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A new paper led by Dr Johanna Michl and Professor Pawel Swietach from DPAG’s Swietach Group has identified a new gene that allows cancer cells to survive in the typically acidic microenvironment of a malignant tumour. They have discovered drugs that inhibit the gene in other medical conditions also selectively kill cancer cells at acidic pH, without damaging healthy tissue. This defines a novel strategy for targeting acidic tumour regions.

Cy5.5-conjugated pH-(low)-insertion peptide (pHLIP, red) to label acidic tumour regions and Hoechst-33342 (blue) to label cell nuclei in the fresh frozen tumor sections of wild-type SW1222 xenografts. © Dr Jana Koth, MRC Weatherall Institute for Molecular Medicine
Acidic regions of a cancer tumour labelled red

Cancer cells create uniquely acidic environments for tumours to invade formerly healthy tissues and metastasise. Their higher metabolic rates produce greater volumes of lactic acid and CO2, and a lack of blood vessels prevent efficient wash-out of acidic waste products from the tumour. A great deal of research over the years has attempted to explain how cancer cells adapt to survive in these acidic conditions. However, presently none of the major approved therapies for managing tumour growth actively target acid handling.

New research led by Dr Johanna Michl and Professor Pawel Swietach performed a genome-wide CRISPR-Cas9 screen to simultaneously study all genes potentially involved in cancer cell survival under acid stress. They have identified, for the first time, that a fundamental mitochondrial process called oxidative phosphorylation (OXPHOS) is the principal and most critical survival pathway in acidic tumour environments. Corresponding author Dr Johanna Michl said: “Targeting mitochondrial pathways such as OXPHOS has previously been considered a promising avenue for cancer therapy. However, we are the first to show that the efficacy of targeting mitochondrial metabolism in tumours depends on an acidic environment.”

In particular, researchers have discovered the NDUFS1 gene as a novel druggable target for selectively killing cancer cells under acidic conditions. Dr Michl said: “NDUFS1 is an essential component of the OXPHOS pathway, which facilitates mitochondrial respiration, a means for energy production. Cancer cells rely on two main pathways for their energy production: glycolysis and mitochondrial respiration. Tumour acidity strongly inhibits glycolysis. When one source of energy becomes limited (glycolysis), the cells rely increasingly on the other (mitochondrial respiration). If both sources of energy production are inhibited (glycolysis through acidity and mitochondrial respiration through genetic or chemical inhibition) the cells are killed.”

In a new paper published in Cell Reports, the team examined two FDA-approved drugs, atovaquone and pioglitazone which inhibit the OXPHOS pathway. Atovaquone is currently used to treat malaria and pneumonia, while pioglitazone is currently used as medication for type II diabetes. The researchers found that both drugs are specifically toxic to cancer cells at acidic pH, but not to cells surrounded by physiological pH, and therefore do not damage normal tissues. Consequently, they have uncovered two potential candidates that could be repurposed as tumour therapies.

Dr Michl said: “The aim of most cancer therapies is to specifically kill cancer cells only, while leaving surrounding normal tissues unharmed, thereby preventing toxic side effects. Our strategy takes advantage of the fact that tumour tissues typically have an acidic pH, while normal tissues are surrounded by a physiological, more neutral pH. The NDUFS1 gene is essential for the OXPHOS pathway to function, so if we inhibit NDUFS1 under physiological pH conditions, the cells survive as they are able to obtain energy through the glycolysis pathway. If we block NDUFS1 under acidic pH conditions, the cells die, as they are unable to source enough energy to survive.”

“Our findings raise the possibility of therapeutically targeting OXPHOS in combination with acid stress as a potential cancer treatment option. Non-tumoral side effects could be reduced by appropriate chemical designs or delivery systems. For example, a pH-sensitive cell penetrating peptide (pHLIP) has been used as a delivery platform to specifically target the acidic tumour microenvironment. Novel drugs could be developed which use OXPHOS inhibitors linked to pHLIP as a novel strategy to target OXPHOS in acidic tumours.”

The full paper “CRISPR-Cas9 screen identifies oxidative phosphorylation as essential for cancer cell survival at low extracellular pH” is available to read in Cell Reports. This project was made possible through a successful collaboration between the Weatherall Institute of Molecular Medicine (WIMM) and DPAG.