Acid handling and signalling in the heart and in cancer
We study how the smallest of ions – protons – can trigger and potently modulate the function of living cells in human tissue. Protons determine the acidity of a solution, commonly measured on a pH scale, and are thus the most ubiquitous modulators of biological function. Since essentially all tissues are pH-sensitive, we undertake studies of various systems of the body. Currently, the main pillars of our work relate to the heart and to cancer, where changes in pH have a particularly powerful effect on physiology and disease processes. By understanding these pH-responses, our ambition is to better understand cardiac diseases and cancer, and propose improved treatments.
Our current projects address the following scientific questions:
- Tumours, such as colorectal cancers, are characteristically acidic. How does this acidity affect their growth and cellular behaviours?
- Most cancer cells are acid-sensitive, but some are acid-resistant. What molecules determine this phenotype, and how does this relate to aggressiveness of cancer and treatment options?
- The nucleus can be a distinct compartment with respect to pH. How is nuclear pH controlled and how can it influence the gene expression landscape in the heart and in cancer?
- Changes in pH produce powerful effects on calcium signals, which drive various processes in the heart, ranging from contraction to growth. What role does aberrant acid-handing play in cardiac diseases such as hypertrophy and failure?
- A number of inherited metabolic disorders produce acidaemias. How do diseases such as propionic acidaemia affect cardiac gene expression and physiology in the long term?
- Iron deficiency anaemia is associated with cardiac disease. What are the cellular mechanisms underpinning this relationship?
- Red blood cells have a highly specialised shape and many disease produce abnormal geometry. How does the shape and size of red cells influence their capacity to carry and exchange gases?
E.R.C. CONSOLIDATOR AWARD
Metabolism generates vast quantities of acid (protons). Essentially all biological processes are pH-sensitive, therefore the regulation of acid/base chemistry is a fundamental homeostatic priority. However, controlled intracellular pH (pHi) dynamics are, potentially, a versatile form of cell signalling with a broad remit of targets because protonation of proteins is an enzyme-independent post-translational modification. Indeed, many examples of orchestrated spatio-temporal changes in pHi have been demonstrated to take place inside cells, yielding the concept of protons as bona fide signals.
We and others have now made a compelling case for studying acid handling and signalling in cancer. Acidity is an established chemical signature of the tumour microenvironment. It arises because cancer metabolism releases an exceptionally large acid-load into the extracellular space. Due to abnormal vascular function, this acid-load is not promptly washed away; instead, it produces the low extracellular pH (pHe) measured reproducibly in solid tumours in vivo. Extracellular acidity is not merely a chemical consequence of metabolism, but a biological signal that feeds back on tumour biology somewhat analogously to hypoxia.
Carefully exercised acid handling is pivotal for cancer survival because it aims to maintain a favourable combination of pHi and pHe. Essentially all cells devolve a substantial fraction of their energetic and synthetic resources to keeping pHi within a narrow range that is conducive for biological activity, although a degree of cell-to-cell variation in pHi control is normally observed within a population of cells. Dysregulated acid-base balance has been shown to perturb or even kill cancer cells therefore each cell, based on its acid handling phenotype, can be ascribed a fitness to survive at a particular microenvironmental pHe. An important pHi-regulating process is acid-extrusion by membrane-bound proteins that export H+ ions (e.g. Na+/H+ exchangers) or import base (e.g. Na+-HCO3- cotransporters), but in the diffusion-limited tumour microenvironment, acid handling must also consider the diffusive transport of protons across the intra- and extracellular fluids and the role of non-cancer cells present in the tumour stroma, such as fibroblasts.
Proton signalling underlies the cellular responses to changes in acid/base chemistry. The majority of proton targets are intracellular and many examples of proton sensors have been reported, mostly on the basis of acute readouts. The longer-term effects of protons, such as on gene expression, are highly relevant to cancer cells living under acid-stress, but remain poorly characterised, despite evidence for proton-sensing transcription factors. Extracellular acidity has been proposed to exert a Darwinian selection pressure that favours a sub-population of cancer cells bearing a compatible acid handling and signalling phenotype. An analogy can be drawn to hypoxic-selection, although acid-selection has the added complexity of an intricately regulated pHe/pHi relationship. On the premise that more fit ‘pH phenotypes’ are more aggressive (e.g. are associated with cancer stem cells, CSC), acid-selection could play a major role in cancer progression. However, the definition of ‘pH-fitness’ and its relationship with stemness remain unclear.
To summarise: acidity is a potent, endogenous and broad-spectrum modulator of biological function that is regulated by a relatively small number of proteins. In principle, these characteristics should make acidity an ideal candidate for the therapeutic management of tumour growth. In reality, translating the sum of our understanding of acid handling and signalling into therapy is not trivial, and none of the major approved therapies are based explicitly on disrupting acid handling and/or signalling. Reasons for this paradox relate to inadequacies in our understanding of pH handling and signalling in cancer, exacerbated by the experimental challenges associated with pH studies.