Cellular Pliancy and the Multistep Process of Tumorigenesis

Completion of early stages of tumorigenesis relies on the dynamic interplay between the initiating oncogenic event and the cellular context. Here, we review recent findings indicating that each differentiation stage within a defined cellular lineage is associated with a unique susceptibility to malignant transformation when subjected to a specific oncogenic insult. This emerging notion, named cellular pliancy, provides a rationale for the short delay in the development of pediatric cancers of prenatal origin. It also highlights the critical role of cellular reprogramming in early steps of malignant transformation of adult differentiated cells and its impact on the natural history of tumorigenesis. Completion of early stages of tumorigenesis relies on the dynamic interplay between the initiating oncogenic event and the cellular context. Here, we review recent findings indicating that each differentiation stage within a defined cellular lineage is associated with a unique susceptibility to malignant transformation when subjected to a specific oncogenic insult. This emerging notion, named cellular pliancy, provides a rationale for the short delay in the development of pediatric cancers of prenatal origin. It also highlights the critical role of cellular reprogramming in early steps of malignant transformation of adult differentiated cells and its impact on the natural history of tumorigenesis. Cancer is believed to be one end result of a process of somatic evolution in which a single clonal lineage acquires a complement of driver mutations that endows cells with adaptive and proliferative advantages (Hahn and Weinberg, 2002Hahn W.C. Weinberg R.A. Rules for making human tumor cells.N. Engl. J. Med. 2002; 347: 1593-1603Crossref PubMed Scopus (776) Google Scholar, Martincorena et al., 2017Martincorena I. Raine K.M. Gerstung M. Dawson K.J. Haase K. Van Loo P. Davies H. Stratton M.R. Campbell P.J. Universal patterns of selection in cancer and somatic tissues.Cell. 2017; 171: 1029-1041.e21Abstract Full Text Full Text PDF PubMed Scopus (599) Google Scholar). This model highlights the requirement of the stepwise accumulation of a series of independent events for a normal human cell to be transformed. Consistently, classic epidemiological studies reveal that the process of tumor development proceeds over an extended period (likely decades) and predict that adult solid tumors require up to eight rate-limiting events before becoming clinically detectable (Armitage and Doll, 1954Armitage P. Doll R. The age distribution of cancer and a multi-stage theory of carcinogenesis.Br. J. Cancer. 1954; 8: 1-12Crossref PubMed Scopus (1212) Google Scholar). By adapting methods from evolutionary genomics and applying them to thousands of cancer genomes, Campbell and collaborators recently reported a universal pattern of selection in somatic evolution, characterized by a dominance of positive over negative selection. They further estimated that, on average, tumors carry around four coding substitutions under positive selection, with up to ten per tumor in endometrial and colorectal carcinomas (Martincorena et al., 2017Martincorena I. Raine K.M. Gerstung M. Dawson K.J. Haase K. Van Loo P. Davies H. Stratton M.R. Campbell P.J. Universal patterns of selection in cancer and somatic tissues.Cell. 2017; 171: 1029-1041.e21Abstract Full Text Full Text PDF PubMed Scopus (599) Google Scholar). However, some rare malignancies exhibit peak incidence in the first years of life. This very short delay in development appears to be incompatible with the expected time required to accumulate the necessary abnormalities for cellular transformation and tumor progression, advocating the principle that the roads to tumorigenesis depend on the state of the cell of origin. Consistent with this hypothesis, significant variations in the proportion of coding driver mutations per tumor among different tumor types have been reported (Martincorena et al., 2017Martincorena I. Raine K.M. Gerstung M. Dawson K.J. Haase K. Van Loo P. Davies H. Stratton M.R. Campbell P.J. Universal patterns of selection in cancer and somatic tissues.Cell. 2017; 171: 1029-1041.e21Abstract Full Text Full Text PDF PubMed Scopus (599) Google Scholar, Vogelstein et al., 2013Vogelstein B. Papadopoulos N. Velculescu V.E. Zhou S. Diaz L.A. Kinzler K.W. Cancer genome landscapes.Science. 2013; 339: 1546-1558Crossref PubMed Scopus (5210) Google Scholar). In the context of pediatric cancers, the term “developmental pliancy” was recently proposed by Dyer and collaborators to define the intrinsic competence of a discrete developmental state to adapt to changes in homeostasis or environment and to undergo malignant transformation after sustaining a specific oncogenic insult (Chen et al., 2015Chen X. Pappo A. Dyer M.A. Pediatric solid tumor genomics and developmental pliancy.Oncogene. 2015; 34: 5207-5215Crossref PubMed Scopus (40) Google Scholar). We propose to extend the concept of pliancy to adult tumors, wherein each differentiation stage of a given cell lineage is associated with a unique susceptibility to malignant transformation. In that context, cellular differentiation generally acts as a barrier against tumorigenesis. However, reprogramming of differentiated cells can affect cellular pliancy, opening the gate to the emergence of cellular states prone to malignant transformation. We outline a growing body of evidence supporting this model and indicating that the differentiation status of the cell of origin and the process of oncogene-induced reprogramming are critical determinants of the natural history of tumorigenesis. In the mid-19th century, pathologists noticed the similarity between embryonic tissues and cancer and suggested that tumors may originate from embryo-like cells. Although this hypothesis may only apply to rare malignancies, it is now well established that cancers involving the fewest genetic events are childhood tumors (Vogelstein et al., 2013Vogelstein B. Papadopoulos N. Velculescu V.E. Zhou S. Diaz L.A. Kinzler K.W. Cancer genome landscapes.Science. 2013; 339: 1546-1558Crossref PubMed Scopus (5210) Google Scholar), suggesting that dynamic developmental tissues are at risk of malignant transformation. Retinoblastoma, atypical teratoid/rhabdoid tumor (AT/RT), and neuroblastoma are prototypic embryonal tumors that develop under the influence of the genetic dysregulation of a unique driver factor (Figure 1). The median age at diagnosis of retinoblastoma is 18 months, and there are reports of premature infants diagnosed with retinoblastoma, establishing the embryonic origin of the disease (Abramson et al., 2002Abramson D.H. Du T.T. Beaverson K.L. (Neonatal) retinoblastoma in the first month of life.Arch. Ophthalmol. 2002; 120: 738-742Crossref PubMed Scopus (44) Google Scholar). Retinoblastoma initiates in response to biallelic RB1 inactivation and loss of function of the retinoblastoma (RB) protein, a critical regulator of the coordination between the cell-cycle machinery and differentiation during development (Knudson, 1992Knudson A.G. Stem cell regulation, tissue ontogeny, and oncogenic events.Semin. Cancer Biol. 1992; 3: 99-106PubMed Google Scholar). Although RB is inactivated in many sporadic cancers, the homogeneity of the tumor spectrum found in children with germline RB1 mutations suggests that molecular pathways unique to a subpopulation of retinal cells may confer intrinsic sensitivity to the inactivation of this tumor suppressor. By depleting the RB protein in dissociated human fetal retinal cells, Xu and colleagues showed that loss of RB specifically induces the proliferation of precursor cells destined to become cone photoreceptors, while it induces apoptosis in other retinal cell populations through a p53-dependent response (Xu et al., 2014Xu X.L. Singh H.P. Wang L. Qi D.-L. Poulos B.K. Abramson D.H. Jhanwar S.C. Cobrinik D. Rb suppresses human cone-precursor-derived retinoblastoma tumours.Nature. 2014; 514: 385-388Crossref PubMed Scopus (145) Google Scholar). These authors further demonstrated that the molecular circuitry of cone precursors efficiently cooperates with RB1 mutations to foster tumorigenesis. Notably, this circuitry involves the ubiquitin ligase enzymes SKP2 and MDM2, which are negative regulators of p27KIP1 and p53, respectively, thereby sustaining cell proliferation and preventing programmed cell death. Similar to retinoblastoma, AT/RTs most commonly occur in infants under 2 years of age. AT/RTs are rhabdoid tumors localized in the central nervous system that are believed to originate from stem cells. They are characterized by a unique genomic stability, with biallelic inactivation of the SMARCB1 tumor suppressor gene as the only known recurrent genetic event. SMARCB1 is a core member of the SWI/SNF chromatin remodeling complex and a critical regulator of signaling pathways controlling cellular differentiation during development, including the WNT/β-catenin and Sonic Hedgehog pathways (Roberts and Biegel, 2009Roberts C.W.M. Biegel J.A. The role of SMARCB1/INI1 in development of rhabdoid tumor.Cancer Biol. Ther. 2009; 8: 412-416Crossref PubMed Scopus (146) Google Scholar). Its oncosuppressive activity has also been shown to rely on its capacity to negatively regulate cell-cycle progression from G0/G1 to S phase through transcriptional repression of CCND1 (cyclin D1), induction of p16INK4a, and hypophosphorylation of RB. Bourdeaut and colleagues generated a mouse model with temporal control of Smarcb1 inactivation (Han et al., 2016Han Z.-Y. Richer W. Fréneaux P. Chauvin C. Lucchesi C. Guillemot D. Grison C. Lequin D. Pierron G. Masliah-Planchon J. et al.The occurrence of intracranial rhabdoid tumours in mice depends on temporal control of Smarcb1 inactivation.Nat. Commun. 2016; 7: 10421Crossref PubMed Scopus (65) Google Scholar). They demonstrated that Smarcb1 inactivation between embryonic day (E) 6 and E10 provokes the development of intracranial tumors similar to human AT/RTs, while the same event induced before E6 or at 2 months of age causes embryonic lethality, hepatic toxicity, or development of T cell lymphomas, thus supporting the concept of developmental pliancy. The pathogenic link between the MYCN oncogene and neuroblastoma, a tumor originating from embryonic neural crest cells, further illustrates the notion that cells in a discrete differentiation state can withstand a specific oncogenic insult, thereby fostering malignant transformation. MYCN is mostly expressed during early developmental stages in a tissue-specific manner. Its genomic amplification defines a subgroup of aggressive and undifferentiated neuroblastomas, the most common extracranial solid tumor in infants. Mice with targeted misexpression of Mycn to the peripheral neural crest via the rat tyrosine hydroxylase promoter develop neuroblastoma, establishing that dysregulation of Mycn in migrating neural crest cells can initiate this disease (Weiss et al., 1997Weiss W.A. Aldape K. Mohapatra G. Feuerstein B.G. Bishop J.M. Targeted expression of MYCN causes neuroblastoma in transgenic mice.EMBO J. 1997; 16: 2985-2995Crossref PubMed Scopus (629) Google Scholar). Like MYC, MYCN is known to activate both proliferation and apoptosis, with the latter mediated by the p14ARF/p53 oncosuppressive pathway (Petroni et al., 2012Petroni M. Veschi V. Gulino A. Giannini G. Molecular mechanisms of MYCN-dependent apoptosis and the MDM2–p53 pathway: an Achille’s heel to be exploited for the therapy of MYCN-amplified neuroblastoma.Front. Oncol. 2012; 2: 141Crossref PubMed Scopus (21) Google Scholar). Interestingly, MYCN-amplified neuroblastomas display a low frequency of TP53 gene mutations but highly express TWIST1, a transcription factor involved in the control of the epithelial-to-mesenchymal transition (EMT) and a master regulator of the migration and differentiation of neural crest cells during development. TWIST1 inhibits the p14ARF/p53 oncosuppressive pathway by binding to p53, inhibiting its transcriptional activity and repressing key effectors of the pathway, including p14ARF (Maestro et al., 1999Maestro R. Dei Tos A.P. Hamamori Y. Krasnokutsky S. Sartorelli V. Kedes L. Doglioni C. Beach D.H. Hannon G.J. Twist is a potential oncogene that inhibits apoptosis.Genes Dev. 1999; 13: 2207-2217Crossref PubMed Scopus (453) Google Scholar, Valsesia-Wittmann et al., 2004Valsesia-Wittmann S. Magdeleine M. Dupasquier S. Garin E. Jallas A.-C. Combaret V. Krause A. Leissner P. Puisieux A. Oncogenic cooperation between H-Twist and N-Myc overrides failsafe programs in cancer cells.Cancer Cell. 2004; 6: 625-630Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar). The mitigation of this fail-safe program is thus likely to render embryonic TWIST1-expressing neural crest cells highly susceptible to undergoing malignant transformation following MYCN activation. The biology of retinoblastoma, AT/RT, and neuroblastoma illustrates two interconnected principles in pediatric tumorigenesis: first, the cell lineage and developmental-stage specificity of most oncogenes and tumor suppressor genes involved in childhood cancers, which directly reflects their spatially and temporally defined functions in the control of cellular differentiation (Maris and Knudson, 2015Maris J.M. Knudson A.G. Revisiting tissue specificity of germline cancer predisposing mutations.Nat. Rev. Cancer. 2015; 15: 65-66Crossref PubMed Scopus (13) Google Scholar); and second, the existence of private developmental stages that exhibit the appropriate context, including intrinsic cellular competence and developmental microenvironment, for a specific oncogenic event to drive malignant transformation rather than induce fail-safe programs. In their seminal paper, Chen et al., 2015Chen X. Pappo A. Dyer M.A. Pediatric solid tumor genomics and developmental pliancy.Oncogene. 2015; 34: 5207-5215Crossref PubMed Scopus (40) Google Scholar posited that the partitioning of the genome is a major determinant of cellular pliancy, as highly pliant cells display a permissive chromatin state, enabling them to adapt efficiently to changes in homeostasis or the environment, as well as to a driving oncogenic lesion. Further supporting this notion, the same group recently demonstrated that retinoblastomas are arrested at an intermediate stage of development, suggesting that a specific selection for a unique epigenetic state occurs during retinogenesis when malignant transformation is initiated as a result of RB inactivation (Aldiri et al., 2017Aldiri I. Xu B. Wang L. Chen X. Hiler D. Griffiths L. Valentine M. Shirinifard A. Thiagarajan S. Sablauer A. et al.The dynamic epigenetic landscape of the retina during development, reprogramming, and tumorigenesis.Neuron. 2017; 94: 550-568.e10Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar). Of note, the cell of origin of retinoblastoma, a cone photoreceptor precursor, is a differentiating and postmitotic cell (Xu et al., 2014Xu X.L. Singh H.P. Wang L. Qi D.-L. Poulos B.K. Abramson D.H. Jhanwar S.C. Cobrinik D. Rb suppresses human cone-precursor-derived retinoblastoma tumours.Nature. 2014; 514: 385-388Crossref PubMed Scopus (145) Google Scholar), indicating that, within a given cell lineage, the cellular competence to cope with a specific oncogenic event is not necessarily confined to stem cells. The classic view of cellular differentiation as an irreversible one-way road was first challenged by the demonstration by Gurdon and colleagues, through somatic cell nuclear transfer, that the nuclei of differentiated somatic cells maintain all genetic information and plasticity (Gurdon and Melton, 2008Gurdon J.B. Melton D.A. Nuclear reprogramming in cells.Science. 2008; 322: 1811-1815Crossref PubMed Scopus (256) Google Scholar). Following these pioneering studies, the identification of a reprogramming cocktail encoding four embryonic transcription factors, OCT4, SOX2, KLF4, and MYC (hereafter OSKM), allowed 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 (18864) Google Scholar to epigenetically reprogram differentiated somatic cells to pluripotency, generating induced pluripotent stem cells (iPSCs). Beyond the implications of this breakthrough in reprogramming-based tissue repair, the molecular dissection of mechanisms underlying induced pluripotency and the characterization of the consequences of deploying gene regulatory mechanisms in inappropriate developmental contexts might illuminate the processes that control cellular pliancy and lead to a better understanding of the initiating steps of tumorigenesis. Cellular reprogramming shares significant features with malignant transformation. First, both processes are constrained by oncogenic barriers, such as cell death and senescence, and they are both considered to be stochastic and subject to significant latencies (Hanna et al., 2009Hanna J. Saha K. Pando B. van Zon J. Lengner C.J. Creyghton M.P. van Oudenaarden A. Jaenisch R. Direct cell reprogramming is a stochastic process amenable to acceleration.Nature. 2009; 462: 595-601Crossref PubMed Scopus (793) Google Scholar, Ischenko et al., 2013Ischenko I. Zhi J. Moll U.M. Nemajerova A. Petrenko O. Direct reprogramming by oncogenic Ras and Myc.Proc. Natl. Acad. Sci. USA. 2013; 110: 3937-3942Crossref PubMed Scopus (75) Google Scholar, Li et al., 2013Li Y. Feng H. Gu H. Lewis D.W. Yuan Y. Zhang L. Yu H. Zhang P. Cheng H. Miao W. et al.The p53-PUMA axis suppresses iPSC generation.Nat. Commun. 2013; 4: 2174Crossref PubMed Scopus (53) Google Scholar, Marión et al., 2009aMarión R.M. Strati K. Li H. Murga M. Blanco R. Ortega S. Fernandez-Capetillo O. Serrano M. 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Consistent with this hypothesis, a large number of factors controlling induced pluripotency are known to be genuine oncoproteins (Suvà et al., 2013Suvà M.L. Riggi N. Bernstein B.E. Epigenetic reprogramming in cancer.Science. 2013; 339: 1567-1570Crossref PubMed Scopus (529) Google Scholar). OSKM proteins illustrate this notion, with OCT4 driving germ cell tumor initiation, SOX2 controlling skin tumor initiation and acting as a lineage survival oncogene in pancreatic cancers, KLF4 promoting breast and pancreatic malignancies, and MYC being amplified in a variety of human cancers where it promotes aberrant cellular proliferation (Dang, 2012Dang C.V. MYC on the path to cancer.Cell. 2012; 149: 22-35Abstract Full Text Full Text PDF PubMed Scopus (2106) Google Scholar, Herreros-Villanueva et al., 2013Herreros-Villanueva M. Zhang J.-S. Koenig A. Abel E.V. Smyrk T.C. Bamlet W.R. de Narvajas A.A.-M. Gomez T.S. Simeone D.M. 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As a remarkable example, by using a mouse model in which reprogramming factor expression in vivo can be controlled temporally with doxycycline, Yamada and colleagues reported that the abbreviated induction of OSKM results in tumor formation in multiple tissues, including the kidney, with the development of malignancies resembling Wilms tumor, a common childhood cancer (Ohnishi et al., 2014Ohnishi K. Semi K. Yamamoto T. Shimizu M. Tanaka A. Mitsunaga K. Okita K. Osafune K. Arioka Y. Maeda T. et al.Premature termination of reprogramming in vivo leads to cancer development through altered epigenetic regulation.Cell. 2014; 156: 663-677Abstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar). 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The latter observation indicates that the level of cellular pliancy of differentiated cells is not fixed and can be modulated under the influence of environmental cues and cellular stress, a notion consistent with epigenetic control. Interestingly, studies conducted by Serrano's team have recently shed light on mechanisms of in vivo reprogramming by revealing a connection between cellular senescence, proinflammatory signals, and OSKM-driven reprogramming (Mosteiro et al., 2016Mosteiro L. Pantoja C. Alcazar N. Marión R.M. Chondronasiou D. Rovira M. Fernandez-Marcos P.J. Muñoz-Martin M. Blanco-Aparicio C. Pastor J. et al.Tissue damage and senescence provide critical signals for cellular reprogramming in vivo.Science. 2016; 354 (aaf4445)Crossref PubMed Scopus (349) Google Scholar). 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