Stem Cell Fate in Cancer Growth, Progression and Therapy Resistance
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REVIEWS Stem cell fate in cancer growth, progression and therapy resistance Nikki K. Lytle1,2,3, Alison G. Barber1,2,3 and Tannishtha Reya1,2,3* Abstract | Although we have come a long way in our understanding of the signals that drive cancer growth, and how these signals can be targeted, effective control of this disease remains a key scientific and medical challenge. The therapy resistance and relapse that are commonly seen are driven in large part by the inherent heterogeneity within cancers that allows drugs to effectively eliminate some, but not all, malignant cells. Here, we focus on the fundamental drivers of this heterogeneity by examining emerging evidence that shows that these traits are often controlled by the disruption of normal cell fate and aberrant adoption of stem cell signals. We discuss how undifferentiated cells are preferentially primed for transformation and often serve as the cell of origin for cancers. We also consider evidence showing that activation of stem cell programmes in cancers can lead to progression, therapy resistance and metastatic growth and that targeting these attributes may enable better control over a difficult disease. Stem cell Over the past several decades, cancer has largely been that are preferentially aggressive and pose a high risk 7 A cell that has the ability to treated as a disease of aberrant proliferation and survival, of therapy resistance and disease relapse . Thus, under- perpetuate itself through self- and the therapies most commonly used today — radia- standing and targeting the signals critical to sustaining renewal and to generate tion and chemotherapy — mainly target these proper- these cells are essential to improving outcomes. Here, we differentiated cells. Stem cells are relatively rare among other ties. Despite the successes of cytotoxic therapies, which focus on how regulation of stem cell fate can not only cell types and can be more include cures achieved in childhood acute lymphoblastic influence cancer initiation but also serve as a driver quiescent and resistant to leukaemia (ALL)1 and lymphoma2, it is also clear that we event for disease progression, therapy resistance and toxins and chemicals as well as are reaching the limits of how effective these approaches metastatic growth. display enhanced DNA repair. can be, at least in their current form. Thus, it has become important to examine aspects of oncogenesis beyond Stem cell states in cancer initiation aberrant survival and proliferation. Transcriptional context and the cell of origin. Key stud- One critical aspect of the changes that occur as ies have shown that subsets of cells with stem and pro- benign lesions transition to malignant ones is the pro- genitor characteristics in normal tissues are particularly gressive acquisition of the undifferentiated state. Benign susceptible to oncogenic transformation. Beginning with lesions are often more differentiated, while malignancies work in haematological malignancies, in which chronic are more undifferentiated, suggesting a reversal of the myeloid leukaemia (CML) arose only when the BCR–ABL differentiation signals put in place during development. mutation occurred in stem cells8,9, this paradigm has 1Departments of As many of the signals that drive the undifferentiated now been extended to other haematological10,11 and solid Pharmacology and Medicine, state are also key to conferring a stem cell fate, it is per- cancers3,12. Defining the cell of origin can be critical for San Diego School of Medicine, haps not surprising that many cancers show an acute understanding both the environments that are permis- University of California, La Jolla, CA, USA. dependence on these signals to maintain their more sive for transformation and the signals required for trans- 2Sanford Consortium for aggressive state. formation. BCR–ABL provides an interesting example of Regenerative Medicine, San In addition, stem cell signals are also integrally linked an oncogene that produces different outcomes depend- Diego School of Medicine, to cancer initiation, propagation and therapy resistance. ing on the cell in which it is expressed. While BCR–ABL University of California, While driver mutations are key to initiating oncogene- rapidly triggered CML when introduced into stem cells, La Jolla, CA, USA. sis, the cells in which these mutations occur are of equal it triggered B cell ALL (B- ALL) when expressed in 3 Moores Cancer Center, San importance; thus, mutations that cannot transform dif- progenitor cells13. Interestingly, this difference in cell of Diego School of Medicine, 3–6 University of California, ferentiated cells can transform undifferentiated ones , origin is closely coupled to differential signal dependen- La Jolla, CA, USA. suggesting that the stem or progenitor cell state provides cies: while loss of β- catenin blocked CML propagation, 13 *e- mail: [email protected] a more permissive context for transformation. Even after it did not impact B- ALL to the same extent . Thus, the https://doi.org/10.1038/ cancer establishment, perpetuation of a stem cell state in cell of origin can define both the nature of the cancer s41568-018-0056-x some cells creates cancer stem cells (CSCs), ‘driver cells’ and its dependencies. NATURE REVIEWS | CANCER REVIEWS Stem cell signals The link between the cell of origin and tumour types stem cell programmes (Fig. 1b). Given the impact of these Also called stem cell holds true across some solid cancers. For example, early tumorigenic events in determining tumour evo- programmes, these are signals expression of KRAS in the context of p53 loss triggered lution, it may be important to better understand the or gene expression squamous cell carcinoma when targeted to either inter- factors that control tumour cell fate. programmes that are often 14 associated with the follicular epidermis cells or hair follicle cells . Despite undifferentiated state in both cell types giving rise to squamous cell carcinoma, Epigenetic mechanisms and the cell of origin. In addi- embryonic and adult stem interfollicular epidermis- derived tumours were largely tion to the transcriptional context dictating susceptibil- cells. Many stem cell epithelial in nature and had limited metastatic potential, ity to transformation, epigenetic states may also direct programmes or signalling pathways are reactivated in whereas hair follicle- derived tumours contained a mix- tumour- initiating capacity and mutational state. Recent 19 20 oncogenesis. ture of both epithelial and mesenchymal tumour cells and studies have shown that changes in DNA or histone were associated with a higher incidence of metastasis14. methylation patterns can override oncogene- induced Cancer stem cells Similarly, the cell of origin in glioblastoma can dictate sen- senescence programmes. Moreover, transformed cells (CSCs). Cells with enriched sitivity to transformation and the type of tumour formed. that escape senescence have increased DNA methylation, functional capacity to drive tumour growth and recreate its Concurrent inactivation of Trp53, Nf1 and Pten in neural leading to inactivation at promoters of differentiation- 19 heterogeneity. CSCs generally stem cells, neural progenitor cells or oligodendrocyte pro- associated genes . This suggests that the epigenetic share many of the defining genitors triggered the development of unique subtypes of landscape is a critical determinant of both transfor- characteristics of normal stem glioblastoma with distinct gene expression profiles that mation susceptibility and the acquisition of a stem or cells, including increased drug 15,16 resistance and DNA repair. were predictive of differential molecular dependencies . progenitor phenotype. These studies suggest that the transcriptional context of Work in zebrafish models has shown that there is an the cell of origin can be selectively permissive for specific early permissive epigenetic signature within tumour- tumour types and can be at least as strong a determinant of initiating cells in melanoma21. In a field of melanocytes tumorigenesis as the driver mutations themselves (Fig. 1a). expressing driver mutations, only cells harbouring an By contrast, activation of Hedgehog signalling via epigenetic profile that enabled SRY- box 10 (Sox10)- genetic deletion of its receptor, patched homologue 1 driven expression of the fetal oncogene crestin were (PTC1, which is encoded by Ptch1), in either neural stem sensitive to transformation21. Furthermore, chromatin cells or granule neural precursors leads to development accessibility in melanocytes substantially overlapped of aggressive medulloblastomas with similar molecu- with mutational density in human melanoma samples, lar profiles17. This suggests that in some cases certain suggesting that the combination of mutations that drive driver mutations, rather than the cell of origin, define tumorigenesis mirrors the permissive epigenetic land- the tumour profile by leading to a convergence of cell scape of the cells within the tissue of origin22. Consistent states17,18 (Fig. 1b). However, it remains unclear which with this, the epigenetic landscape of normal cells and tumours are predominantly determined by the cell of the mutational status of tumours from the same tissue origin versus by the relevant mutations. It is possible were also congruent in liver cancer, multiple myeloma, that certain mutations are powerful enough in terms of colorectal cancer, oesophageal cancer, glioblastoma, defining cell fate that they can override the transcrip- lung adenocarcinoma and