Cancer stem cells (CSCs): metabolic strategies for their identification and eradication

Abstract

Phenotypic and functional heterogeneity is one of the most relevant features of cancer cells within different tumor types and is responsible for treatment failure. Cancer stem cells (CSCs) are a population of cells with stem cell-like properties that are considered to be the root cause of tumor heterogeneity, because of their ability to generate the full repertoire of cancer cell types. Moreover, CSCs have been invoked as the main drivers of metastatic dissemination and therapeutic resistance. As such, targeting CSCs may be a useful strategy to improve the effectiveness of classical anticancer therapies. Recently, metabolism has been considered as a relevant player in CSC biology, and indeed, oncogenic alterations trigger the metabolite-driven dissemination of CSCs. More interestingly, the action of metabolic pathways in CSC maintenance might not be merely a consequence of genomic alterations. Indeed, certain metabotypic phenotypes may play a causative role in maintaining the stem traits, acting as an orchestrator of stemness. Here, we review the current studies on the metabolic features of CSCs, focusing on the biochemical energy pathways involved in CSC maintenance and propagation. We provide a detailed overview of the plastic metabolic behavior of CSCs in response to microenvironment changes, genetic aberrations, and pharmacological stressors. In addition, we describe the potential of comprehensive metabolic approaches to identify and selectively eradicate CSCs, together with the possibility to ‘force’ CSCs within certain metabolic dependences, in order to effectively target such metabolic biochemical inflexibilities. Finally, we focus on targeting mitochondria to halt CSC dissemination and effectively eradicate cancer.

New quantitative approach reveals heterogeneity in mitochondrial structure-function relations in tumor initiating cells

“…Regulation of TICs by mitochondrial energetics has been demonstrated in certain cases, but remains controversial (De Francesco et al, 2018). Our data indicate that interconversion between mitochondrial ATP hi/lo states occurs during self-renewal and proliferation of ovTICs (Fig.…”

Subpopulation targeting of pyruvate dehydrogenase and GLUT1 decouples metabolic heterogeneity during collective cancer cell invasion

“…Cancer cells exhibit altered glucose metabolism largely relying on glycolysis even in the presence of oxygen (Warburg effect) 45,46 ; however, the metabolism of invasive and metastatic cancer cells can differ from the proliferating bulk of the tumor cell population [47][48][49] . While the downregulation of mitochondrial pathways is a common feature of metabolic rewiring across invasive cancer cells and is a poor prognostic indicator 50 , these studies focus on the bulk of the tumor cell population and would likely not detect rare, specialized subpopulations that are sensitive to mitochondrial inhibitors 51 . Maintaining intact mitochondrial function is considered essential for cancer cell invasion and metastasis to occur 52,53 , and enhanced OXPHOS, mitochondrial biogenesis, and oxygen consumption rates are observed in invasive breast cancer and pancreatic cancer [54][55][56] .…”

A mitochondrial based oncology platform for targeting cancer stem cells (CSCs): MITO-ONC-RX

“…In further support of this notion, please see the following articles for further reading on the subject [39–45]. …”