Elías Sigüenza

Postdoctoral Researcher


Dr Sigüenza is a mathematical modeller that specialises in cell physiology. He develops 'in-silico' simulations that enable experimental researchers to understand those cellular processes responsible for life. In 2020, he was awarded a doctorate degree from the University of Auckland, New Zealand, under the mentorship of Prof. James Sneyd (FRSNZ). His work involved developing a mathematical model to understand how cell calcium signalling drives saliva secretion in parotid epithelia.

In March 2020, Dr Sigüenza began a postdoctoral appointment at the University of Birmingham, England, at Prof. Daniel Tennant's Laboratory in the Institute of Metabolism and Systems Research where he leads a mathematical-biology effort, joint with Dr Spill, to optimise the laboratory's bench-side research. Under this post he developed novel methodologies to systemically incorporate radioactive stable-isotope labelling-13C and 2H NMR data into large metabolic models and thus facilitate analysis of metabolic pathway remodelling resultant from cancer.

In 2022, Dr Sigüenza began an appointment under the Paradifference Foundation to study a rare tumour provoked by genetic mutations of the succinate-dehydrogenase, sub-unit B, complex.

Research Themes

Ongoing Research Projects

Identifying the mechanisms of metabolic escape in SDHB defective tumors.

Paragangliomas and Pheochromocytomas are sporadic neuroendocrine tumours (neuroendocrine means they arise from cells of hormonal and nervous systems). They can be either benign or malignant (in an estimated 97% of cases, they are benign). When paragangliomas are situated in the adrenal gland, they are called pheochromocytomas.

30% of paragangliomas are due to hereditary gene mutations (such as SDHD, SDHA, SDHC, SDHB, VHL and RET). The SDHB mutation is most commonly associated with malignant metastasis. Currently, there is no cure for the disease. There are several treatment methods for individual tumours and palliative treatment once the tumours have started to spread. It is becoming increasingly difficult for researchers to get funding for this rare disease.

We are developing a mathematical model to study in-depth the tricarboxylic acid (TCA) cycle. The TCA cycle is a central metabolic pathway responsible for supplying reducing potential for oxidative phosphorylation and anabolic substrates for cell growth, repair and proliferation. As such, it might be considered essential for the ongoing viability and proliferation of a cell or tissue. However, since the first report in 2000 of an inactivating mutation in the TCA cycle enzyme complex, succinate dehydrogenase (SDH) in paraganglioma (PGL), it has become clear that some cells and tissues are not only able to survive with a truncated TCA cycle, but they are also able to support the cell growth and proliferative phenotype observed in tumours. Our model aims to explain how the loss of SDH activity leads to changes in the metabolism of non-essential amino acids: in particular, how pyruvate carboxylase is essential to re-fill the depleted pool of aspartate in SDH-deficient cells. 

Uncovering the metabolic relationship between bone marrow mesenchymal stem cells and malignant plasma cells in multiple myeloma.

Multiple myeloma is an incurable cancer characterised by the clonal expansion of malignant plasma cells in the bone marrow. Recent hypotheses have emerged in which the lactate produced by bone marrow mesenchymal stem cells (BMMCs) acts as an energy source to sustain myeloma proliferation. At the centre of this interaction lie the monocarboxylate transporters 1 and 4 (MCT1-MCT4), encoded by the Slc16a1 and Slc16a3 genes, respectively. When co-expressed, these mechanisms have been hypothesised to form part of a poorly understood metabolic axis hypothesised to be essential for the survival and proliferation of multiple myeloma.  To address this issue we have developed an integratedin-silico/in-vitro co-culture model able to underpin the intercellular metabolic interactions taking place in these cells. Our goal is to elucidate those pathways whereby "bioenergetic" precursor metabolites, synthesised by BMMSCs, are incorporated into malignant plasma cells and ensure their survival. Identification of such pathway will lead to a therapeutic target able to improve patient prognosis and quality of life.

Succinyl-coA ligase ATP-forming subunit a2 (SUCLA2): a commonly suppressed metabolic enzyme that may reveal novel means for therapeutic targeting. 

The conversion of succinyl-coA to succinate in the mitochondrial tricarboxylic acid (TCA) cycle is catalysed by succinyl-coA ligase, of which there are two isozymes – one ATP-forming and one GTP-forming. Data from patients with germline mutations in SUCLA2, which specifies the ATP-forming isozyme, suggests that these enzymes have distinct yet currently undescribed differences in their activity. Expression of the SUCLA2 subunit is lost in a significant number of tumour types (prostate and bladder cancers, multiple myeloma and chronic lymphocytic leukaemia) as a passenger deletion alongside the Retinoblastoma gene (RB1). Loss of SUCLA2 is therefore a relatively common tumour-associated deletion with currently unresolved metabolic consequences for the cell. We hypothesise that SUCLA2 deletion in cancer results in a less flexible metabolic network that results in reduced functional redundancy, revealing novel therapeutic opportunities to better treat patients across multiple tumour types. We aim to define the implications of reduced expression of SUCLA2 in myeloma cells for the cellular metabolic network, and the nature of any conditional lethality exposed by this perturbation. 

A matter of life and death

Every day, around a kilogram of cells die in our bodies. Although this might sound ominous, cell death is essential for life. For instance, apoptosis, one of 12 known types of cell death, is key to many homeostatic processes, including tissue engineering and ageing. Moreover, although apoptosis is considered the holy grail of all cell deaths, not all is known. Despite an explosion of interest caused by the Nobel Prize in 2002, research has steered to other facets of cell death due to its difficulty. However, a recently proposed mechanism is renewing interest in apoptosis.

A pore called the mitochondrial permeability transition pore can be found lodged in the mitochondrial inner membrane. In addition to regulating electrophysiological events, known as mitochondrial permeability transitions, the pore plays a pivotal role in cell metabolism, signalling, and apoptosis. We aim to develop a computational methodology to conjecture a testable fundamental theory of pore-mediated cell apoptosis under hypoxia to resolve the links between Ca2+ signalling, metabolism, and cell death.



School of MathematicsUniversity of BirminghamWatson Building 3rd FloorOffice 318EdgbastonBirmingham, England B15 2TS