Publication highlights

Researchers at the Crick examined unusually large and abnormal cells called polyploid giant cancer cells (PGCCs) in ten pleomorphic sarcomas, types of soft-tissue cancers known to be highly aggressive and genetically complex. Using advanced single-cell DNA sequencing, they analysed the genetic material of individual PGCCs to see how they differ from the rest of the tumour. They found that PGCCs were scattered randomly rather than forming groups in the tumour, suggesting that they arise spontaneously. They appeared to come from the main tumour cell population but had more genetic variation and many had signs of chromosomal instability. Chromothripis, where chromosomes shatter and reassemble in a chaotic pattern, was frequently seen in PGCCs. This ongoing genomic reshaping may explain why pleomorphic sarcomas often behave aggressively and are difficult to treat.

Scientists at the Crick and Barts Cancer Institute (Queen Mary University of London) have discovered that a single letter change in the PRKCA gene drives a rare and hard-to-treat brain cancer, chordoid glioma. The PRKCA gene contains instructions for making a protein called protein kinase C alpha (PKCa). Until now, many believed blocking kinases would be useful for treating cancer, but in this study the team discovered that the mutation in PRKCA blocks the kinase but paradoxically drives tumour growth. This was because it became locked in a shape that allowed it to promote cancer cell growth signalling and because it interacted with epigenetic regulators in a way that promoted cancer growth.

COVID-19 restrictions including social distancing were lifted in the UK in 2021 after the majority of the population had two doses of vaccine. Researchers at the Crick analysed data from the Legacy study to find out if either infection or vaccine as a third exposure generated different immunity. We found overall that both antibody-mediated and cellular immunity was similar, but when T cells were exposed to spike protein challenge in vitro, infection exposure drove production of more innate immune cytokines from T cells and expansion of mucosal-homing T cells, whereas vaccine-only exposed cells led to expansion of the T cell memory population that produced more inflammatory cytokines.

Researchers at the Crick have found that some particularly aggressive lung cancer cells can develop their own electric network, like that seen in the body’s nervous system. They found that small cell lung cancer cells (which mainly arise from neuroendocrine cells in the lungs) had gone 'off grid' - they were able to generate their own electrical activity, becoming independent of the body's main electrical supply. They also saw important changes in gene expression as the cancer progressed, resulting in some neuroendocrine cells becoming non-neuroendocrine cancer cells. Genes enabling electrical communication were switched on in the NE cells, and genes relating to producing a supportive environment were switched on in the non-NE cells, which were shuttling lactate as an energy source for NE cells. Markers of increased electrical activity were also seen in cancer cells in people with SCLC. As their cancer progressed, non-NE cells showed markers suggesting they were increasingly pumping out lactate. These changes drive the tumour's ability to grow and spread.

Researchers at the Crick and Barts Cancer Institute, Queen Mary University of London, have shown that the amount of a protein called CD74 can indicate which people with bowel cancer may respond best to immunotherapy. Bowel cancer falls into two categories: a deficient subtype and proficient subtype, and immunotherapy isn't yet used to treat both subtypes. The team found that three types of immune cells needed to be present for the tumour to respond to treatment: T cells, NK cells and macrophages. When all three were present and near to cancer cells, the T cells produced interferons, triggering a signal in macrophages and tumour cells. The researchers then found that a measurable component of this signal was a protein called CD74. This finding was mirrored in clinical trial data, showing that people who responded to immunotherapy had significantly higher levels of CD74. Therefore measuring CD74 levels could predict whether someone will respond to immunotherapy regardless of subtype.

Researchers at the Crick, the UCL Cancer Institute and UCLH have shown that a test called ORACLE can predict lung cancer survival at the point of diagnosis better than currently used clinical risk factors. This could help doctors make more informed treatment decisions for people with stage 1 lung cancer, potentially reducing the risk of the cancer returning or spreading. ORACLE was developed in 2019 to overcome the lack of biological markers in lung cancer, which is important for people with stage 1 lung cancer, who are normally given surgery without chemotherapy. In this study ORACLE was validated in 158 people with lung cancer in the Cancer Research UK-funded TRACERx study. The team found that ORACLE could predict which patients with stage 1 lung cancer had a lower chance of survival, and might benefit from chemotherapy as well as surgery. The researchers also found that high ORACLE risk scores were linked to regions of the tumour that were more likely to spread to another part of the body.

Researchers at the Francis Crick Institute and UCL, funded by Cancer Research UK, have unveiled the first computer algorithm capable of identifying which cell populations within a tumour drive aggressive growth. The innovative algorithm, called SPRINTER, analyses individual cells within a tumour to identify those that are growing the most rapidly. The algorithm was used to analyse nearly 15,000 cancer cells from a patient with non-small cell lung cancer (in TRACERx and PEACE studies). SPRINTER revealed that the cells that were growing the fastest were responsible for spreading the cancer to other parts of the body, even from other metasasised tumours. It also showed that these cells shed more of their DNA into the bloodstream. The possibility of detecting aggressive cancer cell populations early and monitoring them over time offers a new avenue for more proactive and personalised cancer care.