Periodic Reporting for period 4 - Survive (Surviving metabolism: acid handling and signalling)
Okres sprawozdawczy: 2021-12-01 do 2023-11-30
A quarter of deaths in the EU (equating to 1.1 million people) are linked to cancer. Geographically, death rates range from 200 per 100,000 in Malta to 300 per 100,000 in Hungary and Croatia. Despite improvements in early diagnosis, many patients do not respond to treatments, which is often a reflection of how cancers adapt to become a highly heterogenous disease that is difficult to target with one type of strategy alone. Cancers progress in this way because they respond to selection pressures brewing within the tumour through a process that resembles Darwinian evolution in ecology. To understand these pro-oncogenic events, it is important to identify the factors that challenge cancer cell survival, and the biological responses that enable selected cells to thrive and become more malignant.
Although many factors can affect cell viability, the one that our project focused on is acidity because cancer metabolism generates vast amounts of acidic end-products that accumulate in tumours, contributing to their unique chemical microenvironment. Acidity, in turn, is generally deleterious to cell growth, unless cancer cells acquire resistance mechanisms. This response bears resemblance to drug resistance, with the notable difference that acidity is produced endogenously by the tumour, rather than being introduced as a treatment. We postulate that influencing the trajectory of acid-driven selection can swerve the evolution of cancers away from the most malignant forms because it narrows the survival advantage of cancer cells over host tissues and defences.
The objective of the SURVIVE project was to describe how cancer cells respond to acidity, a chemical signature of the tumour microenvironment, and to test vulnerabilities in these mechanisms for their therapeutic potential. Our major focus was colorectal and pancreatic cancer because these cancers tend to produce profoundly acidic tumours that can become highly malignant. The opportunities provided by the funder were conducive for investigating the interplay between acidity and low oxygen levels (hypoxia), the role of red blood cells as carriers of oxygen and acidity, as well as the broader context of acid-evoked signalling in biological systems. Our aspiration was to deliver high-quality data that can bring paradigm-shifting discoveries on the role and opportunities of tumour acidosis. Impact was expected because acidity is widely recognised as being relevant to tumours but has often been ignored or not adequately controlled experimentally.
We concluded the project with 23 publications in peer-reviewed journals, and a review article in Nature Reviews Cancer. SURVIVE trained four postdoctoral scientists and two PhD students, and interacted with a parallel EU action “pHIONIC”. We disseminated guidelines for studying pH, and developed new methods and technologies including an ERC proof-of-concept project. Our outputs included discoveries of new survival mechanisms that are attractive targets for therapy. Ongoing research efforts since the conclusion of SURVIVE are testing these targets in a therapeutic context.
Although many factors can affect cell viability, the one that our project focused on is acidity because cancer metabolism generates vast amounts of acidic end-products that accumulate in tumours, contributing to their unique chemical microenvironment. Acidity, in turn, is generally deleterious to cell growth, unless cancer cells acquire resistance mechanisms. This response bears resemblance to drug resistance, with the notable difference that acidity is produced endogenously by the tumour, rather than being introduced as a treatment. We postulate that influencing the trajectory of acid-driven selection can swerve the evolution of cancers away from the most malignant forms because it narrows the survival advantage of cancer cells over host tissues and defences.
The objective of the SURVIVE project was to describe how cancer cells respond to acidity, a chemical signature of the tumour microenvironment, and to test vulnerabilities in these mechanisms for their therapeutic potential. Our major focus was colorectal and pancreatic cancer because these cancers tend to produce profoundly acidic tumours that can become highly malignant. The opportunities provided by the funder were conducive for investigating the interplay between acidity and low oxygen levels (hypoxia), the role of red blood cells as carriers of oxygen and acidity, as well as the broader context of acid-evoked signalling in biological systems. Our aspiration was to deliver high-quality data that can bring paradigm-shifting discoveries on the role and opportunities of tumour acidosis. Impact was expected because acidity is widely recognised as being relevant to tumours but has often been ignored or not adequately controlled experimentally.
We concluded the project with 23 publications in peer-reviewed journals, and a review article in Nature Reviews Cancer. SURVIVE trained four postdoctoral scientists and two PhD students, and interacted with a parallel EU action “pHIONIC”. We disseminated guidelines for studying pH, and developed new methods and technologies including an ERC proof-of-concept project. Our outputs included discoveries of new survival mechanisms that are attractive targets for therapy. Ongoing research efforts since the conclusion of SURVIVE are testing these targets in a therapeutic context.
The project began with installing state-of-the-art equipment, recruiting staff, and obtaining one of the largest collections of cell lines in academia. Our first milestone was to disseminate guidelines for good practice in studying the effects of acidosis on cancer cells. These instructions enabled well-controlled experiments, including our milestone identification of genes that are essential for surviving acidity. For this, we performed a screen to test which genes confer resistance to acidosis, identifying NDUFS1, part of a complex required for mitochondrial respiration. We showed that blocking respiration can selectively eliminate the survival advantage of acid-resistant cells, causing a stable disruption to acid-driven selection. We explained why respiration is essential in terms of its robustness under acidic conditions, which is in stark contrast to the acid-sensitivity of the other major energy and resource harnessing pathway, glycolysis. Additionally, we described how the pH-regulatory apparatus of cells adapts to acidic conditions through a novel mechanism that degrades acid-loading transporters, a process that normally operates to prevent excessively alkaline conditions inside cells. Further work classified cancer cells according to their acid-sensitivity, and associated resistant lines with the expression of CEACAM5 and CEACAM6 on the surface membrane. The significance of this marker is in acting as a moiety for targeting drugs specifically to acid-resistant cells, the ones that are most likely to survive selection by acidity. Our work also described how cancer cells interact through connections called gap junctions, which confers a novel level of resilience by allowing neighbours to compensate for each other’s deficiencies. This discovery challenged the paradigm that individual cells are the substrates of selection, and made a case for cell-networks. We described methods for extracting cells according to metabolic activity, and characterised an intrinsic rhythm-generator that causes cell populations to show metabolic heterogeneity, a survival advantage when resources are limited. Our collaborative work with Moffitt Cancer Center described how lymph nodes are acidic and how this attenuates T cells, a type of immune cell important for killing cancer cells. This discovery provided new insight into the mechanisms by which acidic tumours evade immune surveillance, and how this can be overcome. We developed a method to study oxygen transport by red cells, deployed it to study red cell quality in blood banks and anaemias, and developed algorithms to understand its impact for cancer oxygenation and pH. Our molecular investigations identified new pathways in which acids influence gene expression, ranging from rare diseases to general mechanisms relevant also to tissue development. These findings were disseminated through 23 scientific publications, including reviews and conference presentations.
We produced a comprehensive description of the pH-related phenotype in a large panel of cell lines, and described new mechanisms of acid-signalling and acid-resistance in tumours. Our achievements have been contextualised in our recent Nature Reviews Cancer article, which also demarcated future directions that build on our paradigm-shifts. The vulnerabilities we described are now promising targets for therapy. The impact of our work spans beyond cancer cells: we described factors affecting oxygen release from red cells, a process that determines the extent of tissue hypoxia and hence the operation of respiration in acid-resistant cancer cells, the effect of acidity on immune cells, hence consequences for immunotherapy, and the signalling cascades triggered by acidity that apply to other tissues, notably the heart.
See also: https://cordis.europa.eu/article/id/450239-understanding-acidity-s-role-in-cancer-survival?WT.mc_id=exp
See also: https://cordis.europa.eu/article/id/450239-understanding-acidity-s-role-in-cancer-survival?WT.mc_id=exp