Phenotypic Plasticity: Driver of Cancer Initiation, Progression, and Therapy Resistance
2018; Elsevier BV; Volume: 24; Issue: 1 Linguagem: Inglês
10.1016/j.stem.2018.11.011
ISSN1934-5909
AutoresPiyush B. Gupta, Ievgenia Pastushenko, Adam Skibinski, Cédric Blanpain, Charlotte Kuperwasser,
Tópico(s)Genomics and Chromatin Dynamics
ResumoOur traditional understanding of phenotypic plasticity in adult somatic cells comprises dedifferentiation and transdifferentiation in the context of tissue regeneration or wound healing. Although dedifferentiation is central to tissue repair and stemness, this process inherently carries the risk of cancer initiation. Consequently, recent research suggests phenotypic plasticity as a new paradigm for understanding cancer initiation, progression, and resistance to therapy. Here, we discuss how cells acquire plasticity and the role of plasticity in initiating cancer, cancer progression, and metastasis and in developing therapy resistance. We also highlight the epithelial-to-mesenchymal transition (EMT) and known molecular mechanisms underlying plasticity and we consider potential therapeutic avenues. Our traditional understanding of phenotypic plasticity in adult somatic cells comprises dedifferentiation and transdifferentiation in the context of tissue regeneration or wound healing. Although dedifferentiation is central to tissue repair and stemness, this process inherently carries the risk of cancer initiation. Consequently, recent research suggests phenotypic plasticity as a new paradigm for understanding cancer initiation, progression, and resistance to therapy. Here, we discuss how cells acquire plasticity and the role of plasticity in initiating cancer, cancer progression, and metastasis and in developing therapy resistance. We also highlight the epithelial-to-mesenchymal transition (EMT) and known molecular mechanisms underlying plasticity and we consider potential therapeutic avenues. All stem cells are defined by the key properties of self-renewal (the ability to generate more of themselves) and differentiation potential (the ability to divide asymmetrically and generate more differentiated progeny) (reviewed in Reya et al., 2001Reya T. Morrison S.J. Clarke M.F. Weissman I.L. Stem cells, cancer, and cancer stem cells.Nature. 2001; 414: 105-111Crossref PubMed Scopus (6399) Google Scholar). Adult tissue stem cells typically have a more restricted potential, and they can produce only a limited number of cell types. However, tissue stem cells persist throughout adult life in organs that continually or periodically regenerate, such as the skin, intestine, mammary gland, and the hematopoietic system. Because of their long life, tissue stem cells have an enhanced potential to acquire the necessary oncogenic hits for tumor formation, and they are the suspected cells of origin for many cancers, including breast cancer (Visvader, 2011Visvader J.E. Cells of origin in cancer.Nature. 2011; 469: 314-322Crossref PubMed Scopus (740) Google Scholar). Development from a fertilized egg to a mature organism is thought to proceed in a fundamentally hierarchical manner (Marjanovic et al., 2013Marjanovic N.D. Weinberg R.A. Chaffer C.L. Cell plasticity and heterogeneity in cancer.Clin. Chem. 2013; 59: 168-179Crossref PubMed Scopus (0) Google Scholar). Each stem cell asymmetric division produces a progressively more differentiated cell type, beginning with the zygote and ending with all of the terminally differentiated cells of the body. At the branch points of the hierarchy are stem cells and/or multipotent progenitor cells, which, during asymmetric division, generate lineage-committed progeny that no longer possess self-renewal (also termed transit amplifying cells). In most tissues, the progeny cells eventually give rise to post-mitotic, terminally differentiated cell types. The classic and best-studied example of a developmental hierarchy is the hematopoietic system (Reya et al., 2001Reya T. Morrison S.J. Clarke M.F. Weissman I.L. Stem cells, cancer, and cancer stem cells.Nature. 2001; 414: 105-111Crossref PubMed Scopus (6399) Google Scholar). Long-term hematopoietic stem cells reside in the bone marrow and generate transit-amplifying progenitors and progressively more differentiated cell types, including lymphocytic and myelocytic cells. The strength of the hematopoietic paradigm has influenced the belief that solid tissues are similarly organized. However, certain phenomena have challenged the concept of differentiation as a permanent or unidirectional process. These phenomena suggest that many “terminally differentiated” cells retain the potential to change fate. Here, we use the term “plasticity” to refer generally to a broad set of such phenomena including dedifferentiation (the loss of lineage commitment and reacquisition of stem cell features) and transdifferentiation (direct fate switching to another differentiated cell type) (Cunha et al., 1995Cunha G.R. Young P. Christov K. Guzman R. Nandi S. Talamantes F. Thordarson G. Mammary phenotypic expression induced in epidermal cells by embryonic mammary mesenchyme.Acta Anat. (Basel). 1995; 152: 195-204Crossref PubMed Google Scholar, Booth et al., 2008Booth B.W. Mack D.L. Androutsellis-Theotokis A. McKay R.D. Boulanger C.A. Smith G.H. The mammary microenvironment alters the differentiation repertoire of neural stem cells.Proc. Natl. Acad. Sci. USA. 2008; 105: 14891-14896Crossref PubMed Scopus (0) Google Scholar, Bonfanti et al., 2012Bonfanti P. Barrandon Y. Cossu G. ‘Hearts and bones’: the ups and downs of ‘plasticity’ in stem cell biology.EMBO Mol. 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A well-described example of transdifferentiation is the regeneration of the amphibian retina by pigment epithelial cells that specifically respond to tissue damage (Okada, 1980Okada T.S. Cellular metaplasia or transdifferentiation as a model for retinal cell differentiation.Curr. Top. Dev. Biol. 1980; 16: 349-380Crossref PubMed Google Scholar). Similarly, as Godlewski, 1928Godlewski Jr., E. Untersuchungen Über Auslösung und Hemmung der Regeneration beim Axolotl.Wilhelm Roux Arch. Entwickl. Mech. Org. 1928; 114: 108-143Crossref PubMed Scopus (23) Google Scholar first reported in 1928, dedifferentiation of epidermal cells to generate chondrocytes and skeletal muscle cells occurs in the regenerating axolotl limb (Rose, 1947Rose S.M. Dedifferentiation in the regenerating amphibian limb.Anat. Rec. 1947; 99: 568PubMed Google Scholar). However, generally, these observations were limited to “lower” vertebrates such as amphibians, which have a capacity for tissue regeneration far exceeding that of mammals. Recently, however, it has become clear that mammalian cells can also be induced to dedifferentiate or transdifferentiate. Typically, investigators achieve “reprogramming” of mammalian cells by introducing one or more transcription factors into a differentiated cell type. Davis et al., 1987Davis R.L. Weintraub H. Lassar A.B. Expression of a single transfected cDNA converts fibroblasts to myoblasts.Cell. 1987; 51: 987-1000Abstract Full Text PDF PubMed Scopus (2103) Google Scholar performed the earliest example of this type of reprogramming with MyoD, which induced conversion to myoblasts when ectopically expressed in fibroblasts. Then came the seminal discovery that a combination of four transcription factors, OCT4, SOX2, KLF4, and MYC (OSKM), could “reprogram” adult human or mouse fibroblasts to an embryonic stem-like state (Takahashi and Yamanaka, 2006Takahashi K. Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.Cell. 2006; 126: 663-676Abstract Full Text Full Text PDF PubMed Scopus (13589) Google Scholar, Takahashi et al., 2007Takahashi K. Tanabe K. Ohnuki M. Narita M. Ichisaka T. Tomoda K. Yamanaka S. Induction of pluripotent stem cells from adult human fibroblasts by defined factors.Cell. 2007; 131: 861-872Abstract Full Text Full Text PDF PubMed Scopus (10740) Google Scholar). The reality of induced pluripotency has led to an extensive re-evaluation of the permanence of the differentiated state. Lately, investigators have demonstrated that fibroblasts and other cell types could be transdifferentiated or “directly reprogrammed” to cardiomyocytes, neurons, and pancreatic neuroendocrine cells, among other cell types (Zhou et al., 2008Zhou Q. Brown J. Kanarek A. Rajagopal J. Melton D.A. In vivo reprogramming of adult pancreatic exocrine cells to β-cells.Nature. 2008; 455: 627-632Crossref PubMed Scopus (1359) Google Scholar, Vierbuchen et al., 2010Vierbuchen T. Ostermeier A. Pang Z.P. Kokubu Y. Südhof T.C. Wernig M. Direct conversion of fibroblasts to functional neurons by defined factors.Nature. 2010; 463: 1035-1041Crossref PubMed Scopus (1705) Google Scholar, Szabo et al., 2010Szabo E. Rampalli S. Risueño R.M. Schnerch A. Mitchell R. Fiebig-Comyn A. Levadoux-Martin M. Bhatia M. Direct conversion of human fibroblasts to multilineage blood progenitors.Nature. 2010; 468: 521-526Crossref PubMed Scopus (501) Google Scholar, Ieda et al., 2010Ieda M. Fu J.D. Delgado-Olguin P. 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In these cases, introduction of genes could induce a shift in the developmental fate of cells in liver and convert them into pancreatic-like cells in the absence of a stem cell intermediate. All of these examples involved transient or permanent expression of one or more transcription factor in the original cell type, which appeared to transition into a different cell type without proceeding through an intermediate multipotent stage. These studies proved that differentiation states are changeable, metastable entities, and the studies demonstrated that specific transcription factors could shift cells from one state to another. It is useful to distinguish plasticity induced by forced expression of transcription factors, sometimes termed “intrinsic plasticity,” from plasticity induced by changes in the microenvironment, termed “extrinsic plasticity” (Bonfanti et al., 2012Bonfanti P. Barrandon Y. Cossu G. ‘Hearts and bones’: the ups and downs of ‘plasticity’ in stem cell biology.EMBO Mol. 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Investigators have definitively mapped the fates of differentiated cells and their progeny with genetic markers following ablation of a particular cell population within the tissue. In both cases, the non-ablated, differentiated cell populations underwent dedifferentiation to regenerate the ablated cells. Therefore, plasticity has a regenerative function in vivo. In addition, extrinsic cues and certain pathologic states may trigger transdifferentiation. For instance, in a mouse model of calcifying atherosclerosis, adoption of an osteogenic or chondrogenic phenotype by vascular smooth muscle cells preceded calcification of the vessel intima (Speer et al., 2009Speer M.Y. Yang H.Y. Brabb T. Leaf E. Look A. Lin W.L. Frutkin A. Dichek D. Giachelli C.M. Smooth muscle cells give rise to osteochondrogenic precursors and chondrocytes in calcifying arteries.Circ. Res. 2009; 104: 733-741Crossref PubMed Scopus (292) Google Scholar). In some of these cases, the induction or expression of certain TFs regulates the switch between hierarchy and plasticity. Plasticity may also be triggered artificially by experimental manipulation. Ex vivo cell culture often fails to recapitulate most aspects of the tissue microenvironment, and such cell culture often results in dedifferentiation. In 2D cultures, mammary epithelial cells (MECs) stochastically acquire stem-like traits upon short-term culture in vitro (Chaffer et al., 2011Chaffer C.L. Brueckmann I. Scheel C. Kaestli A.J. Wiggins P.A. Rodrigues L.O. Brooks M. Reinhardt F. Su Y. Polyak K. et al.Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state.Proc. Natl. Acad. Sci. USA. 2011; 108: 7950-7955Crossref PubMed Scopus (638) Google Scholar, Keller et al., 2012Keller P.J. Arendt L.M. Skibinski A. Logvinenko T. Klebba I. Dong S. Smith A.E. Prat A. Perou C.M. Gilmore H. et al.Defining the cellular precursors to human breast cancer.Proc. Natl. Acad. 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Growth of human breast tissues from patient cells in 3D hydrogel scaffolds.Breast Cancer Res. 2016; 18: 19Crossref PubMed Scopus (27) Google Scholar). Similarly, articular chondrocytes growing in monolayer culture lose the ability to express cartilage proteins, but this behavior can be reversed if the chondrocytes are grown in soft agar, which is more mechanically similar to cartilage (Benya and Shaffer, 1982Benya P.D. Shaffer J.D. Dedifferentiated chondrocytes reexpress the differentiated collagen phenotype when cultured in agarose gels.Cell. 1982; 30: 215-224Abstract Full Text PDF PubMed Scopus (1747) Google Scholar). These findings underscore the importance of instructive structural inputs that alter cellular differentiation potential. Transplanting cells from their native microenvironment to a different site in vivo can also trigger dedifferentiation or transdifferentiation because of inductive signals present in the recipient tissues (Booth et al., 2008Booth B.W. Mack D.L. Androutsellis-Theotokis A. McKay R.D. Boulanger C.A. Smith G.H. The mammary microenvironment alters the differentiation repertoire of neural stem cells.Proc. Natl. Acad. Sci. USA. 2008; 105: 14891-14896Crossref PubMed Scopus (0) Google Scholar, Boulanger et al., 2007Boulanger C.A. Mack D.L. Booth B.W. Smith G.H. Interaction with the mammary microenvironment redirects spermatogenic cell fate in vivo.Proc. Natl. Acad. Sci. USA. 2007; 104: 3871-3876Crossref PubMed Scopus (0) Google Scholar, Bonfanti et al., 2012Bonfanti P. Barrandon Y. Cossu G. ‘Hearts and bones’: the ups and downs of ‘plasticity’ in stem cell biology.EMBO Mol. Med. 2012; 4: 353-361Crossref PubMed Scopus (0) Google Scholar) (Figure 1). For example, Bonfanti et al., 2012Bonfanti P. Barrandon Y. Cossu G. ‘Hearts and bones’: the ups and downs of ‘plasticity’ in stem cell biology.EMBO Mol. Med. 2012; 4: 353-361Crossref PubMed Scopus (0) Google Scholar showed that thymic epithelial cells could generate hair follicle multipotent stem cells when transplanted into the inductive microenvironment of the dermis. Booth et al., 2008Booth B.W. Mack D.L. Androutsellis-Theotokis A. McKay R.D. Boulanger C.A. Smith G.H. The mammary microenvironment alters the differentiation repertoire of neural stem cells.Proc. Natl. Acad. Sci. USA. 2008; 105: 14891-14896Crossref PubMed Scopus (0) Google Scholar and Boulanger et al., 2007Boulanger C.A. Mack D.L. Booth B.W. Smith G.H. Interaction with the mammary microenvironment redirects spermatogenic cell fate in vivo.Proc. Natl. Acad. Sci. USA. 2007; 104: 3871-3876Crossref PubMed Scopus (0) Google Scholar showed that neuronal and lymphoid cells could generate mammary structures when transplanted into the inductive microenvironment of the mammary fat pad. In adult mammary glands, both luminal and myoepithelial lineages contain long-lived unipotent stem cells displaying extensive renewing capacities (Van Keymeulen et al., 2011Van Keymeulen A. Rocha A.S. Ousset M. Beck B. Bouvencourt G. Rock J. Sharma N. Dekoninck S. Blanpain C. Distinct stem cells contribute to mammary gland development and maintenance.Nature. 2011; 479: 189-193Crossref PubMed Scopus (442) Google Scholar). This multipotency is associated with embryonic development and hybrid signatures of both basal and luminal markers (Wuidart NCB 2018; Lilja et al., 2018Lilja A.M. Rodilla V. Huyghe M. Hanezzo E. Landragin C. Renaud O. Leroy O. Rulands S. Simons B.D. Fre S. Clonal analysis of Notch1-expressing cells reveals the existence of unipotent stem cells that retain long-term plasticity in the embryonic mammary gland.Nat. Cell Biol. 2018; 20: 677-687Crossref PubMed Scopus (4) Google Scholar). Expression of p63 in adult luminal progenitors can also reprogram these cells into an intermediate hybrid multipotent-like state before the formation of mature basal cells (Wuidart et al., 2018Wuidart A. Sifrim A. Fioramonti M. Matsumura S. Brisebarre A. Brown D. Centonze A. Dannau A. Dubois C. Van Keymeulen A. et al.Early lineage segregation of multipotent embryonic mammary gland progenitors.Nat. Cell Biol. 2018; 20: 666-676Crossref PubMed Scopus (2) Google Scholar) (Figure 1). Likewise, expression of active Notch1 in basal cells reactivate an embryonic multipotent program in adult basal cells before giving rise to luminal cells (Lilja et al., 2018Lilja A.M. Rodilla V. Huyghe M. Hanezzo E. Landragin C. Renaud O. Leroy O. Rulands S. Simons B.D. Fre S. Clonal analysis of Notch1-expressing cells reveals the existence of unipotent stem cells that retain long-term plasticity in the embryonic mammary gland.Nat. Cell Biol. 2018; 20: 677-687Crossref PubMed Scopus (4) Google Scholar). However, all the molecular signals operative in these de- or trans-differentiation processes are not clear, nor is it clear if all progenitor types will be equally amenable to modification by an instructive environment (Lu et al., 2012Lu C.P. Polak L. Rocha A.S. Pasolli H.A. Chen S.C. Sharma N. Blanpain C. Fuchs E. Identification of stem cell populations in sweat glands and ducts reveals roles in homeostasis and wound repair.Cell. 2012; 150: 136-150Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar). Plasticity is relevant to the understanding of tumorigenesis and pathogenesis. Cancer is a highly diverse disease, exhibiting heterogeneity both between different tumors (intertumor heterogeneity) and between cells among a single tumor (intertumor heterogeneity). It is becoming increasingly clear that tumors hijack the normal differentiation programs of the normal tissues in which they develop as part of the mechanism by which tumor diversity is generated. Therefore, to understand cancer pathogenesis, we require a clearer picture of cancer development. In this review, we discuss the role of phenotypic plasticity during cancer initiation, progression, and resistance to therapy, and we review the relevant factors that dictate the switch from hierarchy to plasticity in normal tissues and in cancer. The cell of origin (also referred to as the tumor precursor cell or the tumor-initiating cell) refers to the original cell that receives the first oncogenic hits and undergoes clonal expansion in the earliest stage of tumor progression. The identity of the cell of origin can have a substantial impact on the behavior and progression of the resulting tumor because, in many cases, the characteristics of the tumor precursor cell are passed on epigenetically to the tumor cells (Gupta et al., 2005Gupta P.B. Kuperwasser C. Brunet J.P. Ramaswamy S. Kuo W.L. Gray J.W. Naber S.P. Weinberg R.A. The melanocyte differentiation program predisposes to metastasis after neoplastic transformation.Nat. Genet. 2005; 37: 1047-1054Crossref PubMed Scopus (299) Google Scholar, Ince et al., 2007Ince T.A. Richardson A.L. Bell G.W. Saitoh M. Godar S. Karnoub A.E. Iglehart J.D. Weinberg R.A. Transformation of different human breast epithelial cell types leads to distinct tumor phenotypes.Cancer Cell. 2007; 12: 160-170Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar). Conversely, the characteristics of the tumor cell of origin are not necessarily equivalent or even similar to the characteristics of the cancer stem cell (CSC) (Visvader, 2011Visvader J.E. Cells of origin in cancer.Nature. 2011; 469: 314-322Crossref PubMed Scopus (740) Google Scholar). Moreover, although in many breast tumors the cell of origin is suspected to be a long-lived tissue stem cell, this supposition is not universally true. Even when the cell of origin is a stem cell, it is by no means guaranteed that the resulting cancer cells will resemble their original precursor or that the stem cell program will survive neoplastic transformation intact. Therefore, CSCs, tissue stem cells, and cells of origin are distinct concepts. Identifying the cell of origin seems straightforward in principle, but identification can be quite challenging to accomplish experimentally because (1) transformation of the original precursor cell cannot usually be observed directly, and (2) the influence of the cell of origin on the tumor phenotype is not always overt. In the case of breast cancer, intrinsic subtypes have been intensely studied from a biological perspective, with the two main subtypes being luminal and basal-like; but how they are generated in the first place has only started to be defined (Prat and Perou, 2011Prat A. Perou C.M. Deconstructing the molecular portraits of breast cancer.Mol. Oncol. 2011; 5: 5-23Crossref PubMed Scopus (600) Google Scholar). In principle, both genetic and epigenetic influences can act at early stages of cancer progression to determine the overall phenotype of the tumor. First, there is epigenetic influence imparted by the features of the tumor cell of origin. In addition, mutations, copy number aberrations, or other derangements in key developmental regulators, such as transcription factors, can drive tumor phenotype. Both forces collude to generate intertumor diversity in breast cancer. To identify the cell of origin of breast cancer, investigators have used two main approaches. The first approach involves isolating normal cell subsets by FACS and either comparing them to the tumor subtypes or using lentiviral vectors to transduce these cells ex vivo with a combination of oncogenes that will lead to tumorigenesis. Interestingly these studies revealed that the global gene expression profiles of basal-like tumors were most similar to the luminal progenitor profile in normal tissues (Lim et al., 2009Lim E. Vaillant F. Wu D. Forrest N.C. Pal B. Hart A.H. Asselin-Labat M.L. Gyorki D.E. Ward T. Partanen A. et al.Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers.Nat. Med. 2009; 15: 907-913Crossref PubMed Scopus (801) Google Scholar). Further, transformation of luminal progenitor cells led to tumors with both luminal and basal features (Keller et al., 2012Keller P.J. Arendt L.M. Skibinski A. Logvinenko T. Klebba I. Dong S. Smith A.E. Prat A. Perou C.M. Gilmore H. et al.Defining the cellular precursors to human breast cancer.Proc. Natl. Acad. Sci. USA. 2012; 109: 2772-2777Crossref PubMed Scopus (0) Google Scholar). In contrast, transformation of human cells with an EpCAMlow/CD49fhigh immunophenotype, thought to contain basal and myoepithelial (ME), stem and/or bipotent progenitor cells, gave rise to aggressive tumors with squamous differentiation and other metaplastic features (Keller et al., 2012Keller P.J. Arendt L.M. Skibinski A. Logvinenko T. Klebba I. Dong S. Smith A.E. Prat A. Perou C.M. Gilmore H. et al.Defining the cellular precursors to human breast cancer.Proc. Natl. Acad. Sci. USA. 2012; 109: 2772-2777Crossref PubMed Scopus (0) Google Scholar). These tumors were molecularly most similar to the claudin-low intrinsic subtype, which displays high expression of MaSC-associated genes and mesenchymal markers. Metaplastic breast cancer is rare in humans; therefore, these tumors may represent the rare transformation of basal and ME progenitors or stem cells (Prat and Perou, 2011Prat A. Perou C.M. Deconstructing the molecular portraits of breast cancer.Mol. Oncol. 2011; 5: 5-23Crossref PubMed Scopus (600) Google Scholar). A complementary approach is to direct conditional expression of oncogenes (or deletion of tumor suppressor genes) to specific mammary epithelial subpopulations to initiate tumorigenesis in a defined cell population. Molyneux et al., 2010Molyneux G. Geyer F.C. Magnay F.A. McCarthy A. Kendrick H. Natrajan R. Mackay A. Grigoriadis A. Tutt A. Ashworth A. et al.BRCA1 basal-like breast cancers originate from luminal epithelial progenitors and not from basal stem cells.Cell Stem Cell. 2010; 7: 403-417Abstract Full Text Full Text PDF PubMed Scopus (379) Google Scholar employed a mouse model in which loss of the BRCA1 tumor suppressor was targeted to either KR14-expressing basal and ME or to β-lactoglobulin (Blg)-expressing luminal cells on a p53-heterozygous background. This approach revealed that targeting BRCA1 loss to luminal cells recapitulated the basal-like phenotype of human BRCA1-associated breast tumors. KR14-driven BRCA1 loss also led to tumor formation; however, histology was that of malignant adenomyoepithelioma, which is not usually seen in BRCA1-associated human cancer. Together, these studies enshrine progenitor cells as the likely cells of origin, but recent findings have demonstrated that plasticity is relevant to understanding the origins
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