce the different types of cells found in an organ. These cells self-organize to mimic the structure and function of real organs. Using an inhibitor to the block the activity of the growth factor receptor that we are studying, the growth of organoids derived from the mammary gland and the intestine was inhibited. These results indicate a central role of this receptor in the development and growth of these organs.
We are now using these laboratory models to investigate whether the inter-organelle communication network is present and, if so, how it is regulated. We also want to understand what the effects of inhibiting this communication route are on cell/organoid function. These experiments will provide insights into the normal function and regulation of the inter-organelle communication network and possibly how its deregulation could contribute to diseases such as cancer.