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Disease and treatment

Cancer treatment could soon target a protein

Researchers have found a protein that is important in helping tumours to survive, grow and metastasize. The protein could become a new target for cancer treatment.

Cancer treatment should not always target the cancer cells alone. This is the conclusion of new research that suggests that the support cells surrounding the tumour may also be a suitable target in combating cancer.

One of these potential targets may include the protein nicotinamide N-methyltransferase (NNMT), a metabolic enzyme that supports tumour growth and the ability to metastasize.

NNMT may therefore also become a treatment target because, if researchers can reduce the expression or activity of this cancer-promoting protein, they may also slow down tumour growth to give other treatments time to cure the person with cancer.

At least this what a researcher behind the discovery hopes.

“For a long time, researchers have almost exclusively focused on the cancer cells to understand cancer and find ways to treat people with the disease. But a tumour is a complex entity with many other cell types involved – collectively called the tumour stroma or microenvironment – that are by definition non-cancerous. We have investigated some of these support cells to determine how they behave during metastasis and discovered a common protein pattern in these cells that new treatments can target,” says Fabian Coscia, postdoctoral fellow, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen.

The new research results were recently published in Nature.

Cancer needs help to proliferate

Cancer cells depend on support to proliferate and metastasize.

They need help from many different support cells that they reprogramme to assist their aggressive growth.

One way cancer cells do this is by inducing nearby cells to send them nutrients or growth signals or to create space in the adjacent tissue so that the cancer cells can divide or metastasize.

Fibroblasts are one type of support cell that are present throughout the body. Under normal conditions, they fulfil important physiological tasks during wound healing, for example.

“However, fibroblasts near cancer cells promote tumour growth because the cancer cells induce the fibroblast cells to act on their behalf. This is interesting that cancer cells can communicate with their surroundings and make them work for rather than against them, but this clearly also provides some therapeutic opportunities,” says Fabian Coscia.

Similar protein profiles among all cancer cases

Fabian Coscia and colleagues examined more than 5000 proteins in the tumour and tumour stroma (support cells) from normal and cancer tissue to see whether any behaved differently in the two groups.

The study is the first to systematically compare the protein profiles of the tumour stroma during ovarian cancer metastasis.

The most interesting discovery is that the protein profiles of the metastatic stroma were highly similar across tumours from different women with advanced-stage ovarian cancer, which was the opposite in the cancer cell compartment.

“Cancer cells seldom have common characteristics in the expression of proteins, which also creates difficulty in identifying common targets for treatments across the people with cancer. It is therefore interesting that we found a common signature in the support cells, because then general treatments could be developed,” says Fabian Coscia.

Proteins induce cells to work for cancer cells

The researchers focused on one specific metabolic regulation protein that is extremely active in reprogrammed fibroblasts in cancer: cancer-associated fibroblasts.

NNMT causes several changes in the gene expression and metabolism of fibroblasts, and when the activity of NNMT changes, the fibroblast changes from a normal fibroblast to a cancer-associated fibroblast that supports cancer growth.

Overexpression of NNMT leads to increased cell division, growth and metastasis in the related cancer cells.

“NNMT regulates the tumour-promoting effect of fibroblasts,” says Fabian Coscia.

A novel NNMT inhibitor

In further studies, the researchers used a novel NNMT inhibitor (NNMTi) that was then tested to inhibit cancer growth and metastasis in pre-clinical models.

The idea was that, if they suppressed the activity of NNMT, the cancer-associated fibroblasts would revert to their normal state of not supporting tumour growth.

The researchers tested NNMTi on fibroblasts, and it worked well in inhibiting cancer cell growth.

“We tested NNMTi in pre-clinical mouse models and it worked. It slowed down the ability of cancer cells to metastasize, so the cancer did not progress as rapidly as it might otherwise,” says Fabian Coscia.

A new type of treatment?

Fabian Coscia thinks that the discovery could be the mechanistic basis for a new class of cancer treatment in the future.

The vast majority of current treatments focus on attacking the cancer cells, such as standard chemotherapy. However, cancer cells often acquire drug resistance so that the same drug cannot be used again. It is therefore important to identify alternative treatment regimens that have a different mode of action.

If researchers can use NNMTi to keep cancer cells from taking control of the other cells, doctors can attack cancer in several ways.

”We hope that one day we will be able to treat people with combination therapy – for example, chemotherapy in parallel with an NNMT inhibitor – so the nearby tissue no longer works for the tumour but even fights it. Many treatments could become much more effective if they do not have to fight the effects of the support cells that strengthen the tumour,” says Fabian Coscia.

Proteomics reveals NNMT as a master metabolic regulator of cancer-associated fibroblasts” has been published in Nature. Several authors are employed in the Clinical Proteomics Group, Proteomics Program, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen.

Fabian Coscia
Post.doc.
The main research focus of Professor Matthias Mann’s laboratory is to identify novel biomarkers that can be used for patient diagnosis and possibly for the prevention and treatment of metabolic diseases, such as diabetes and cancer. To this end, the lab is developing and using cutting-edge mass spectrometry-based proteomics; an area in which the Mann Group is world-leading. The Mann Group undertakes ambitious research projects involving proteomics of blood, plasma, cerebrospinal fluid and tissue for the phenotyping of patients. One goal is to establish robust, high-throughput proteome profiling pipelines for these materials, allowing for the proteomic screening of clinical cohorts. The group’s overarching aim is to identify biological markers for early detection of metabolic disorders, to improve diagnosis and help to develop individualized therapies. “Our eventual goal is to prevent the development of the metabolic syndrome in the first place, by targeted and personalized life style interventions,” says Professor and Group Leader, Matthias Mann. To this end, the group builds on its longstanding expertise in mass spectrometry to implement an artificial intelligence-guided platform for analyzing the proteomes of patient tissue from low amounts of formalin-fixed, paraffin-embedded samples at high accuracy and sensitivity. “Our highly sensitive methods now enable us to simultaneously profile thousands of proteins derived from only a few hundred cells, allowing us to identify the proteins that are most critical for various diseases,” Mann says. Another area of focus is the interpretation of ‘multi-omics’ data, which is still a challenge. Often, a single ‘omics’ dimension is not sufficient to capture the full complexity of a disease. To overcome these challenges, the Mann Group is developing the Clinical Knowledge Graph where multi-omics data, together with vast amounts of meta-data, is collected and harmonized – enabling analyses and providing an excellent ecosystem for machine learning.