Pawel Swietach - Selected Publications#

1. Swietach, Boedtkjer, Pedersen “How protons pave the way to aggressive cancers”, Nature Reviews Cancer [in press]

This review, commissioned on the centennial of Warburg’s original discovery of lactic acidosis in tumours, provides a summary of the field, discusses its impact on our understanding of cancer, and presents new avenues for treatment. Pawel is lead author on the review.

2. Park, Crump, Louwman, Krywawych, Cheong, Vendrell, Gill, Gunadasa-Rohling, Ford, Hauton, Fournier, Pires, Watson, Roseman, Holder, Koschinski, Carnicer, Curtis, Zaccolo, Hulikova, Fischer, Kramer, McCullagh, Trefely, Milne, Swietach “Park, Crump, Louwman, Disrupted propionate metabolism evokes transcriptional changes in the heart by increasing histone acetylation and propionylation” Nature Cardiovasc Res [in press]

This is the first demonstration of a novel epigenetic control mechanism operating in the heart, discovered by studying a rare metabolic disease, propionic acidaemia. The work identifies a novel therapeutic strategy for restoring metabolic flows, and has impact on disorders where propionate is elevated, including abnormal gut bacteria activity and diabetes. Pawel is the senior investigator on this study.

3. Michl, Monterisi, White, Blaszczak, Hulikova, Abdullayeva, Bridges, Yin, Bodmer & Swietach. "Acid-adapted cancer cells alkalinize their cytoplasm by degrading the acid-loading membrane transporter anion exchanger 2, SLC4A2". Cell Rep (2023)

This article describes how cancer cell pH homeostasis adapts to an acidic environment, conferring a survival advantage in the tumour microenvironment. Strikingly, the mechanism involves an acid-evoked degradation of SLC4A2, an acid-loader, which is counter-intuitive. The findings highlight the importance of physiology-based approaches because such a result would evade genetics-based screening. Pawel is lead investigator on this work.

4. Monterisi, Michl, Hulikova, Koth, Bridges, Hill, Abdullayeva, Bodmer, Swietach & Jiang. "Solute exchange through gap junctions lessens the adverse effects of inactivating mutations in metabolite-handling genes". Elife (2022)

The authors show evidence that diffusive coupling between cancer cells can rescue sub-populations deficient in a particular transporter or enzyme activity (e.g. due to a mutation). This paradigm-shift can explain why negative selection of metabolic-related genes is rare, and why targeting metabolism is challenging. The impact of this work is that it challenges the dogma that the single cell is the unit under selection in Darwinian evolution, and argues for clusters of cells being more critical substrates for evolutionary dynamics. Pawel is lead investigator on this work.

5. Michl, Wang, Monterisi, Blaszczak, Beveridge, Bridges, Koth, Bodmer & Swietach. "CRISPR-Cas9 screen identifies oxidative phosphorylation as essential for cancer cell survival at low extracellular pH". Cell Rep (2022)

This work describes an unbiased knockout screen that discovered genes essential for survival under acidosis. The findings include a description of how regimens of metabolic inhibitors can be titrated to selectively kill cells under acid stress, such as cancer cells in their tumour microenvironment. Pawel is lead investigator on this work.

6. Hulikova, Park, Loonat, Gunadasa-Rohling, Curtis, Chung, Wilson, Carr, Trafford, Fournier, Moshnikova, Andreev, Reshetnyak, Riley, Smart, Milne, Crump & Swietach. "Alkaline nucleoplasm facilitates contractile gene expression in the mammalian heart". Basic Res Cardiol (2022)

The article presents evidence for a role of acidic niches in the developing myocardium and a mechanism for controlling gene expression under the control of pH. This discovery adds a new regulator to cardiac development, gauging the balance between metabolic acid production and perfusion. Pawel is lead investigator on this work.

7. Richardson, Hulikova, Proven, Hipkiss, Akanni, Roy & Swietach. "Single-cell O-2 exchange imaging shows that cytoplasmic diffusion is a dominant barrier to efficient gas transport in red blood cells". P Natl Acad Sci USA (2020)

The article presents a novel method, called single cell oxygen saturation imaging, that quantified a previously under-studied parameter of red blood cells. This method has since been used as a gold standard in assessing oxygen release from red cells, with prominent uses in screening bloods for kinetic anaemias and transfusion products for storage lesion. Pawel is lead investigator on this study.

8. Wu, Estrella, Beatty, Abrahams, El-Kenawi, Russell, Ibrahim-Hashim, Longo, Reshetnyak, Moshnikova, Andreev, Luddy, Damaghi, Kodumudi, Pillai, Enriquez-Navas, Pilon-Thomas, Swietach & Gillies. "T-cells produce acidic niches in lymph nodes to suppress their own effector functions". Nat Commun (2020)

This collaborative work between Oxford and Moffitt Cancer Center reports how acidosis blocks T cell effector functions, and how this operates physiologically as a control mechanism in the lymph node. The discovery adds to our understanding of how tumours evade immune surveillance and highlights opportunities to improve the efficacy of immunotherapy. Pawel is joint senior author on this study.

9. Swietach, Youm, Saegusa, Leem, Spitzer & Vaughan-Jones. "Coupled Ca2+/H+ transport by cytoplasmic buffers regulates local Ca2+ and H+ ion signaling". P Natl Acad Sci USA (2013)

This paradigm-shift in ion transport shows how gradients of ions can be generated within cells, even in the absence of a partitioning membrane. This study lay the foundations to our understanding of microdomains and how they can be maintained. Pawel was lead researcher on this postdoctoral project.

10. Swietach, Wigfield, Cobden, Supuran, Harris & Vaughan-Jones. "Tumor-associated carbonic anhydrase 9 spatially coordinates intracellular pH in three-dimensional multicellular growths". J Biol Chem (2008)

This was the first demonstration of the physiological role of carbonic anhydrase 9 in tumours. This tumour-associated enzyme facilitates CO2/HCO3 diffusion and allows tumours to overcome long diffusion distances. CA9 has since been considered an attractive target for therapy and efforts have been made, including by Pawel’s team, to capitalise on this critical role in cancer biology. Pawel was lead researcher on this postdoctoral project.