Publication highlights

Researchers have shown how genetic defects in Toxoplasma gondii are rescued if co-infected with normal parasites, thanks to supportive secreted proteins. The protein MYR1 is a key player in helping Toxoplasma parasites secrete proteins into host cells to manipulate their function. The researchers infected mice with a mix of MYR1-deficient parasites and either normal or mutant parasites. The MYR1-deficient parasites grew better when normal parasites were present, confirming that secreted factors from the normal parasites supported their growth. The findings also reveal a potential limitation of pooled CRISPR screens in studying parasite biology in live hosts.

Researchers at the Francis Crick Institute, UCL and AstraZeneca have discovered the reason why targeted treatment for non-small cell lung cancer fails to work for some patients, particularly those who have never smoked. The study shows that lung cancer cells with two particular genetic mutations are more likely to double their genome, which helps them to withstand treatment and develop resistance to it. The researchers re-analysed data from the trials of a new EGFR inhibitor, which blocks a common genetic mutation in this type of lung cancer. They compared the impact of treatment for patients with either EGFR-only or with EGFR and p53 mutations, finding that tumours got smaller in response to treatment for patients with just EGFR mutations. But for patients with both mutations, some tumours had grown, providing evidence of rapid drug resistance. This was confirmed in mice with both mutations - resistant cells had doubled their genomes.

Endogenous retroviruses (ERVs) are a specific group of viruses that altered human evolution by inserting themselves into our DNA. Often these alterations do not cause any changes in human health and disease, however in some cases they may impact the way a disease progresses by changing the way our genes function. This happens because ERVs can help to generate new versions of proteins. In this paper, the aim was to explore whether the calcium regulatory protein calbindin influenced lung cancer cells when present in the ERV-altered form (ERV-calbindin).

Lung cancer cell growth and inflammation was compared in the presence and absence of ERV-calbindin. The results indicated that ERV-calbindin aided lung cancer cell survival and tumour-promoting inflammation. On the other hand, ERV-calbindin deficient lung cancer cells grew slower, initiated the recruitment of immune cells called neutrophils and released the inflammatory marker interleukin-8. This creates an interplay between pro and anti-tumour immune reactions. Altogether the reduction in growth and increase in inflammation observed in the absence of ERV-calbindin is a phenomenon called “senescence”. These results imply that the presence of the ERV altered form of calbindin aids cancer cell growth and survival and could potentially pose as a future target for therapies.

Immunodeficient mouse models have been instrumental in improving our understanding of human healthy haemopoietic stem cells and their hierarchical organisation as well as of the functional and phenotypic heterogeneity of leukaemic stem cells in acute myeloid leukaemia. However, xenotransplantation models failed at reconstituting the human bone marrow niche which remains of mouse origin. Using a bioengineered scaffold, we developed a new versatile humanised bone marrow niche which supports the engraftment of both normal and leukaemia stem cells in vivo. This 3D scaffold represents a suitable model to study and dissect the human bone marrow composition and test the effect of specific stroma cell types and niche factor functions during both normal human haemopoiesis and leukaemia.

Children with intestinal failure cannot absorb the nutrients that are essential to be healthy. In the most severe cases, patients may require transplantation. However, there is a shortage of donor organs and complications can arise after surgery. We have shown how intestinal stem cells and intestinal tissues taken from patients can be used to grow functioning intestinal grafts in the laboratory, which could offer a safe and longer-lasting alternative to traditional donor transplants.

In this study we found that via the release of leukotrienes, neutrophils selectively support the more metastatic subset of cancer cells infiltrating the distant tissue and that this activity can be blocked by an inhibitor of leukotriene production. This is one of the most important publications from my laboratory, as it has contributed to the understanding of the crucial responses of neutrophils during metastatic progression.