Age-induced metabolic reprogramming underlies cancer progression

ABSTRACT

Aging is a main risk factor for cancer. Using human serum we demonstrated that tumor progression and metastases occur, at least in part, as a manifestation of global metabolic deregulation of the aged host. This shows that the role of aging in cancer goes far beyond increased exposure time to mutagens; the aging process coordinates various aspects required for malignancy.

Aging is the most robust risk factor for cancer development, which is underscored by the fact that more than 60% of cancers occur in those aged 60 and above. Despite this, how aging and tumorigenesis are intertwined is poorly understood and is a matter of significant debate. Further, aging predicts both cancer incidence and prognosis: older patients have worse outcomes with unfavorable progression-free and overall survival rates.^1,2 For example, older women are twice as likely to die from ovarian cancer than younger women with this malignancy.¹ Early-stage and lower grade tumors are in part responsible for the higher survival rate of younger patients; however, after controlling for these factors younger patients still display better prognosis suggesting that there are other underlying contributors to the increase in mortality in older patients.³

In older patients, the probability of developing invasive metastatic disease is also more than double that of younger patients⁴ suggesting that acquisition of aggressive properties plays a role in the higher cancer-associated mortality observed in old patients. Considering the organismal reprogramming that occurs through the aging process, we sought to understand if the systemic alterations that occur as one ages affect how tumors progress. We found that several carcinoma cell lines, when in the presence of serum from old but otherwise healthy individuals (≥60 y of age), displayed aggressive properties such as induction of epithelial-to-mesenchymal transition (a genetic program associated with metastasis), resistance to chemotherapeutic agents, and significantly increasing the capacity of these cells to promote metastatic lesions in the lung of mice.⁵ This was in stark contrast to the absence of these aggressive traits in the same carcinoma cells cultured in the presence of serum from young individuals (≤30 y of age).⁵ Compelled by these observations, we went on to determine what in old people’s circulation could be inducing pro-aggressive phenotypes in pre-established cancer cells. Proteomics analysis of the donor sera did not reveal a signature of pro-aggressive molecules that could explain these phenotypes. Rather, we found that the accumulation of a single metabolite, methylmalonic acid, in circulation was the culprit of the pro-aggressive phenotypes induced by old serum. In fact, raising circulatory levels of methylmalonic acid in mice to levels similar to the ones present in the serum from old donors was sufficient to drive tumor growth, metastatic spread and ultimately lead to a higher cancer-associated mortality.

Methylmalonic acid, which in healthy individuals is only present at a very low level, is a by-product of propionate metabolism downstream of branched chain amino acid (BCAA) and odd chain fatty acid (OCFA) catabolism. Under physiological conditions, BCAA and OCFA-derived propionyl-CoA is carboxylated into methylmalonyl-coenzyme A (CoA), which is then converted into succinyl-CoA by the action of methylmalonyl-CoA mutase (MMUT) in a reaction that requires vitamin B12 as a cofactor. Succinyl-CoA subsequently enters the tricarboxylic acid (TCA) cycle. Thus, propionyl-CoA carboxylation is a critical convergence point in catabolism of BCAA and OCFA to promote TCA cycle anaplerosis. However, under certain circumstances, methylmalonyl-CoA accumulation leads to the loss of its CoA moiety driving the formation and excretion of methylmalonic acid. Elevation of methylmalonic acid in circulation is best known as a result of vitamin B12 deficiency, and its association with several age-related disorders, including diabetes, dementia and cardiovascular disease,^6–8 have been described. However, its role in cancer and cancer progression was poorly understood.

Considering how little was known about the mechanisms by which methylmalonic acid affects cancer cells, we sought to understand at a molecular level how an increase in circulatory methylmalonic acid induced tumor progression. Through unbiased transcriptional profiling, we discovered that methylmalonic acid drives the production of transforming growth factor beta (TGFβ) ligand, a well-known inducer of tumor progression, in the cancer cells. We went on to determine that methylmalonic acid-induced activation of the TGFβ signaling pathway in an autocrine way drove the expression of the transcription factor SRY-BOX Transcription Factor 4 (SOX4), which then promoted the pro-aggressive transcriptional remodeling necessary to enable tumor progression and metastasis formation.⁵ The crucial role of methylmalonic acid as a mediator of age-induced tumor progression leads to the emergence of an important line of questioning: why does methylmalonic acid increase with aging? How does methylmalonic acid signal in healthy versus cancer cells? Does methylmalonic acid affect other cell types within the tumor microenvironment? Can we use methylmalonic acid as a biomarker for the propensity of tumors to metastasize? The answers to these questions remain unknown but are essential for our understanding of how methylmalonic acid works to promote tumor progression and may prove methylmalonic acid and its metabolism as valuable therapeutic targets for late-stage carcinomas.

Together our work discovered a new concept of age-induced tumorigenesis: tumor progression and metastasis occur, at least in part, as a manifestation of global metabolic deregulation of the aged host through accumulation of methylmalonic acid in circulation (Figure 1). These findings are well in line with recent observations showing a role for aged fibroblasts in promoting metastasis and resistance to therapeutic interventions in melanomas⁹ as well as the pro-metastatic role of the senescence-associated secretory phenotype.¹⁰ Thus, our observations support the idea that the role of aging in cancer goes far beyond increased exposure time to mutagens, and puts the aging process at the center stage coordinating the different aspects required for the evolution of malignant phenotypes. We cannot hold back the hands of time but understanding how aging impacts the tumorigenic process can result in the discovery of more efficacious therapeutic strategies and have a significant impact on how we treat the average and most vulnerable cancer patients – the elderly.

Figure 1.

Aging-driven systemic metabolic reprogramming promotes tumor progression. Age-induced accumulation of circulatory methylmalonic acid (MMA) elicits a transcriptional reprogramming that supports aggressiveness, promoting tumor progression and metastasis formation

Funding Statement

This work was supported by the National Cancer Institute [R00CA218686].