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Don’t Stop Re-healin’! Cancer as an Ongoing Stem Cell Affair

2017; Cell Press; Volume: 169; Issue: 4 Linguagem: Inglês

10.1016/j.cell.2017.04.030

1097-4172

Samuel P. Rowbotham, Carla F. Kim,

Tumors and Oncological Cases

Tumors have long been suspected of hijacking stem cell mechanisms used for tissue maintenance and repair. Ge et al. now show that skin tumors exhibit merged chromatin profiles from distinct stem cell lineages. This "lineage infidelity" recreates a state akin to transient wound repair that persists to maintain uncontrolled growth. Tumors have long been suspected of hijacking stem cell mechanisms used for tissue maintenance and repair. Ge et al. now show that skin tumors exhibit merged chromatin profiles from distinct stem cell lineages. This "lineage infidelity" recreates a state akin to transient wound repair that persists to maintain uncontrolled growth. Similarities between stem cells and tumor cells have not escaped the notice of scientists. They share the ability to survive, expand, and continually generate cellular progeny, even when removed from their endogenous location and transplanted elsewhere. In this issue of Cell, Ge et al., 2017Ge Y. Gomez N.C. Adam R.C. Nikolova M. Yang H. Verma A. Lu C.P.-J. Polak L. Yuan S. Elemento O. Fuchs E. Cell. 2017; 169 (this issue): 636-650Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar explore a more specific interpretation of the general "hijack hypothesis," comparing tumors to healing wounds, where the balance of proliferation and differentiation required for normal homeostasis is perturbed. One of the main barriers to investigating these ideas is the small number of cells involved here, which are likely from very specific lineages or from transient states. While promising technologies for analyzing the transcriptome from single cells are being used and refined, methods to look at chromatin are not as advanced. To overcome this limitation, Ge et al. used ATAC-seq (assay for transposase-accessible chromatin with high-throughput sequencing) (Buenrostro et al., 2013Buenrostro J.D. Giresi P.G. Zaba L.C. Chang H.Y. Greenleaf W.J. Nat. Methods. 2013; 10: 1213-1218Crossref PubMed Scopus (3189) Google Scholar), a high-throughput sequencing technology that identifies areas of low nucleosome occupancy and, therefore, high transcriptional activity. By analyzing isolated cell populations from tumors and from wounded and resting skin, the authors have shown that a distinct open chromatin landscape combining active signature genes from two distinct lineages of stem cells—hair follicle stem cells (HFSCs) and epidermal stem cells (EdSCs) —exists transiently during wound healing but permanently in some tumor cells (Ge et al., 2017Ge Y. Gomez N.C. Adam R.C. Nikolova M. Yang H. Verma A. Lu C.P.-J. Polak L. Yuan S. Elemento O. Fuchs E. Cell. 2017; 169 (this issue): 636-650Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar). Furthermore, the authors were able to advance a theory as to why this state is not resolved in tumors and persists through malignancy. The skin has two compartments, the hair follicle and the epidermis, each with its own stem cell population. Upon injury, the two populations cooperate to restore the epithelium. Both stem cell lineages are capable of giving rise to squamous cell carcinoma (SCC), primarily driven by oncogenic Hras mutations (White et al., 2011White A.C. Tran K. Khuu J. Dang C. Cui Y. Binder S.W. Lowry W.E. Proc. Natl. Acad. Sci. USA. 2011; 108: 7425-7430Crossref PubMed Scopus (144) Google Scholar). Recent studies have focused on the transcription factors and chromatin landscape in HFSCs and demonstrated that SOX9 is not only essential for this normal stem cell population but also retained in the stem-like tumor-initiating cells of SCC (Kadaja et al., 2014Kadaja M. Keyes B.E. Lin M. Pasolli H.A. Genander M. Polak L. Stokes N. Zheng D. Fuchs E. Genes Dev. 2014; 28: 328-341Crossref PubMed Scopus (139) Google Scholar, Lapouge et al., 2012Lapouge G. Beck B. Nassar D. Dubois C. Dekoninck S. Blanpain C. EMBO J. 2012; 31: 4563-4575Crossref PubMed Scopus (62) Google Scholar). Ge et al. identify an EdSC transcription factor, KLF5, that is usually excluded from HFSCs, setting the stage for comparison with the SOX9 stem cell lineage. Initially, ATAC-seq showed that squamous cell carcinoma and both stem cell populations have distinct open chromatin landscapes. Combining ATAC-seq and previous transcriptome data allowed for the identification of KLF5 as a unique EdSC transcription factor. Advanced SCC stem cells expressed both Klf5 and Sox9, along with unique genes from EdSCs and HFSCs, leading to the idea of lineage infidelity (Figure 1). Loss of either factor compromised the ability of SCC cells to propagate new tumors after transplantation, regardless of which lineage initiated the tumor. In controlled wounding experiments, mobilized HFSCs expressed both KLF5 and SOX9, but dual expressing cells resolved following healing (Figure 1A). Deleting either factor in EdSCs and HFSCs prevented transplanted stem cells from contributing to wound repair. ATAC-seq comparison of tumor cells and wound-induced stem cells revealed that stress factors ETS2 and STAT3 were activated in both populations, and activated ETS2 could induce lineage infidelity. In tumor cells, stress signals like ETS2 were sustained, and forced sustained ETS2 signaling could prevent the antagonism between SOX9 and KLF5 that would drive the resolution of lineage infidelity after wound healing (Figure 1B). Therefore, SCC cells could bypass the normal feedback loop, allowing them to maintain a proliferative state that molecularly resembles "a wound that never heals." Several fascinating questions are raised by the findings of Ge et al. For instance, how prevalent is this phenomenon of lineage infidelity? Does it occur only in SCC, or does the similar mechanism contribute to basal cell carcinoma, which originates from EdSCs, instead of HFSCs, in the skin? Does it apply to other tissues? Single-cell transcript profiling has revealed that the intestine harbors an abundant population within the famed Lgr5-expressing stem cell compartment that simultaneously expresses markers of stem cells and mature secretory cells (Kim et al., 2016Kim T.H. Saadatpour A. Guo G. Saxena M. Cavazza A. Desai N. Jadhav U. Jiang L. Rivera M.N. Orkin S.H. et al.Cell Rep. 2016; 16: 2053-2060Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar). Would lineage infidelity underlie this observation in the gut? Our previous work has shown that progenitor cells in normal lung tissue and lung-tumor-propagating cells co-express markers of distinct epithelial lineages (Curtis et al., 2010Curtis S.J. Sinkevicius K.W. Li D. Lau A.N. Roach R.R. Zamponi R. Woolfenden A.E. Kirsch D.G. Wong K.-K. Kim C.F. Cell Stem Cell. 2010; 7: 127-133Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar, Lee et al., 2014Lee J.-H. Bhang D.H. Beede A. Huang T.L. Stripp B.R. Bloch K.D. Wagers A.J. Tseng Y.-H. Ryeom S. Kim C.F. Cell. 2014; 156: 440-455Abstract Full Text Full Text PDF PubMed Scopus (310) Google Scholar). It would be interesting to see whether these progenitors share overlapping lineage-specific chromatin states. Moreover, recent studies in several tumor types, including lung, liver, and stomach cancer, indicate that lineage-defining genes are more prone to insertions and deletions (Imielinski et al., 2017Imielinski M. Guo G. Meyerson M. Cell. 2017; 168: 460-472.e14Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar). One could ask whether direct mutation is another way to interfere with lineage fidelity in cancer. From a technical point of view, findings in this study also raise the question of how much "lineage infidelity" could be present in the various assays used for analyzing stem and progenitor cells. Especially for tissues with infrequent turnover, are the cells that we purify, culture, and manipulate more akin to the cells in a healing wound than their true natural resting state in their endogenous environment? Perhaps inadvertently, when considering lineage infidelity as part of the normal wound-healing process, we encounter a philosophical question: what constitutes infidelity? This is much argued over in the recognizable sphere of human relationships; specifically, if an act or type of act is a priori sanctioned, can it constitute infidelity? Could closing a wound resemble an allowable kiss of a stranger and thus not count as an act of infidelity, whereas a tumor constitutes a full-blown affair and a clear violation? This study gives much to ponder to all biologists who are used to categorizing cells, fates, and states as discrete entities. Stem Cell Lineage Infidelity Drives Wound Repair and CancerGe et al.CellApril 20, 2017In BriefStem cell lineage infidelity occurs transiently in wounds and persists in cancer, driving wound repair and malignancy. Full-Text PDF Open Archive