The Lalaoui laboratory studies the causes and consequences of inflammatory cell death programs to improve cancer treatment

Cell death programs are crucial processes in development, tissue homeostasis and immunity. ‘Too much’ cell death can lead to neurodegenerative and immune diseases and ‘too little’ cell death causes cancer. Consequently, re-activation of cell death within tumours is one of the major goals of cancer therapies. Until recently, it was thought that the unique purpose of programmed cell death was to kill cells. However, it has become clear that dying cells release a variety of signals which communicate with the microenvironment and the immune system. Thus, how the body responds to dying cells can influence cancer progression and cancer treatments.

The Lalaoui laboratory uses a range of cellular, molecular techniques and in vivo models to investigate the causes and consequences of cell death programs regulated by the RIP kinases 1 and 3 (RIPK1/3). We apply this fundamental knowledge to design new therapeutic strategies for cancer and inflammatory diseases and to understand the impact of inflammatory cell death in cancer immunity and cancer progression.

Research projects

How is the cell death machinery regulated?

The RIPK1/3 cell death molecular machinery is triggered by various innate immune ligands (e.g. TNF or TLR ligands), several therapeutics as well as under genotoxic stresses9. The formation and lethal activity of the molecular platform are tightly regulated by different molecular checkpoints including ubiquitylation, phosphorylation, cleavage or ribosylation of component of the RIPK1/3 machinery. We aim to uncover new post translational modifications that regulate RIPK1/3 function. This project will investigate how known and unknown post translational modifications inhibit or activate RIPK1/3-dependent cell death. Gaining a better understanding on how RIPK1/3 pro-death function is regulated will allow us to design new therapeutic approaches and anticipate mechanisms of resistance to RIPK1/3 dependent cell death.

How do in born errors of cell death pathways impact health?

Inappropriate activation of RIPK1/3 leads to excessive cell death and uncontrolled inflammation. In human mutations in RIPK1 or in genes encoding its regulators causes inflammatory syndromes. We will characterise new candidate mutations in RIPK1 and its regulators carried by patient affect patients affected with inflammatory disorders of unknown cause. These studies will determine the role of RIPK1/3 in development, inflammation and immune responses. Altogether, this knowledge will be used to understand how activation of RIPK1/3 impact cancer treatment and cancer immunity.

How is the cell death molecularly link to other signalling pathways?

We and others have shown that the RIPK1/3 molecular machinery can induce the secretion of myriad of cytokines and chemokines. The molecular mechanisms underlying the inflammatory functions of RIPK1/3 are still unclear. We aim to determine how RIPK1/3 activate inflammatory signalling pathways at the molecular level and uncover novel functions of this platform. This will provide molecular insights into the relationship between cell death and inflammation and increase our understanding on the impact of targeting RIPK1/3 in cancer.


HongTri Tran, PhD Student
Tobias Kratina, Research Assistant

Key publications

Anderton H, Chopin M, Dawson CA, Nutt SL, Whitehead L, Silke N, LALAOUI N* and Silke J* (2022). Langerhans cells are an essential cellular intermediary in chronic dermatitis. Cell Reports.

Liu L, Sandow JJ, Pedrioli DML, Samson AL, Silke N, Kratina T, Ambrose RL, Doerflinger M, Hu Z, Morrish E, Chau D, Kueh AJ, Fitzibbon C, Pellegrini M, Pearson JS, Hottiger MO, Webb AI, LALAOUI N* and Silke J* (2022). Tankyrase-mediated ADP-ribosylation is a novel regulator of TNF-induced cell death. Science Advances. 8, eabh2332.

Liu L and LALAOUI N (2021). 25 years of research put RIPK1 in the clinic. Seminars in Cell Developmental Biology. 

LALAOUI N, Merino D, Giner G, Vaillant F, Chau D, Liu L, Kratina T, Pal B, Whittle JR, Etemadi N, Berthelet J, Gräsel J, Hall C, Ritchie ME, Ernst M, Smyth GK, Vaux DL, Visvader JE, Lindeman GJ, and Silke J (2020). Targeting triple-negative breast cancers with the Smac-mimetic birinapant. Cell Death and Differentiation. 27, 2768-80.

LALAOUI N*, Boyden SE*, Oda H*, Wood GM, Stone DL, Chau D, Liu L, Stoffels M, Kratina T, Lawlor KE, Zaal KJM, Hoffmann PM, Etemadi N, Shield-Artin K, Biben C, Tsai WL, Blake MD, Kuehn HS, Yang D, Anderton H, Silke N, Wachsmuth L, Zheng l, Sampaio Moura N, Beck DB, Gutierrez-Cruz G, Ombrello AK, Pinto-Patarroyov GP, Kueh AJ, Herold MJ, Hall C, Wang H, Chae JJ, Dmitrieva NI, McKenzie M, Light A, Barham BK, Jones A, Romeo TM, Zhou Q, Aksentijevich I, Mullikin JC, Gross AJ, Shum AK, Hawkins ED, Masters SL, Lenardo MJ, Boehm M, Rosenzweig SD, Pasparakis M, Voss AK, Gadina M, Kastner DL and Silke J (2020). Mutations that prevent caspase-8 cleavage of RIPK1 cause autoinflammatory disease. Nature. 557,103-108.

LALAOUI N and Vaux DL (2018). Recent advances in understanding inhibitor of apoptosis proteins. F1000Research. 7.

Anderton H, Rickard JA, Varigos GA, LALAOUI N* and Silke J*(2017).  IAPs limit RIPK1-mediated skin inflammation. Journal of Investigative Dermatology. 137, 2371-79.

Jaco I*, Annibaldi A*, LALAOUI N*, Wilson R, Tenev T, Laurien L, Kim C, Jamal K, Wicky John S, Liccardi G, Chau D, Murphy JM, Brumatti G, Feltham R, Pasparakis M, Silke J and Meier P (2017). MK2 phosphorylates RIPK1 to prevent TNF-induced cell death. Molecular Cell. 66, 698-710.

LALAOUI N and Brumatti G (2017). Relevance of necroptosis in cancer. Immunology and Cell Biology. 95, 137-45.

LALAOUI N Hänggi K, Brumatti G, Chau D, Nguyen NYN, Vasilikos L, Spilgies LM, Heckmann DA, Ma C, Ghisi M, Salmon JM, Matthews GM, de Valle E, Moujalled DM, Menon MB, Spall SK, Glaser SP, Richmond J, Lock RB, Condon SM, Gugasyan R, Gaestel M, Guthridge M, Johnstone RW, Munoz L, Wei A, Ekert PG, Vaux DL, Wong WWL and Silke J (2016). Targeting p38 or MK2 enhances the anti-leukemic activity of Smac-mimetics. Cancer Cell. 29, 145-58.

Research programs