Final Report Summary - INCA (Genetic and environmental factors that control inflammation-driven colon cancer)
The human gastrointestinal tract is colonized by trillions of diverse bacteria collectively referred to as the microbiome that exist in a mutualistic relationship with the host that promotes intestinal health. Maladaptation in this host-microbial dialogue leads to a deranged inflammatory response and inflammatory bowel disease (IBD) that can progress to colorectal cancer (CRC). Supported by funding from the ERC we have examined the complex interplay between host genetic and environmental factors and their impact on intestinal inflammation and the transition from colitis to CRC.
Our previous studies identified a genetic locus called Hiccs that controls bacteria-driven invasive colon cancer through effects on innate inflammation. In this grant we have identified the Hiccs locus gene, Alpk1, as a potent regulator of intestinal inflammation. These studies showed Alpk1 in macrophages regulates intestinal inflammatory T cell responses following microbial challenge. Loss of Alpk1 in macrophages led to increased cytokine IL-12 expression, skewing T cell responses from a Th17 to Th1 phenotype thus promoting intestinal inflammation and colitis. Our findings complement work from others showing Alpk1 is a sensor of bacterial cell wall metabolites, which taken together suggest a central role for this pathway in host recognition of intestinal bacteria.
We have also examined the interplay between bacterial communities in the gut and intestinal inflammation. Using a mouse model of colitis and high-throughput sequencing technologies we have found an increased transcription and abundance of microbial gene families involved in responses to nutrient deprivation, antimicrobial peptide production and oxidative stress, suggesting an adaptation of microbial communities to withstand environmental stressors in the inflammatory environment. As part of this research direction, we also found that a polysaccharide produced by Helicobacter hepaticus induces an anti-inflammatory and repair programme in macrophages via a TLR2-MSK-CREB pathway. This provides a molecular mechanism underpinning mutualism between host cells and commensal bacteria, which with further investigation may open up new therapeutic strategies for infectious disease and IBD.
Building on our previous studies linking the cytokine IL-22 to inflammation-driven colorectal cancer, we have also examined further the role of the IL-22 pathway in human CRC. We have identified a synergistic pathway between IL-22 signalling and an oncogene commonly mutated in CRC. Our work shows this synergistic pathway is associated with worse outcomes in human disease and promotes increased proliferation of cancer cells in organoid models. We are now beginning to define the mechanism of synergy in ongoing studies. On the basis of these data we are also progressing to experimental medicine studies exploring anti-cytokine therapy in a subset of CRC patients with clinically aggressive disease.
In sum, our work supported by the ERC identifies novel pathways promoting intestinal homeostasis that may pave the way for new strategies to combat intestinal inflammation. Additionally, our studies have revealed how inflammatory signalling may drive CRC progression of patients whose tumours have defined molecular profiles. We we are now planning experimental medicine trials to test anti-cytokine therapies in colorectal cancer patients.
Our previous studies identified a genetic locus called Hiccs that controls bacteria-driven invasive colon cancer through effects on innate inflammation. In this grant we have identified the Hiccs locus gene, Alpk1, as a potent regulator of intestinal inflammation. These studies showed Alpk1 in macrophages regulates intestinal inflammatory T cell responses following microbial challenge. Loss of Alpk1 in macrophages led to increased cytokine IL-12 expression, skewing T cell responses from a Th17 to Th1 phenotype thus promoting intestinal inflammation and colitis. Our findings complement work from others showing Alpk1 is a sensor of bacterial cell wall metabolites, which taken together suggest a central role for this pathway in host recognition of intestinal bacteria.
We have also examined the interplay between bacterial communities in the gut and intestinal inflammation. Using a mouse model of colitis and high-throughput sequencing technologies we have found an increased transcription and abundance of microbial gene families involved in responses to nutrient deprivation, antimicrobial peptide production and oxidative stress, suggesting an adaptation of microbial communities to withstand environmental stressors in the inflammatory environment. As part of this research direction, we also found that a polysaccharide produced by Helicobacter hepaticus induces an anti-inflammatory and repair programme in macrophages via a TLR2-MSK-CREB pathway. This provides a molecular mechanism underpinning mutualism between host cells and commensal bacteria, which with further investigation may open up new therapeutic strategies for infectious disease and IBD.
Building on our previous studies linking the cytokine IL-22 to inflammation-driven colorectal cancer, we have also examined further the role of the IL-22 pathway in human CRC. We have identified a synergistic pathway between IL-22 signalling and an oncogene commonly mutated in CRC. Our work shows this synergistic pathway is associated with worse outcomes in human disease and promotes increased proliferation of cancer cells in organoid models. We are now beginning to define the mechanism of synergy in ongoing studies. On the basis of these data we are also progressing to experimental medicine studies exploring anti-cytokine therapy in a subset of CRC patients with clinically aggressive disease.
In sum, our work supported by the ERC identifies novel pathways promoting intestinal homeostasis that may pave the way for new strategies to combat intestinal inflammation. Additionally, our studies have revealed how inflammatory signalling may drive CRC progression of patients whose tumours have defined molecular profiles. We we are now planning experimental medicine trials to test anti-cytokine therapies in colorectal cancer patients.