Understanding the complex biology of AHR activation in cancer

Project Information

CancAHR

Grant agreement ID: 101045257

DOI

10.3030/101045257

EC signature date 13 November 2022

Start date 1 January 2023

End date 31 December 2027

Funded under

• European Research Council (ERC)

Total cost

€ 1 999 925,00

EU contribution

€ 1 999 925,00

Coordinated by

DEUTSCHES KREBSFORSCHUNGSZENTRUM HEIDELBERG
Germany

Periodic Reporting for period 1 - CancAHR (Understanding the complex biology of AHR activation in cancer)

Reporting period: 2023-01-01 to 2025-06-30

Summary of the context and overall objectives of the project

The aryl hydrocarbon receptor (AHR) was originally identified as a key player in the harmful effects of environmental pollutants like dioxin. However, research has since revealed that AHR plays a broader role in regulating critical biological functions, including immune responses, metabolism, and cancer progression. While it was once thought that only certain toxic chemicals could activate AHR, scientists now know that a wide range of natural and internally produced molecules, including tryptophan metabolites, can also trigger its activity.
AHR is highly expressed in tumors, where it promotes cancer cell survival, invasion, and resistance to treatment. It also weakens the body’s natural immune defenses by suppressing key immune cells, making it easier for cancer to grow unchecked. These insights have led to the development of drugs designed to block AHR or reduce the production of its activators, but so far, success has been limited. One challenge is that different cancer types respond differently to AHR inhibition, and the molecular pathways involved are not yet fully understood. Additionally, differences between human and animal AHR functions complicate research and drug development.
Interestingly, not all AHR activation promotes cancer—some studies suggest that in certain contexts, AHR can actually help suppress tumors. This dual role likely depends on the type of AHR activator involved and the specific biological environment.
The CancAHR project aims to fill these knowledge gaps by uncovering the precise mechanisms of AHR activation in cancer. Researchers will investigate how AHR is influenced, which metabolic pathways regulate its activation, and why its effects vary between different cell types. A key goal is to determine whether AHR activity can serve as a predictive marker for cancer progression. This research could pave the way for personalized therapies that either block AHR’s harmful effects in aggressive cancers or harness its protective potential in certain cases, ultimately improving patient outcomes.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Recent discoveries have shed new light on the aryl hydrocarbon receptor (AHR) - a protein initially known for its role in responding to environmental toxins like dioxin. Our research has revealed that AHR is much more than a simple sensor of pollutants; it is a critical regulator of cell behavior, metabolism, and immune function. By investigating how AHR is activated and inhibited, we are uncovering new ways to target it for cancer therapy.
One of our most exciting findings is that AHR acts as a sensor of cellular stress, particularly when cells experience tryptophan shortage. When key nutrients like tryptophan are scarce, AHR becomes activated, influencing how cells adapt to these stressful conditions. Instead of merely responding to external toxins, AHR helps cells survive by regulating metabolism and energy use. This means that AHR plays an even bigger role in human health than previously thought, linking nutrition, metabolism, and disease progression.
Another breakthrough in our research is the discovery of novel metabolic enzymes and compounds that naturally activate AHR. While scientists knew that some tryptophan breakdown products could trigger AHR, we have identified additional molecules produced by the body that also influence its activity. These findings help explain why AHR plays such a complex role in cancer—some of these naturally occurring activators may fuel tumor growth, while others might help regulate immune responses. By pinpointing these molecules, we are opening new possibilities for designing drugs that either block harmful AHR activation in cancer or enhance its beneficial effects in certain diseases.
Since AHR activation has been linked to cancer progression, many researchers have sought ways to block its effects. We have identified key factors that determine whether an AHR-blocking drug will be effective, helping to refine future therapies. These discoveries are reshaping our understanding of AHR in cancer. By uncovering the details of how AHR is activated and inhibited, we are laying the groundwork for personalized cancer treatments that consider an individual patient’s unique tumor environment.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Results beyond the state of the art in unraveling the complex biology of AHR in cancer
Cancer remains one of the most challenging diseases to treat, with scientists constantly searching for new ways to fight it. One exciting area of research focuses on a protein called the Aryl Hydrocarbon Receptor (AHR), which plays a crucial role in how cells respond to their environment. While AHR was originally known for helping the body process toxins, researchers have discovered that it also influences cancer growth, making it a potential game-changer in treatment. AHR is a protein found inside cells that helps regulate genes. When certain molecules bind to AHR, it activates and moves into the cell’s nucleus, where it influences which genes turn on or off. This function is essential for various biological processes, such as immune responses, cell growth, and detoxification. However, scientists have recently found that AHR can also contribute to cancer development and progression. Depending on the type of cancer, AHR can either help or harm the body. In some cancers, AHR promotes tumor growth by supporting cell survival and preventing immune cells from attacking the tumor. In contrast, in other cancers, AHR can act as a protective factor by reducing inflammation and blocking cancer spread. Understanding how AHR functions in different cancers will open the door to new treatment possibilities. Scientists are now exploring ways to block or activate AHR depending on the type of cancer. For example, drugs that inhibit AHR could help the immune system recognize and attack cancer cells more effectively. On the other hand, in cancers where AHR is beneficial, activating it could slow down tumor growth and improve patient outcomes.

Overview CancAHR project