Periodic Reporting for period 4 - DualRP (Exploring cell interactions in the tumor microenvironment with dual ribosome profiling)
Reporting period: 2022-12-01 to 2024-05-31
This research is important for society because understanding and targeting the metabolic needs of tumors could lead to more effective cancer treatments with fewer side effects than current options. Cancer remains one of the leading causes of death worldwide, and many patients face treatment resistance or relapse. By identifying specific amino acid limitations in the TME, researchers can develop therapies that disrupt the metabolic support that tumors rely on to grow. This approach has the potential to improve outcomes for patients, particularly those with cancers that are difficult to treat or resistant to existing therapies.
The main goals of the project are to identify these metabolic vulnerabilities using tools like DualRP and diricore, to understand how cancer cells interact with surrounding stromal cells in ways that promote tumor growth, and to apply these insights to develop new therapies. Ultimately, the project aims to reprogram the TME to block tumor growth and overcome treatment resistance, offering new avenues for cancer treatment.
One of our significant findings was that cancer cells and fibroblasts, which support the tumor, experience shortages of key amino acids, such as alanine and glycine, under low glucose conditions. However, when these cells are co-cultured, they manage to overcome this shortage by activating a specific signaling pathway, allowing them to produce the nutrients they need to make proteins. Additionally, we developed mouse models that let us examine different cell types' interactions and metabolic activities in a more natural, living environment. This has been crucial in discovering how amino acid restrictions can affect immune cells, particularly T-cells, during cancer treatment with checkpoint inhibitors. Our research showed that when T-cells lack certain amino acids, their ability to respond to cancer therapies weakens.
Our findings are being shared through scientific publications and conferences, contributing to the broader understanding of cancer metabolism. Moving forward, we aim to develop new therapies that target these metabolic weaknesses, with the hope of improving cancer treatments and overcoming drug resistance. This research sets the stage for future innovations in cancer therapy by shedding light on the complex metabolic interactions within the TME.
Overall, the project has advanced our understanding of the TME's metabolic complexities, setting the stage for future therapeutic innovations in cancer treatment.
The project has also uncovered specific metabolic vulnerabilities, particularly in amino acid dependencies. DualRP, in combination with another tool called diricore, identified limitations in amino acids like alanine and glycine in cancer and stromal cells. Interestingly, these limitations were resolved in co-cultures, revealing critical metabolic interactions that could be targeted in future therapies. Additionally, the discovery that the Interferon-β1 signaling pathway plays a role in triggering lysosomal acidification and nutrient generation offers a new understanding of TME dynamics and potential therapeutic interventions.
Further progress has been made using transgenic mouse models, which allow for in vivo studies of these metabolic interactions. These models, with ribosome-tagged immune and cancer cells, provide more physiologically relevant insights than traditional lab-based (in vitro) studies. For example, research into checkpoint inhibitor therapies, such as anti-PD-1 treatments, revealed that they cause serine and glycine shortages in T-cells, underscoring the importance of the serine synthesis pathway for an effective immune response. This insight could lead to improvements in cancer immunotherapy strategies. The project shed light on how gene expression and metabolic processes contribute to tumor growth and metastasis. By identifying specific metabolic weaknesses in the interactions between cancer and stromal cells, new therapeutic targets could emerge.