Metabolic reprogramming in cancer

Metabolomics, a study of small molecules — or metabolites — within organisms, cells and tissues, is an important and rapidly growing branch of ‘omics’.

Metabolomics has demonstrated significant potential in early diagnosis of diseases, in therapy monitoring and in understanding the pathogenesis of different diseases, according to research firm Technavio.

“Researchers are investigating metabolome coverage in human breast cancer tissues to undertake metabolic profiling. The derived metabolomic results can be used to classify breast cancer based on tumour biology. They also allow the identification of new prognostic and predictive markers and the discovery of new targets for future therapeutic interventions. The increasing applications of metabolomics offer researchers insights into human health and these are necessary to understand chronic diseases,” according to a senior research analyst at Technavio.

“The biomarker and drug discovery segment held the largest metabolomics market share in 2018, accounting for over 45% of the market. This application segment is expected to dominate the global market throughout the forecast period.”

Considering the growing significance of the field, it was only fitting for Lorne Proteomics to dedicate one full day to metabolomics. The 24th Annual Lorne Proteomics Symposium featured the 1st Lorne Metabolomics Symposium (held on 8 February 2019) — which included sessions on a range of topics including metabolomics in health and disease, small molecules, new methods, lipids and lipidomics, and lipid/small molecule imaging MS.

The symposium featured leading international and local metabolomics researchers, including Dr Kristin Brown, Peter MacCallum Cancer Centre, Victoria; Professor Dr Ron Heeren, Maastricht University, The Netherlands; Dr Jessica Lasky-Su, Brigham and Women’s Hospital, United States; and Dr Robert Trengove, Murdoch University, Western Australia. We interviewed Dr Brown to get some insights on the field of metabolomics and her research focus.

Dr Kristin Brown is a group leader in the Cancer Therapeutics Program at the Peter MacCallum Cancer Centre and also holds a joint appointment in the Department of Biochemistry and Molecular Biology at the University of Melbourne.

Curiosity, passion and science

Brown became interested in science at a very young age. “Science was always my favourite subject at school. I’m not entirely sure why this was the case — I loved the fact that there was so much to be discovered and I loved learning about famous scientists and how their research had changed the world we live in — [for] example, Marie Curie and Edward Jenner. Regardless, I knew from quite an early age that I wanted to be a scientist,” Brown said.

She undertook a science degree at the University of Canterbury, New Zealand, after completing high school. “My laboratory-based practical classes convinced me that science was the career for me. I loved being in the lab — the challenge of designing an experiment, learning how to troubleshoot when things went wrong and the thrill of generating an exciting piece of data. I was hooked!”

Brown’s love for the laboratory saw her complete a Master of Science (MSc) from the University of Canterbury, with the research component of the MSc degree in a laboratory based at the Christchurch School of Medicine. She then proceeded to undertake PhD studies through the University of Otago but still based at the Christchurch School of Medicine. Following that, Brown relocated to Boston in 2010 to undertake a postdoctoral fellowship at Harvard Medical School (HMS). Her passion and hard work paid off and she was promoted to the position of instructor at HMS. “I absolutely loved the research environment provided by HMS and HMS-affiliated institutions. It was amazing to be surrounded by so many like-minded individuals.”

Metabolic reprogramming

In September 2016, Brown relocated from Boston to Melbourne to establish an independent research laboratory at the Peter MacCallum Cancer Centre. By integrating metabolomics, transcriptomics and proteomics data, the Brown Lab investigates how cell metabolism contributes to cancer development, progression and therapy resistance.

“Metabolic reprogramming is a hallmark of cancer that is required to fulfil the unique metabolic demands of cancer cells.”

Innovations in mass spectrometry platforms have enabled metabolomics to complement other — omics technologies (including proteomics) as key technologies in research, said Brown. “Increasingly, cancer researchers are employing metabolomics methodologies to try to understand the diverse ways in which metabolism impacts cancer.”

In recent years, there has been growing interest in developing strategies to exploit the metabolic vulnerabilities of cancer cells for therapeutic gain. However, our ability to do this is dependent on a thorough understanding of the molecular mechanisms underpinning metabolic reprogramming in cancer. This is the research focus of my lab. Moreover, we investigate how reprogramming of cellular metabolism contributes to malignant transformation, tumour progression and therapy resistance, with a particular focus on breast cancer.”

TNBC

In Australia, around 15,000 women are diagnosed with breast cancer every year, of which around 15% have triple-negative breast cancer (TNBC) — a particularly aggressive subtype of breast cancer with limited treatment options.

“Approximately 15–30% of breast tumours detected by screening are unlikely to be problematic if left alone. We need to work out better ways to identify the tumours that actually pose a threat and focus on treating these patients,” Brown said.

“We need to better understand the ‘risk factors’ for the disease (genetic, environmental, etc). This will allow more focus to be put toward breast cancer prevention, as opposed to trying to treat the disease once it has taken hold.

“Conventional chemotherapy agents remain the standard of care for TNBC, yet only 30–40% of patients with early-stage TNBC respond to chemotherapy. The long-term prognosis for patients with residual disease after chemotherapy is poor. There is an urgent need to identify mechanisms that limit the efficacy of chemotherapy, and to develop combination therapy approaches to improve the efficacy of chemotherapy for treating TNBC. We have previously shown that chemotherapy agents reprogram pyrimidine metabolism and demonstrated that a clinically approved inhibitor of pyrimidine synthesis can sensitise TNBC cells to chemotherapy. This study provided evidence that chemotherapy-treated cancer cells have unique metabolic requirements that can be exploited for therapeutic gain.”

Cancer cell metabolism

At the 1st Lorne Metabolomics Symposium, Brown talked about some of her lab’s studies investigating the ways in which cancer cell metabolism is influenced by both cell-intrinsic (eg, oncogenes) and cell-extrinsic (eg, anticancer therapy) factors.

Signalling networks downstream of oncogenes regulate cancer cell metabolism. “Our recent studies have focused on the oncogenic transcriptional co-activator YAP. Aberrant activation of YAP is widespread in human cancers, yet there is little knowledge regarding mechanisms by which YAP drives tumourigenesis. We find that YAP overexpression induces de novo lipogenesis in vitro and in vivo via transcriptional upregulation of a critical effector of the oncogenic phosphoinositide 3-kinase (PI3K) pathway.

“Importantly, inhibition of key enzymes in the de novo lipogenesis pathway blocks the uncontrolled proliferation associated with YAP-driven transformation. Our data reveal a mechanism of crosstalk between two important oncogenic signalling pathways and reveal a metabolic vulnerability that can be targeted to disrupt oncogenic YAP activity.

“A variety of factors in the tumour microenvironment also have a major impact on cancer cell metabolism. Our studies have focused on characterising metabolic reprogramming events triggered upon chemotherapy exposure. Using in vitro and in vivo metabolomic profiling, we find that chemotherapy exposure induces an increase in the abundance of pyrimidine nucleotides as a result of increased flux through the de novo pyrimidine synthesis pathway. We find that pharmacological inhibition of de novo pyrimidine synthesis sensitises cancer cells to genotoxic chemotherapy agents by exacerbating DNA damage.

“Our studies provide preclinical evidence to demonstrate that adaptive reprograming of de novo pyrimidine synthesis represents a metabolic vulnerability that can be exploited to improve the anticancer activity of genotoxic chemotherapy agents for the treatment of TNBC.”

The ultimate goal

While metabolomics methods and technologies may assist in finding new treatments for cancer, the field has its own challenges. One of the major challenges, according to Brown, is trying to identify the most appropriate models to study cancer cell metabolism. “There are strengths and weaknesses to all laboratory models (2D cell culture, 3D cell culture, ex vivo culture and animal models). Researchers need to think carefully about the benefits and limitations of each model system before undertaking metabolomics studies.”

Brown and her team continue to investigate the ways in which adaptive reprogramming of metabolism contributes to chemotherapy resistance in TNBC. “We hope that this will allow us to identify additional combination therapy strategies to improve the treatment of TNBC. Our ultimate goal is to see these rationally designed combination therapy strategies be employed in the clinic to improve patient survival.”

Image credit: ©stock.adobe.com/au/crevis