The immunomodulatory role of WNT in intestinal regeneration and cancer
Lead Research Organisation:
The Francis Crick Institute
Abstract
WNT signaling is responsible for regulating proliferation and differentiation of intestinal stem cells (ISCs). The importance of this pathway is highlighted in injury induced regeneration, where pharmalogical inhibition of WNT prevents ISC-dependent regeneration of the intestine. However, aberrant WNT activation is a hallmark of colorectal cancer (CRC), and found in ~85% of patients. Recently, a link has been discovered between hyperactivation of WNT and poor infiltration of cytotoxic T lymphocytes (CTL) in both human and mouse CRC. Consistently, WNT-mediated CTLs exclusion has also been found in WNT-high crypts in normal intestine and WNT activating regenerating crypts, suggesting that the WNT- mediated CTL exclusion is possibly a conserved mechanism in normal and regenerating intestinal crypts, as well as in cancer. Therefore, I aim to investigate the relationship between WNT activation and immunosuppression in intestinal regeneration and explore if there is a conserved or context-dependent mechanism between cancer and regeneration. Using the cutting-edge techniques CITE-seq, imaging mass cytometry (IMC) and high- dimensional flow cytometry,
I will spatiotemporally characterize the regenerating intestines upon targeted whole-intestine irradiation. This will be paired with immunomodulation models and pharmalogical inhibition of WNT upon irradiation induced regeneration to determine whether WNT dependent immunomodulation is required for intestinal regeneration. Finally, I will use endoscopy-guided orthotopic transplantation of WNT-high vs WNT-low tumor organoids to determine whether WNT-dependent immunomodulation is conserved between intestinal regeneration and cancer. Ultimately, these results will provide novel insights into immune cell dynamics upon regeneration, as well as for the development of tumor-specific therapies in WNT-activated CRCs with minimal toxicity.
I will spatiotemporally characterize the regenerating intestines upon targeted whole-intestine irradiation. This will be paired with immunomodulation models and pharmalogical inhibition of WNT upon irradiation induced regeneration to determine whether WNT dependent immunomodulation is required for intestinal regeneration. Finally, I will use endoscopy-guided orthotopic transplantation of WNT-high vs WNT-low tumor organoids to determine whether WNT-dependent immunomodulation is conserved between intestinal regeneration and cancer. Ultimately, these results will provide novel insights into immune cell dynamics upon regeneration, as well as for the development of tumor-specific therapies in WNT-activated CRCs with minimal toxicity.
| Description | AstraZeneca/Crick Alliance Award |
| Amount | £200,814 (GBP) |
| Funding ID | PRJ_20943 |
| Organisation | AstraZeneca |
| Sector | Private |
| Country | United Kingdom |
| Start | 01/2025 |
| End | 12/2027 |
| Description | Cancer Grand Challenges |
| Amount | £20,000,000 (GBP) |
| Organisation | Cancer Research UK |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 06/2026 |
| End | 06/2031 |
| Title | Antigen removal in vivo CRISPR screens |
| Description | Our lab has developed a series of new mouse CRC model systems that resemble human CRC in many important ways and are a substantial improvement on current preclinical systems. We will use these exciting CRC models to map tumour-intrinsic immune evasion pathways, utilising a newly developed in vivo CRISPR approach. Importantly, this project will bring this exciting screening technology to the Crick. The screening method we will use has been invented and highly optimised by the Manguso Lab, who are a world leader in developing CRISPR technologies to identify new immunotherapy targets. |
| Type Of Material | Technology assay or reagent |
| Year Produced | 2024 |
| Provided To Others? | No |
| Impact | This is still ongoing project. We will conduct a sub-genome screen in our AKPT CRC cell lines, using 10,000 sgRNAs. This will be the first time an in vivo CRISPR immune evasion screen will ever have been conducted with tumour cells that model human CRC in immunocompetent mice. The sub-genome screen will enable us to bring this exciting discovery platform to the Crick and establish the workflow at reasonable scale. |
| Title | CRISPR screen |
| Description | We have established whole genome and targeted CRISPR screening in CRC organoids in vitro as well as tumour development in vivo. This has generated valuable dataset to short list candidates that can sensitise immune checkpoint blockade. We can apply this technique to screen for other drug resistant targets such as for chemotherapy resistance. |
| Type Of Material | Technology assay or reagent |
| Year Produced | 2025 |
| Provided To Others? | No |
| Impact | CRISPR targeting in organoids is challenging due to the 3D culture condition. We have optimised effective targeting in organoids, which can benefit anyone working on organoid research. |
| Description | Antigen removal in vivo CRISPR screening |
| Organisation | Broad Institute |
| Country | United States |
| Sector | Academic/University |
| PI Contribution | Robert Manguso from the Broad Institute has pioneered the antigen removal approach to perform in vivo CRISPR screen. This is particularly useful for our project to study anti-PD1 resistance in colorectal cancer. We contribute the experimental design, including syngeneic CRC models, immunotherapy treatment and tumour collection and analysis. |
| Collaborator Contribution | The Broad Institute and Robert Manguso's lab provide technical support for the antigen removal CRISPR screening library and technology. |
| Impact | My postdoc Colin has travelled to Robert Manguso's lab in 2023 for 2 months to learn the antigen removal CRISPR screening technology. |
| Start Year | 2023 |
| Description | Crick/AstraZeneca Alliance |
| Organisation | AstraZeneca |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | We collaborate with AstraZeneca to explore the transcriptional changes of Wnt/beta-catenin pathway during colorectal cancer progression, with the aim to find new tumour-specific targets for drug development. We contribute our expertise in organoids, colorectal cancer, transcriptomics, CRISPR targeting and in vivo functional validation in mice. |
| Collaborator Contribution | AZ will contribute their expertise in proteomics and transcriptional analysis to this project. They fund a postdoc for 2 years. |
| Impact | Received a 2 year postdoc to work on this project. |
| Start Year | 2025 |
| Description | Tumour rewiring |
| Organisation | Broad Institute |
| Country | United States |
| Sector | Academic/University |
| PI Contribution | This is the new Cancer Grand Challenge awarded this year. Together we are working to rewire cancer cells to their disadvantage to overcome treatment resistance. My team is involved in testing compounds in mouse tumour models established in the lab. We will also perform genome-wide CRISPR screen to uncover new targetable vulnerabilities against drug resistance. |
| Collaborator Contribution | UCL and Cambridge will generate PI3K activators, knowledge of hyperactivation and CyTOF phenoscaping analysis; the Broad will supply MAPK activators and CRISPR screening in cancer cell lines; Utrecht will focus on Wnt activators; Memorial Sloan Kettering will generate patient-derived organoids from colorectal cancer patients. |
| Impact | Our team together was awarded £20 million from the Cancer Grand Challenges, and £2.3 goes to my lab. The collaboration is multi-disciplinary that includes clinical oncologist, cancer biologists, computational scientists and patient advocates. |
| Start Year | 2026 |
| Description | Tumour rewiring |
| Organisation | Cancer Research UK |
| Country | United Kingdom |
| Sector | Charity/Non Profit |
| PI Contribution | This is the new Cancer Grand Challenge awarded this year. Together we are working to rewire cancer cells to their disadvantage to overcome treatment resistance. My team is involved in testing compounds in mouse tumour models established in the lab. We will also perform genome-wide CRISPR screen to uncover new targetable vulnerabilities against drug resistance. |
| Collaborator Contribution | UCL and Cambridge will generate PI3K activators, knowledge of hyperactivation and CyTOF phenoscaping analysis; the Broad will supply MAPK activators and CRISPR screening in cancer cell lines; Utrecht will focus on Wnt activators; Memorial Sloan Kettering will generate patient-derived organoids from colorectal cancer patients. |
| Impact | Our team together was awarded £20 million from the Cancer Grand Challenges, and £2.3 goes to my lab. The collaboration is multi-disciplinary that includes clinical oncologist, cancer biologists, computational scientists and patient advocates. |
| Start Year | 2026 |
| Description | Tumour rewiring |
| Organisation | Memorial Sloan Kettering Cancer Center |
| Country | United States |
| Sector | Academic/University |
| PI Contribution | This is the new Cancer Grand Challenge awarded this year. Together we are working to rewire cancer cells to their disadvantage to overcome treatment resistance. My team is involved in testing compounds in mouse tumour models established in the lab. We will also perform genome-wide CRISPR screen to uncover new targetable vulnerabilities against drug resistance. |
| Collaborator Contribution | UCL and Cambridge will generate PI3K activators, knowledge of hyperactivation and CyTOF phenoscaping analysis; the Broad will supply MAPK activators and CRISPR screening in cancer cell lines; Utrecht will focus on Wnt activators; Memorial Sloan Kettering will generate patient-derived organoids from colorectal cancer patients. |
| Impact | Our team together was awarded £20 million from the Cancer Grand Challenges, and £2.3 goes to my lab. The collaboration is multi-disciplinary that includes clinical oncologist, cancer biologists, computational scientists and patient advocates. |
| Start Year | 2026 |
| Description | Tumour rewiring |
| Organisation | University College London |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | This is the new Cancer Grand Challenge awarded this year. Together we are working to rewire cancer cells to their disadvantage to overcome treatment resistance. My team is involved in testing compounds in mouse tumour models established in the lab. We will also perform genome-wide CRISPR screen to uncover new targetable vulnerabilities against drug resistance. |
| Collaborator Contribution | UCL and Cambridge will generate PI3K activators, knowledge of hyperactivation and CyTOF phenoscaping analysis; the Broad will supply MAPK activators and CRISPR screening in cancer cell lines; Utrecht will focus on Wnt activators; Memorial Sloan Kettering will generate patient-derived organoids from colorectal cancer patients. |
| Impact | Our team together was awarded £20 million from the Cancer Grand Challenges, and £2.3 goes to my lab. The collaboration is multi-disciplinary that includes clinical oncologist, cancer biologists, computational scientists and patient advocates. |
| Start Year | 2026 |
| Description | Tumour rewiring |
| Organisation | Utrecht University |
| Country | Netherlands |
| Sector | Academic/University |
| PI Contribution | This is the new Cancer Grand Challenge awarded this year. Together we are working to rewire cancer cells to their disadvantage to overcome treatment resistance. My team is involved in testing compounds in mouse tumour models established in the lab. We will also perform genome-wide CRISPR screen to uncover new targetable vulnerabilities against drug resistance. |
| Collaborator Contribution | UCL and Cambridge will generate PI3K activators, knowledge of hyperactivation and CyTOF phenoscaping analysis; the Broad will supply MAPK activators and CRISPR screening in cancer cell lines; Utrecht will focus on Wnt activators; Memorial Sloan Kettering will generate patient-derived organoids from colorectal cancer patients. |
| Impact | Our team together was awarded £20 million from the Cancer Grand Challenges, and £2.3 goes to my lab. The collaboration is multi-disciplinary that includes clinical oncologist, cancer biologists, computational scientists and patient advocates. |
| Start Year | 2026 |
| Description | Curious about the Crick |
| Form Of Engagement Activity | Participation in an open day or visit at my research institution |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Supporters |
| Results and Impact | I help host the annual "Crious about the Crick", which is an evening reception to bring a network of VIP external audiences and stakeholders into the Crick to find out what we do here and meet the people who are doing it. There were 184 attendees, which has created more philanthropy visits to the Crick since the Curious event. |
| Year(s) Of Engagement Activity | 2023,2024,2025 |
| Description | The Bowelbabe laboratory naming |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Public/other audiences |
| Results and Impact | My lab was named as the Bowelbabe laboratory funded by the Bowelbabe Foundation through CRUK, dedicated to the legacy of Dame Deborah James. We focus on developing personalised, targeted treatments for bowel cancer, including the use of innovative "mini-bowel" organoids to study stem cells, supported by a £1.6 million commitment from the Bowelbabe Fund. I met the Deborah family alongside with the Secretary of State for Health, which has been widely covered by various media and CRUK. |
| Year(s) Of Engagement Activity | 2025 |
| URL | https://www.bowelbabe.org/francis-crick-vivian-li |