Ringham-Terry, Benjamin;
(2023)
The Role of SHOC2 in Skin Homeostasis and Inflammation.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
The RAS-RAF-MEK-ERK signalling pathway has a crucial role throughout mammalian development and its aberrant activation is a key driver in many human cancers. A phosphatase complex comprised of SHOC2, MRAS and PP1, plays a key role in RAF activation and has recently emerged as an attractive therapeutic target for the treatment of RAS-driven cancers. SHOC2 has been identified as a top synthetic lethal interactor with MEK inhibitors and drug discovery projects are ongoing to develop pharmacological inhibitors of the complex. To ensure a therapeutic index of potential SHOC2 inhibitors, it is crucial to understand the systemic toxicities an inhibitor may present. Previous data indicates that SHOC2 inhibition in mice is initially well tolerated, but mice develop a dermatitis-like phenotype that progressively deteriorates. We set out to characterise the molecular and cellular mechanisms behind this response. We established a skin-specific model of Shoc2 deletion that demonstrated that the skin inflammation response is primarily driven by keratinocytes. Through transcriptional and biochemical analysis of lesional skin we identified proinflammatory cytokines, including IL-36 cytokines and the chitinase-like protein CHI3L1 as biomarkers and potential targets. We have developed an ex-vivo model of acute SHOC2 inactivation in keratinocytes and identified IL-33 as an additional potential mediator of the inflammatory response. Our lab has previously identified that SHOC2 inhibition synergises with MEK inhibitors in RAS mutant cells, and we show here that combined SHOC2 and MEK inhibition have synergistic toxicities in keratinocytes and rapidly increase the inflammatory response in-vivo compared to SHOC2 inhibition alone. Single-cell transcriptomics identified IL-17-producing dermal γδ Tcells as a key component in this inflammatory response and we show that by specifically ablating γδ T-cells the response can be partially resolved in mice. These studies highlight a key role of SHOC2 in skin homeostasis and highlight the potential skin toxicities of SHOC2 inhibitors. This study also highlights that understanding the cellular and molecular mechanisms driving skin toxicities may allow the targeting of specific nodes driving the inflammatory response, minimising toxicities, and thus increasing the therapeutic window of future SHOC2- based therapies.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | The Role of SHOC2 in Skin Homeostasis and Inflammation |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2023. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| Keywords: | SHOC2, Skin, Inflammation |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10166196 |
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