Auner Lab

Contact


Dr Holger Auner

  • CRUK Advanced Clinician Scientist
  • Clinical Reader in Molecular Haemato-Oncology

+44 (0)20 3313 4017
holger.auner04@imperial.ac.uk

Areas of research


Proteotoxic stress and metabolism

Myeloma cells are characterised by a unique sensitivity to inhibitors of the proteasome, which is responsible for the controlled degradation of most cellular proteins that have become damaged or are otherwise unwanted. Nevertheless, resistance to proteasome inhibitors occurs in essentially all patients to varying degrees. Accumulation of misfolded proteins in the endoplasmic reticulum (ER), which triggers proteotoxic ‘ER stress’, is widely believed to be the main mechanism of action of proteasome inhibitors. However, data from our lab and other research groups suggest complex interactions between proteasomal protein degradation and multiple metabolic processes. Our aim is to find metabolic and proteostatic vulnerabilities that we can exploit therapeutically.


Tissue biophysics in myeloma biology

Several important aspects of cancer cell biology are influenced by mechanical cues from the surrounding tissue. In particular, mechanical interactions and matrix remodelling have been shown to govern cancer cell metabolism. Tissue stiffness also impacts on normal haematopoiesis, and mechanical cues are known to modulate therapeutic responses. Moreover, we have shown that proteostasis-targeting drugs can alter tissue physical properties. We aim to understand how tissue stiffness and nutrient availability act together to rewire metabolic networks and regulate drug responses in myeloma.


Citation

BibTex format

@article{Ponnusamy:2021:10.3324/haematol.2020.274480,
author = {Ponnusamy, K and Tzioni, MM and Begum, M and Robinson, ME and Caputo, VS and Katsarou, A and Trasanidis, N and Xiao, X and Kostopoulos, IV and Iskander, D and Roberts, I and Trivedi, P and Auner, HW and Naresh, K and Chaidos, A and Karadimitris, A},
doi = {10.3324/haematol.2020.274480},
journal = {Haematologica},
title = {The innate sensor ZBP1-IRF3 axis regulates cell proliferation in multiple myeloma.},
url = {http://dx.doi.org/10.3324/haematol.2020.274480},
year = {2021}
}

RIS format (EndNote, RefMan)

TY  - JOUR
AB - Multiple myeloma is a malignancy of plasma cells (PC) initiated and driven by primary and secondary genetic events. Nevertheless, myeloma PC survival and proliferation might be sustained by non-genetic drivers. Z-DNA-binding protein 1 (ZBP1; also known as DAI) is an interferon-inducible, Z-nucleic acid sensor that triggers RIPK3-MLKL-mediated necroptosis in mice. ZBP1 also interacts with TBK1 and the transcription factor IRF3 but the function of this interaction is unclear, and the role of ZBP1-IRF3 axis in cancer is not known. Here we show that ZBP1 is selectively expressed in late B cell development in both human and mouse cells and it is required for optimal T-cell-dependent humoral immune responses. In myeloma PC, interaction of constitutively expressed ZBP1 with TBK1 and IRF3 results in IRF3 phosphorylation. IRF3 directly binds and activates cell cycle genes, in part through co-operation with the PC lineage-defining transcription factor IRF4, and thereby promoting myeloma cell proliferation. This generates a novel, potentially therapeutically targetable and relatively selective myeloma cell addiction to the ZBP1-IRF3 axis. Our data also show a non-canonical function of constitutive ZBP1 in human cells and expand our knowledge of the role of cellular immune sensors in cancer biology.
AU - Ponnusamy,K
AU - Tzioni,MM
AU - Begum,M
AU - Robinson,ME
AU - Caputo,VS
AU - Katsarou,A
AU - Trasanidis,N
AU - Xiao,X
AU - Kostopoulos,IV
AU - Iskander,D
AU - Roberts,I
AU - Trivedi,P
AU - Auner,HW
AU - Naresh,K
AU - Chaidos,A
AU - Karadimitris,A
DO - 10.3324/haematol.2020.274480
PY - 2021///
TI - The innate sensor ZBP1-IRF3 axis regulates cell proliferation in multiple myeloma.
T2 - Haematologica
UR - http://dx.doi.org/10.3324/haematol.2020.274480
UR - https://www.ncbi.nlm.nih.gov/pubmed/33596642
ER -