The cancer stem cell (CSC) concept was proposed four decades ago, and states that tumor growth, analogous to the renewal of healthy tissues, is fueled by small numbers of dedicated stem cells. It has gradually become clear that many tumors harbor CSCs in dedicated niches, and yet their identification and eradication has not been as obvious as was initially hoped. Recently developed lineage-tracing and cell-ablation strategies have provided insights into CSC plasticity, quiescence, renewal, and therapeutic response. Here we discuss new developments in the CSC field in relationship to changing insights into how normal stem cells maintain healthy tissues. Expectations in the field have become more realistic, and now, the first successes of therapies based on the CSC concept are emerging.

Cancer stem cells revisited

Metabolic reprogramming is a hallmark of malignancy. As our understanding of the complexity of tumor biology increases, so does our appreciation of the complexity of tumor metabolism. Metabolic heterogeneity among human tumors poses a challenge to developing therapies that exploit metabolic vulnerabilities. Recent work also demonstrates that the metabolic properties and preferences of a tumor change during cancer progression. This produces distinct sets of vulnerabilities between primary tumors and metastatic cancer, even in the same patient or experimental model. We review emerging concepts about metabolic reprogramming in cancer, with particular attention on why metabolic properties evolve during cancer progression and how this information might be used to develop better therapeutic strategies.

Metabolic reprogramming and cancer progression

Metastasis is the hallmark of cancer that is responsible for the greatest number of cancer-related deaths. Yet, it remains poorly understood. The continuous evolution of cancer biology research and the emergence of new paradigms in the study of metastasis have revealed some of the molecular underpinnings of this dissemination process. The invading tumor cell, on its way to the target site, interacts with other proteins and cells. Recognition of these interactions improved the understanding of some of the biological principles of the metastatic cell that govern its mobility and plasticity. Communication with the tumor microenvironment allows invading cancer cells to overcome stromal challenges, settle, and colonize. These characteristics of cancer cells are driven by genetic and epigenetic modifications within the tumor cell itself and its microenvironment. Establishing the biological mechanisms of the metastatic process is crucial in finding open therapeutic windows for successful interventions. In this review, the authors explore the recent advancements in the field of metastasis and highlight the latest insights that contribute to shaping this hallmark of cancer.

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Molecular principles of metastasis: a hallmark of cancer revisited

Since cancer stem cells (CSCs) were first identified in leukemia in 1994, they have been considered promising therapeutic targets for cancer therapy. These cells have self-renewal capacity and differentiation potential and contribute to multiple tumor malignancies, such as recurrence, metastasis, heterogeneity, multidrug resistance, and radiation resistance. The biological activities of CSCs are regulated by several pluripotent transcription factors, such as OCT4, Sox2, Nanog, KLF4, and MYC. In addition, many intracellular signaling pathways, such as Wnt, NF-κB (nuclear factor-κB), Notch, Hedgehog, JAK-STAT (Janus kinase/signal transducers and activators of transcription), PI3K/AKT/mTOR (phosphoinositide 3-kinase/AKT/mammalian target of rapamycin), TGF (transforming growth factor)/SMAD, and PPAR (peroxisome proliferator-activated receptor), as well as extracellular factors, such as vascular niches, hypoxia, tumor-associated macrophages, cancer-associated fibroblasts, cancer-associated mesenchymal stem cells, extracellular matrix, and exosomes, have been shown to be very important regulators of CSCs. Molecules, vaccines, antibodies, and CAR-T (chimeric antigen receptor T cell) cells have been developed to specifically target CSCs, and some of these factors are already undergoing clinical trials. This review summarizes the characterization and identification of CSCs, depicts major factors and pathways that regulate CSC development, and discusses potential targeted therapy for CSCs.

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Targeting cancer stem cell pathways for cancer therapy

A common feature of cancer cells is their ability to rewire their metabolism to sustain the production of ATP and macromolecules needed for cell growth, division and survival. In particular, the importance of altered fatty acid metabolism in cancer has received renewed interest as, aside their principal role as structural components of the membrane matrix, they are important secondary messengers, and can also serve as fuel sources for energy production. In this review, we will examine the mechanisms through which cancer cells rewire their fatty acid metabolism with a focus on four main areas of research. (1) The role of de novo synthesis and exogenous uptake in the cellular pool of fatty acids. (2) The mechanisms through which molecular heterogeneity and oncogenic signal transduction pathways, such as PI3K–AKT–mTOR signalling, regulate fatty acid metabolism. (3) The role of fatty acids as essential mediators of cancer progression and metastasis, through remodelling of the tumour microenvironment. (4) Therapeutic strategies and considerations for successfully targeting fatty acid metabolism in cancer. Further research focusing on the complex interplay between oncogenic signalling and dysregulated fatty acid metabolism holds great promise to uncover novel metabolic vulnerabilities and improve the efficacy of targeted therapies.

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Reprogramming of fatty acid metabolism in cancer

The fact that the identity of the cells that initiate metastasis in most human cancers is unknown hampers the development of antimetastatic therapies. Here we describe a subpopulation of CD44bright cells in human oral carcinomas that do not overexpress mesenchymal genes, are slow-cycling, express high levels of the fatty acid receptor CD36 and lipid metabolism genes, and are unique in their ability to initiate metastasis. Palmitic acid or a high-fat diet specifically boosts the metastatic potential of CD36+ metastasis-initiating cells in a CD36-dependent manner. The use of neutralizing antibodies to block CD36 causes almost complete inhibition of metastasis in immunodeficient or immunocompetent orthotopic mouse models of human oral cancer, with no side effects. Clinically, the presence of CD36+ metastasis-initiating cells correlates with a poor prognosis for numerous types of carcinomas, and inhibition of CD36 also impairs metastasis, at least in human melanoma- and breast cancer-derived tumours. Together, our results indicate that metastasis-initiating cells particularly rely on dietary lipids to promote metastasis.

Targeting metastasis-initiating cells through the fatty acid receptor CD36

Most of the cells in our body contain the same DNA. However, our bodies are made of many different types of cell, such as nerve cells or skin cells, which perform very different jobs. In each cell type only certain sets of genes encoded by the DNA are active. Proteins known as epigenetic regulators are responsible for producing the different patterns of gene activity. If epigenetic regulators are switched on or off at the wrong time, they can contribute to ageing and diseases such as cancer. Enzymes known as DNA methyltransferases are one group of epigenetic regulators. DNA methyltransferases control the activity of genes by adding small chemical groups known as methyl groups to the DNA. Two of these enzymes – known as Dnmt3a and Dnmt3b – are important during development to help cells mature and specialize into different types. Mice that lack both of these enzymes either die as embryos or just after birth. Furthermore, these enzymes are mutated or less active in some skin cancers and various other human cancers. Here, Rinaldi et al. investigated the role these enzymes play in adult mice. The experiments show that under ordinary laboratory conditions, mutant mice that lacked Dnmt3a and Dnmt3b were as healthy as normal mice. However, when the mice were exposed to chemicals that promote tumor growth, which mimics skin exposure to UV light, the mutant mice developed many more skin tumors than the normal mice. Furthermore, the tumors in the mutant mice were more likely to form secondary tumors in the lung. Rinaldi et al. found that Dnmt3a reduced the production of a protein called PPAR-γ, which helps to break down some types of fat molecules. Treating the mutant mice with a drug that inhibits PPAR-γ activity slowed the growth of the tumors. Overall, these experiments show a new way in which DNA methyltransferases act in adult animals. Future research will investigate whether drugs that inhibit the breakdown of fats could help to treat cancers in which the Dnmt3a and Dnmt3b proteins are mutated or less active.

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Loss of Dnmt3a and Dnmt3b does not affect epidermal homeostasis but promotes squamous transformation through PPAR-γ

Mutations in, and the altered expression of, epigenetic modifiers are pervasive in human tumours, making epigenetic factors attractive antitumour targets. The open-versus-closed chromatin state within the cells-of-origin of cancer correlates with the uneven distribution of mutations. However, the long-term effect of targeting epigenetic modifiers on mutability in patients with cancer is unclear. Here, we increased chromatin accessibility by deleting the histone H3 lysine 9 (H3K9) methyltransferase G9a in murine epidermis and show that this does not alter the single nucleotide variant burden or global genomic distribution in chemical mutagen-induced squamous tumours. G9a-depleted tumours develop after a prolonged latency compared with their wild-type counterparts, but are more aggressive and have an expanded cancer progenitor pool, pronounced genomic instability and frequent loss-of-function p53 mutations. Thus, we call for caution when assessing long-term therapeutic benefits of chromatin modifier inhibitors, which may promote more aggressive disease.

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Mercè Martín

Papers

Targeting metastasis-initiating cells through the fatty acid receptor CD36

Loss of Dnmt3a and Dnmt3b does not affect epidermal homeostasis but promotes squamous transformation through PPAR-γ

Loss of G9a preserves mutation patterns but increases chromatin accessibility, genomic instability and aggressiveness in skin tumours.