Life Sciences Research for Lifelong Health

Michael Wakelam

Research Summary

We aim to understand the essential physiological functions of lipids. Lipids are highly dynamic structures with structural, metabolic and signalling roles. To fully understand the roles that lipids have in cell function during ageing we need the ability to determine their individual changes.

The cellular lipidome is extremely complex, with distinct classes of lipids each containing many molecular species that can differ both in the length of each acyl chain present and in the number and position of double bonds.

In our lab we have pioneered the use of high-sensitivity liquid chromatography-mass spectrometry (LC-MS) technology to rapidly and comprehensively measure the levels of lipids in a wide range of cell types, tissues and tumours. The lipidome of a cell typically comprises of ~ 1500 distinct lipid species measurable with current LC-MS technology. However, this number is most likely an underestimate since there are theoretically closer to 10 000 distinct lipid species in the lipidome.

The principal aim of our laboratory is to better understand how the distinct lipid species of a cell’s lipidome function during the healthy ageing of the whole animal.

​To achieve this we use a multidisciplinary approach combining LC-MS analysis, protein biochemistry, cell biology and genetic manipulation of model organisms. This allows us to identify the cellular signalling pathways and processes that individual lipid species regulate, and to investigate how the enzymes that determine the composition of the lipidome are regulated in response to changes in the environment.

Latest Publications

CD151 regulates expression of FGFR2 in breast cancer cells via PKC-dependent pathways.
Sadej R, Lu X, Turczyk L, Novitskaya V, Lopez-Clavijo AF, Kordek R, Potemski P, Wakelam MJO, Romanska H, Berditchevski F

Expression of the tetraspanin CD151 is frequently upregulated in epithelial malignancies and correlates with poor prognosis. Here we report that CD151 is involved in regulation of the expression of fibroblast growth factor receptor 2 (FGFR2). Depletion of CD151 in breast cancer cells resulted in an increased level of FGFR2. Accordingly, an inverse correlation between CD151 and FGFR2 was observed in breast cancer tissues. CD151-dependent regulation of the FGFR2 expression relies on post-transcriptional mechanisms involving HuR/ELAVL1, a multifunctional RNA binding protein, and the assembly of processing bodies (P-bodies). Depletion of CD151 correlated with inhibition of PKC, a well-established downstream target of CD151. Accordingly, the levels of dialcylglycerol species were decreased in CD151-negative cells, and inhibition of PKC resulted in the increased expression of FGFR2. Whilst expression of FGFR2 itself did not correlate with any of the clinicopathological data, the FGFR2-/CD151+ patients are more likely to develop lymph node metastasis. Conversely, FGFR2-/CD151- patients demonstrated better overall survival. These results illustrate functional interdependency between CD151 complexes and FGFR2 and suggest a previously unsuspected role of CD151 in breast tumourigenesis.

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Journal of cell science, , 1477-9137, , 2018

PMID: 30257985

MS-based lipidomics of human blood plasma - a community-initiated position paper to develop accepted guidelines.
Burla B, Arita M, Arita M, Bendt AK, Cazenave-Gassiot A, Dennis EA, Ekroos K, Han X, Ikeda K, Liebisch G, Lin MK, Loh TP, Meikle PJ, Orešič M, Quehenberger O, Shevchenko A, Torta F, Wakelam MJO, Wheelock CE, Wenk MR

Human blood is a self-regenerating, lipid-rich biologic fluid that is routinely collected in hospital settings. The inventory of lipid molecules found in blood plasma (plasma lipidome) offers insights into individual metabolism and physiology in health and disease. Disturbances in lipid metabolism also occur in conditions that are not directly linked to lipid metabolism; therefore, plasma lipidomics based on mass spectrometry (MS) is an emerging tool in an array of clinical diagnostics and disease management. However, challenges exist in the translation of such lipidomic data to clinical applications. These relate to the reproducibility, accuracy, and precision of lipid quantitation, study design, sample handling, and data sharing. This position paper emerged from a workshop that initiated a community-led process to elaborate and define a set of generally accepted guidelines for quantitative MS-based lipidomics of blood plasma or serum, with harmonization of data acquired on different instrumentation platforms in independent laboratories across laboratories as an ultimate goal. We hope that other fields may benefit from and follow such a precedent.

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Journal of lipid research, , 1539-7262, , 2018

PMID: 30115755

C. elegans Eats Its Own Intestine to Make Yolk Leading to Multiple Senescent Pathologies.
Ezcurra M, Benedetto A, Sornda T, Gilliat AF, Au C, Zhang Q, van Schelt S, Petrache AL, Wang H, de la Guardia Y, Bar-Nun S, Tyler E, Wakelam MJ, Gems D

Aging (senescence) is characterized by the development of numerous pathologies, some of which limit lifespan. Key to understanding aging is discovery of the mechanisms (etiologies) that cause senescent pathology. In C. elegans, a major senescent pathology of unknown etiology is atrophy of its principal metabolic organ, the intestine. Here we identify a cause of not only this pathology but also of yolky lipid accumulation and redistribution (a form of senescent obesity): autophagy-mediated conversion of intestinal biomass into yolk. Inhibiting intestinal autophagy or vitellogenesis rescues both visceral pathologies and can also extend lifespan. This defines a disease syndrome leading to multimorbidity and contributing to late-life mortality. Activation of gut-to-yolk biomass conversion by insulin/IGF-1 signaling (IIS) promotes reproduction and senescence. This illustrates how major, IIS-promoted senescent pathologies in C. elegans can originate not from damage accumulation but from direct effects of futile, continued action of a wild-type biological program (vitellogenesis).

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Current biology : CB, , 1879-0445, , 2018

PMID: 30100339

Group Members

Latest Publications

CD151 regulates expression of FGFR2 in breast cancer cells via PKC-dependent pathways.

Sadej R, Lu X, Turczyk L

Journal of cell science
1477-9137: (2018)

PMID: 30257985

C. elegans Eats Its Own Intestine to Make Yolk Leading to Multiple Senescent Pathologies.

Ezcurra M, Benedetto A, Sornda T

Current biology : CB
1879-0445: (2018)

PMID: 30100339

Extracellular vesicles : lipids as key components of their biogenesis and functions.

Record M, Silvente-Poirot S, Poirot M

Journal of lipid research
1539-7262: (2018)

PMID: 29764923

Phospholipid signaling in innate immune cells.

O'Donnell VB, Rossjohn J, Wakelam MJ

The Journal of clinical investigation
1558-8238: (2018)

PMID: 29683435

Deciphering lipid structures based on platform-independent decision rules.

Hartler J, Triebl A, Ziegl A

Nature methods
1548-7105: (2017)

PMID: 29058722

Autotaxin-lysophosphatidic acid receptor signalling regulates hepatitis C virus replication.

Farquhar MJ, Humphreys IS, Rudge SA

Journal of hepatology
1600-0641: (2017)

PMID: 28126468

Runx1 Orchestrates Sphingolipid Metabolism and Glucocorticoid Resistance in Lymphomagenesis.

Kilbey A, Terry A, Wotton S

Journal of cellular biochemistry
118 1097-4644:1432-1441 (2017)

PMID: 27869314