Congratulations to Prof Bart Vanhaesebroeck, Prof @christophertape.bsky.social & Team REWIRE-CAN on securing $25m in @cancergrand.bsky.social funding to take on the challenge of rewiring cancer cells.
#CancerGrandChallenges @uclmedsci.bsky.social
www.ucl.ac.uk/news/2026/ma...
Today, one year on from that failed grant application and Bart’s ‘shall we explore?’ email, I am very proud to share that REWIRE-CAN has been supported by Cancer Grand Challenges.
Never give up on an idea you believe in.
(8/8)
In December we pitched the project to the Cancer Grand Challenge committee in New York. At this point we’d spent so much time together that the team felt like a scientific family and I think that came across during the interview. (7/8)
For the next 9 months we worked together to create our Cancer Grand Challenge proposal. We went through many, many iterations — but learnt something new from every discussion and built something that none of us could ever have conceived alone. (6/8)
We brought together world-leaders in signalling activators (Bill Sellers, Roger Williams, Madelon Maurice, Steve Wedge) with experts in cancer cell models and signalling dynamics (Karuna Ganesh, Vivian Li, Smita Krishnaswamy) to form team REWIRE-CAN. (5/8)
These ideas had some striking technical overlap with my unfunded grant proposal so the project fundamentals came together very quickly.
Failure of the first grant became information for the next. (4/8)
Our idea was to use novel ‘activator’ drugs to ‘re-wire’ cancer cell signalling. This new class of therapies aim to turn the extreme signalling dependencies of cancer cells against them by hyper-activating signalling. We could also use activators to move cancer cells into vulnerable states. (3/8)
A few days later 7 new Cancer Grand Challenges @cancergrand.bsky.social were announced. I received an email from my UCL colleague Bart Vanhaesebroeck with an idea on how we might address the ‘Rewiring Cancer’ challenge. (2/8)
In early-2025 I was reeling from a ‘scored fundable’ grant application that was not funded. I really believed in this grant and knew the ideas were good but the review panel just weren’t into the project and there nothing more I could do. That’s science, but it hurts. (1/8)
Annual lab curry ‘n’ karting. Incredibly privileged to work alongside these wonderful people
It's been a HUGE privilege to interview for @cancergrand.bsky.social with the incredible REWIRE-CAN team
(1/N) Thrilled to share that our paper HiPoNet (High dimensional Point cloud Network) to be presented at NeurIPS 2025! HiPoNet treats an entire high-dimensional point cloud as a datapoint! It captures multi-scale geometry and topology of the cloud perform classification and regression tasks.
Paul Nurse describing the main job of a PI
(From ‘The Thinking Game’, 2024)
Important new paper from @batllelab.bsky.social showing how the KRAS-G12D inhibitor (RMC-9945) triggers rapid stem cell switching in CRC.
This switch happens in just a few hours — similar to what we see with tumour cell responses to CAFs.
aacrjournals.org/cancerdiscov...
Code to reproduce figures in the paper is available here: github.com/callumnattre...
All single-cell PTM files from γδ T cells and PDOs can be found here: community.cytobank.org/cytobank/pro...
This project was an experimental tour de force from Callum Nattress, Rhianna O'sullivan, Daniel Fowler, Colin Hutton, Petra Vlckova, @vivianlilab.bsky.social, Kerry Chester, John Anderson, @marta-barisa.bsky.social, and Jon Fisher. Thanks to @cruk-cityoflondon.bsky.social for funding. (13/13)
In summary, these results suggest that γδ T cell multimodal cytotoxicity can buffer γδ T cell signalling from patient-specific cancer cell immunomodulation, allowing γδ T cells from a range of donors to kill chemorefractory cancer cells. (12/13)
This demonstrates that these lethal, chemoresistant revCSCs cancer cells are therapeutically targetable by cellular therapies. (11/13)
CRC PDOs comprise an admixture of chemosensitive proliferative colonic stem cells (proCSCs) and chemorefractory revival colonic stem cells (revCSCs). Crucially, stIL-15-γδ T cells can kill PDOs irrespective of stem cell admixture — including chemorefractory PDOs. (10/13)
To confirm that the anti-B7-H3 antibody was only inducing ADCC and not invoking the putative immune checkpoint properties of B7-H3, we also demonstrated that only a complete IgG — and not an Fc-null IgG — could trigger multimodal killing. (9/13)
Importantly, PDO immunomodulation of γδ T cells correlates with reduce AIC killing (i.e. the more PDOs change γδ T cell signalling, the worse γδ T cells kill). However, when γδ T cells also use AIC + ADCC, PTM signalling was restored and γδ T cells could kill all PDOs. (8/13)
We found that γδ T cells can kill both MSS and MSI CRC PDOs. However, when γδ T cells only use AIC, γδ T cell signalling converges on the target PDO, irrespective of T-cell donor. This suggests that γδ T cells are immunomodulated by PDOs and ITH is dominant over IDH. (7/13)
To investigate how γδ T cells from various T-cell donors (IDH) kill cancer cells from a range of CRC patients (ITH) via AIC and ADCC, we performed single-cell signalling analysis of γδ T cells from x4 donors co-cultured with x10 CRC PDOs, +/- B7-H3 mAb (x780 3D cultures). (6/13)
Next, we found that stIL15-engineered γδ T cells can rapidly kill MSI colorectal cancer (CRC) patient-derived organoids (PDOs) in 3D via AIC. Killing could be further increased by inducing ADCC via a novel anti-B7-H3 antibody — demonstrating multimodal cytotoxicity. (5/13)
First, we found that expressing stabilised IL-15Rα–IL-15 (stIL15) enables γδ T cells to survive in 3D cultures without serum or cytokine support. This is important because many T-cell killing assays are performed in 2D with serum, but tumours are 3D and nutrient-deprived. (4/13)
To explore this, we performed a systematic single-cell phenoscaping study of >1,000 organoid cultures testing the combinatorial interactions between γδ T cell killing modalities (AIC vs ADCC), γδ T cell inter-donor heterogeneity, and cancer cell inter-tumour heterogeneity. (3/13)
γδ T cells can kill cancer cells via antibody-independent cytotoxicity (AIC) and antibody-dependent cellular cytotoxicity (ADCC), but how this killing varies across T cell donors (inter-donor heterogeneity, IDH) and patients (inter-tumour heterogeneity, ITH) is unclear. (2/13)
Excited to share our new paper: ‘Phenoscaping Reveals Multimodal γδ T-cell Cytotoxicity as a Strategy to Overcome Cancer Cell–Mediated Immunomodulation’ led by Callum Nattress in collab. with Jonathan Fisher lab (1/13)
aacrjournals.org/cancerres/ar...
