How do healthy cells sense mutant neighbours?

Our cells accumulate mutations throughout the course of our lives, and some organs, such as the skin, are affected by a particularly high mutation burden. Some of these mutations affect genes that are involved in the initiation and progression of cancer, yet most of us cope with these mutations without ever developing disease.

Cells which carry these cancer mutations without displaying an overt neoplastic phenotype (i.e. uncontrolled growth and expansion) are referred to as “pre-neoplastic” cells. When pre-neoplastic cells are found in large patches within a tissue they are virtually indistinguishable from healthy cells; however, when they are interspersed within a healthy tissue, they are often eliminated by non-specialised healthy cells in direct contact with them, through a process termed cell competition.

Whilst we are familiar with many mutations that drive cell competition in a number of organisms and systems, what we do not know is how healthy cells sense that they are in contact with a mutant neighbour, and that they should trigger cell competition.

In order to address this question, we have recently developed modular synthetic tools which allow us to engineer expression of select transgenes in healthy cells interacting with a mutant cell of interest, in pluripotent stem cells and developing embryos. This allows us to identify healthy neighbours of mutant cells (by inducing expression of a reporter transgene), or to engineer pre-programmed cell behaviours in these neighbours (by inducing expression of functional transgenes) (Malaguti et al. 2022, Malaguti et al. 2024).

We now plan to use these tools to identify a “mutant-sensing signature” in healthy cells at the onset of cell competition, both in simple developmental models, and in tissue architecture-relevant organoid models of skin pre-neoplasia. Our aim is to understand how healthy cells sense mutant neighbours, and to use this information to engineer cell competition between pre-neoplastic skin cells and their neighbours, in order to drive elimination of the mutant cells.

In parallel, we are developing tools to allow sustained transgene expression in mouse and human pluripotent cells and their differentiated derivatives. These cell lines make use of site-specific recombinase “landing pads”, and allow rapid and efficient stable integration of transgenes of choice in insulated safe-harbour sites, providing a platform for convenient genetic engineering of synthetic circuits in pluripotent cells, differentiated cultures and organoids (Fairweather & Malaguti in prep). For example, these tools have helped us develop a brand new neighbour-labelling system for identifying “close-by” genetically unmodified healthy neighbours which are not in direct contact with mutant cells (Lebek et al. 2023).

Past research interests

My previous work focused on analysing the output of cell communication events: I characterised how feedbacks between signalling molecules, gene regulatory networks and adhesion molecules can stabilise transitions between cell states in early mouse development (Malaguti et al. 2019, Malaguti et al. 2013, Costa et al. 2022, Rao et al. 2020, Punovuori et al. 2019, Zhou et al. 2013). In Malaguti et al. 2019, I characterised a mechanism that confers robustness to early developmental events by rendering cells deaf to specific signalling cues during a narrow developmental time window. I remain interested in understanding whether a similar mechanism could be operating in other developmental contexts, and whether it may regulate the initiation and progression of malignancy. 

2021-2024: Biotechnology 3 (Tutor, Marker)
2022-2023: MScR Regenerative Medicine & Tissue Repair MScR (Interactive Lecture/Discussion Group)
2020-2021: Developmental Biology 3 (Demonstrator, Marker)
2019-2020: Quantitative Skills for Biologists 1 (Tutor, Marker)
2019: Tissue Repair PhD/MSc cohort (Interactive Lecture/Discussion Group)
2014-2024: Supervision of PhD research students