Mattias Malaguti
Lecturer in Engineering Biology
- Centre for Engineering Biology
- Institute of Quantitative Biology, Biochemistry and Biotechnology
- School of Biological Sciences
Contact details
- Email: mattias.malaguti@ed.ac.uk
Address
- Street
-
Room G.20
Roger Land Building
Alexander Crum Brown Road
The King's Buildings - City
- Edinburgh
- Post code
- EH9 3FF
Undergraduate teaching
2021-2024: Biotechnology 3 (Tutor)
2020-2021: Developmental Biology 3 (Demonstrator, Marker)
2019-2020: Quantitative Skills for Biologists 1 (Tutor)
Open to PhD supervision enquiries?
Yes
Current PhD students supervised
Jennifer Annoh
Aisling Fairweather
Research summary
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.Affiliated research centres
-
Repurposing the lineage-determining transcription factor Atoh1 without redistributing its genomic binding sites
(23 pages)
In:
Frontiers in Cell and Developmental Biology, vol. 10
DOI: https://doi.org/10.3389/fcell.2022.1016367
Research output: Contribution to Journal › Article (Published) -
SyNPL: Synthetic notch pluripotent cell lines to monitor and manipulate cell interactions in vitro and in vivo
(46 pages)
In:
Development, vol. 149
DOI: https://doi.org/10.1242/dev.200226
Research output: Contribution to Journal › Article (Published) -
Cadherins in early neural development
(16 pages)
In:
Cellular and Molecular Life Sciences
DOI: https://doi.org/10.1007/s00018-021-03815-9
Research output: Contribution to Journal › Review article (Published) -
The transcription factor E2A drives neural differentiation in pluripotent cells
In:
Development, vol. 147
DOI: https://doi.org/10.1242/dev.184093
Research output: Contribution to Journal › Article (Published) -
N-cadherin stabilises neural identity by dampening anti-neural signals
In:
Development, vol. 146
DOI: https://doi.org/10.1242/dev.183269
Research output: Contribution to Journal › Article (Published) -
Competence to epithelialise coincides with competence to differentiate in pluripotent cells
(26 pages)
DOI: https://doi.org/10.1101/809467
Research output: › Working paper (Published) -
Id1 stabilises epiblast identity by sensing delays in nodal activation and adjusting the timing of differentiation
(16 pages)
In:
Developmental Cell, vol. 50, pp. 462-477.E
DOI: https://doi.org/10.1016/j.devcel.2019.05.032
Research output: Contribution to Journal › Article (Published) -
Bone Morphogenic Protein signalling suppresses differentiation of pluripotent cells by maintaining expression of E-Cadherin
(20 pages)
In:
eLIFE, vol. 2
DOI: https://doi.org/10.7554/eLife.01197
Research output: Contribution to Journal › Article (Published) -
Hes1 desynchronizes differentiation of pluripotent cells by modulating STAT3 activity
(12 pages)
In:
STEM CELLS, vol. 31, pp. 1511-1522
DOI: https://doi.org/10.1002/stem.1426
Research output: Contribution to Journal › Article (Published)