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Journal ArticleDOI

Tumor evolution: Linear, branching, neutral or punctuated?☆

01 Apr 2017-Biochimica et Biophysica Acta (Elsevier)-Vol. 1867, Iss: 2, pp 151-161
TL;DR: Data is discussed that supports the theory that most human tumors evolve from a single cell in the normal tissue, and suggests that models may change during tumor progression or operate concurrently for different classes of mutations.
About: This article is published in Biochimica et Biophysica Acta.The article was published on 2017-04-01 and is currently open access. It has received 255 citations till now. The article focuses on the topics: Tumor progression.
Citations
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25 May 2011
TL;DR: A quantitative analysis of the timing of the genetic evolution of pancreatic cancer was performed, indicating at least a decade between the occurrence of the initiating mutation and the birth of the parental, non-metastatic founder cell.
Abstract: Metastasis, the dissemination and growth of neoplastic cells in an organ distinct from that in which they originated, is the most common cause of death in cancer patients. This is particularly true for pancreatic cancers, where most patients are diagnosed with metastatic disease and few show a sustained response to chemotherapy or radiation therapy. Whether the dismal prognosis of patients with pancreatic cancer compared to patients with other types of cancer is a result of late diagnosis or early dissemination of disease to distant organs is not known. Here we rely on data generated by sequencing the genomes of seven pancreatic cancer metastases to evaluate the clonal relationships among primary and metastatic cancers. We find that clonal populations that give rise to distant metastases are represented within the primary carcinoma, but these clones are genetically evolved from the original parental, non-metastatic clone. Thus, genetic heterogeneity of metastases reflects that within the primary carcinoma. A quantitative analysis of the timing of the genetic evolution of pancreatic cancer was performed, indicating at least a decade between the occurrence of the initiating mutation and the birth of the parental, non-metastatic founder cell. At least five more years are required for the acquisition of metastatic ability and patients die an average of two years thereafter. These data provide novel insights into the genetic features underlying pancreatic cancer progression and define a broad time window of opportunity for early detection to prevent deaths from metastatic disease.

2,019 citations

Journal ArticleDOI
21 Jul 2017-Science
TL;DR: It is proposed that chromatin and epigenetic aberrations have the potential to confer on cells the full range of oncogenic properties represented in the classic “hallmarks” depiction of cancer, and it is suggested that genetic, environmental, and metabolic factors can make chromatin aberrantly permissive or restrictive.
Abstract: BACKGROUND Chromatin is the essential medium through which transcription factors, signaling pathways, and other cues alter gene activity and cellular phenotypes. It assumes distinct conformations that reinforce regulatory activity or repression at a given locus, and reorganizes in response to appropriate intrinsic and extrinsic signals. The biologist Conrad Waddington famously conceptualized developmental specification as an epigenetic landscape in which differentiating cells proceed downhill along branching canals separated by walls that restrict cell identity. By restricting lineage-specific gene expression and phenotypes, chromatin affects the height of the walls between the canals in this epigenetic landscape. Genetic, metabolic, and environmental stimuli that disrupt chromatin alter cellular states and responses, thereby predisposing individuals to a range of common diseases. Although cancer is typically considered a genetic disease, chromatin and epigenetic aberrations play important roles in tumor potentiation, initiation, and progression. ADVANCES We discuss how the stability of chromatin, or its “resistance” to change, is precisely titrated during normal development, and we propose that deviation from this norm is a major factor in tumorigenesis. We review genetic, environmental, and metabolic stimuli that disrupt the homeostatic balance of chromatin, causing it to become aberrantly restrictive or permissive. Stimuli that increase chromatin resistance may result in a restrictive state that blocks differentiation programs. Stimuli that decrease chromatin resistance may result in a permissive state, which we refer to as epigenetic plasticity. We propose that plasticity allows premalignant or malignant cells to stochastically activate alternate gene regulatory programs and/or undergo nonphysiologic cell fate transitions. Some stochastic changes will be inconsequential “passengers”; others will confer fitness and be selected as “drivers.” As cancer cells divide, acquired epigenetic states may be maintained through cell division by DNA methylation, repressive chromatin, or gene regulatory circuits, giving rise to adaptive epiclones that fuel malignant progression. We highlight specific chromatin aberrations that confer epigenetic restriction or plasticity, and ultimately drive tumor progression via oncogene activation, tumor suppressor silencing, or adaptive cell fate transitions. Aberrations initiated by defined genetic stimuli, such as chromatin regulator gene mutations, are particularly informative regarding mechanism. Examples include gain-of-function mutations of the Polycomb repressor EZH2 that promote chromatin restriction and hinder differentiation, and metabolic enzyme mutations that disrupt the balance of DNA methylation. Changes in DNA methylation resulting from the latter have been tied to tumor suppressor silencing but may also result in stochastic insulator disruption and oncogene activation. We also carefully consider metabolic and environmental stimuli that disrupt chromatin homeostasis in the absence of genetic changes. Examples include links between folate metabolism and methylase activity, environmental factors that promote DNA hypermethylation in gastrointestinal tissues, and potential effects of microenvironmental stress on chromatin regulator expression. Purely epigenetic mechanisms may explain tumors that arise with few or no recurrent mutations, as well as heterogeneous functional phenotypes within tumors that lack genetic explanation. We conclude that chromatin and epigenetic aberrations can confer wide-ranging oncogenic properties and may fulfill all of cancer’s hallmarks. OUTLOOK Initial successes with epigenetic therapies suggest the potential of cancer epigenetics for major clinical impact. Yet realizing this promise will require a clearer understanding of epigenetic mechanisms of tumorigenesis. The identification of increasing numbers of oncogenic epigenetic lesions provides an opportunity to develop and test conceptual and mechanistic models of their functions. Progress will require new technologies for probing chromatin and epigenetic alterations with single-cell precision, as well as experimental models that faithfully recapitulate epigenetic states in tumors. We are optimistic that an improved understanding of epigenetic plasticity and restriction could advance diagnostic strategies for evaluating tumor stage and heterogeneity, and yield new therapeutic strategies for correcting epigenetic lesions or exploiting vulnerabilities of epigenetically altered cells.

856 citations


Cites background from "Tumor evolution: Linear, branching,..."

  • ...Epigenetic alterations may occur individually over time or, alternatively, may arise as multiple simultaneous disruptions, analogous to the catastrophic genetic aberrations associated with “chromothrypsis” (41, 42)....

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Journal ArticleDOI
TL;DR: This compendium is for established researchers, newcomers, and students alike, highlighting interesting and rewarding problems for the coming years in single-cell data science.
Abstract: The recent boom in microfluidics and combinatorial indexing strategies, combined with low sequencing costs, has empowered single-cell sequencing technology. Thousands-or even millions-of cells analyzed in a single experiment amount to a data revolution in single-cell biology and pose unique data science problems. Here, we outline eleven challenges that will be central to bringing this emerging field of single-cell data science forward. For each challenge, we highlight motivating research questions, review prior work, and formulate open problems. This compendium is for established researchers, newcomers, and students alike, highlighting interesting and rewarding problems for the coming years.

677 citations

Journal ArticleDOI
TL;DR: Recent advances in single-cell technologies are reviewed and discussed in detail how they can be leveraged to understand tumour heterogeneity and metastasis.
Abstract: Tumours comprise a heterogeneous collection of cells with distinct genetic and phenotypic properties that can differentially promote progression, metastasis and drug resistance. Emerging single-cell technologies provide a new opportunity to profile individual cells within tumours and investigate what roles they play in these processes. This Review discusses key technological considerations for single-cell studies in cancer, new findings using single-cell technologies and critical open questions for future applications.

369 citations

01 Jan 2014
TL;DR: The analysis of cellular heterogeneity for genetic and phenotypic features and their spatial distribution in breast tumors pre- and post-neoadjuvant chemotherapy found that intratumor genetic diversity was tumor-subtype specific, and it did not change during treatment in tumors with partial or no response.
Abstract: Cancer therapy exerts a strong selection pressure that shapes tumor evolution, yet our knowledge of how tumors change during treatment is limited. Here, we report the analysis of cellular heterogeneity for genetic and phenotypic features and their spatial distribution in breast tumors pre- and post-neoadjuvant chemotherapy. We found that intratumor genetic diversity was tumor-subtype specific, and it did not change during treatment in tumors with partial or no response. However, lower pretreatment genetic diversity was significantly associated with pathologic complete response. In contrast, phenotypic diversity was different between pre- and posttreatment samples. We also observed significant changes in the spatial distribution of cells with distinct genetic and phenotypic features. We used these experimental data to develop a stochastic computational model to infer tumor growth patterns and evolutionary dynamics. Our results highlight the importance of integrated analysis of genotypes and phenotypes of single cells in intact tissues to predict tumor evolution.

204 citations

References
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Journal ArticleDOI
22 May 2009-Science
TL;DR: It is proposed that the metabolism of cancer cells, and indeed all proliferating cells, is adapted to facilitate the uptake and incorporation of nutrients into the biomass needed to produce a new cell.
Abstract: In contrast to normal differentiated cells, which rely primarily on mitochondrial oxidative phosphorylation to generate the energy needed for cellular processes, most cancer cells instead rely on aerobic glycolysis, a phenomenon termed “the Warburg effect.” Aerobic glycolysis is an inefficient way to generate adenosine 5′-triphosphate (ATP), however, and the advantage it confers to cancer cells has been unclear. Here we propose that the metabolism of cancer cells, and indeed all proliferating cells, is adapted to facilitate the uptake and incorporation of nutrients into the biomass (e.g., nucleotides, amino acids, and lipids) needed to produce a new cell. Supporting this idea are recent studies showing that (i) several signaling pathways implicated in cell proliferation also regulate metabolic pathways that incorporate nutrients into biomass; and that (ii) certain cancer-associated mutations enable cancer cells to acquire and metabolize nutrients in a manner conducive to proliferation rather than efficient ATP production. A better understanding of the mechanistic links between cellular metabolism and growth control may ultimately lead to better treatments for human cancer.

12,380 citations

Journal ArticleDOI
01 Jun 1990-Cell
TL;DR: A model for the genetic basis of colorectal neoplasia that includes the following salient features is presented, which may be applicable to other common epithelial neoplasms, in which tumors of varying stage are more difficult to study.

11,576 citations

Journal ArticleDOI
TL;DR: Intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized-medicine and biomarker development.
Abstract: Background Intratumor heterogeneity may foster tumor evolution and adaptation and hinder personalized-medicine strategies that depend on results from single tumor-biopsy samples. Methods To examine intratumor heterogeneity, we performed exome sequencing, chromosome aberration analysis, and ploidy profiling on multiple spatially separated samples obtained from primary renal carcinomas and associated metastatic sites. We characterized the consequences of intratumor heterogeneity using immunohistochemical analysis, mutation functional analysis, and profiling of messenger RNA expression. Results Phylogenetic reconstruction revealed branched evolutionary tumor growth, with 63 to 69% of all somatic mutations not detectable across every tumor region. Intratumor heterogeneity was observed for a mutation within an autoinhibitory domain of the mammalian target of rapamycin (mTOR) kinase, correlating with S6 and 4EBP phosphorylation in vivo and constitutive activation of mTOR kinase activity in vitro. Mutational intratumor heterogeneity was seen for multiple tumor-suppressor genes converging on loss of function; SETD2, PTEN, and KDM5C underwent multiple distinct and spatially separated inactivating mutations within a single tumor, suggesting convergent phenotypic evolution. Gene-expression signatures of good and poor prognosis were detected in different regions of the same tumor. Allelic composition and ploidy profiling analysis revealed extensive intratumor heterogeneity, with 26 of 30 tumor samples from four tumors harboring divergent allelic-imbalance profiles and with ploidy heterogeneity in two of four tumors. Conclusions Intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized-medicine and biomarker development. Intratumor heterogeneity, associated with heterogeneous protein function, may foster tumor adaptation and therapeutic failure through Darwinian selection. (Funded by the Medical Research Council and others.)

6,672 citations

Journal ArticleDOI
01 Oct 1976-Science
TL;DR: Each patient's cancer may require individual specific therapy, and even this may be thwarted by emergence of a genetically variant subline resistant to the treatment, which should be directed toward understanding and controlling the evolutionary process in tumors before it reaches the late stage usually seen in clinical cancer.
Abstract: It is proposed that most neoplasms arise from a single cell of origin, and tumor progression results from acquired genetic variability within the original clone allowing sequential selection of more aggressive sublines. Tumor cell populations are apparently more genetically unstable than normal cells, perhaps from activation of specific gene loci in the neoplasm, continued presence of carcinogen, or even nutritional deficiencies within the tumor. The acquired genetic insta0ility and associated selection process, most readily recognized cytogenetically, results in advanced human malignancies being highly individual karyotypically and biologically. Hence, each patient's cancer may require individual specific therapy, and even this may be thwarted by emergence of a genetically variant subline resistant to the treatment. More research should be directed toward understanding and controlling the evolutionary process in tumors before it reaches the late stage usually seen in clinical cancer.

6,179 citations

Journal ArticleDOI
18 May 2007-Science
TL;DR: It is proposed that MET amplification may promote drug resistance in other ERBB-driven cancers as well after it was found that amplification of MET causes gefitinib resistance by driving ERBB3 (HER3)–dependent activation of PI3K, a pathway thought to be specific to EGFR/ERBB family receptors.
Abstract: The epidermal growth factor receptor (EGFR) kinase inhibitors gefitinib and erlotinib are effective treatments for lung cancers with EGFR activating mutations, but these tumors invariably develop drug resistance. Here, we describe a gefitinib-sensitive lung cancer cell line that developed resistance to gefitinib as a result of focal amplification of the MET proto-oncogene. inhibition of MET signaling in these cells restored their sensitivity to gefitinib. MET amplification was detected in 4 of 18 (22%) lung cancer specimens that had developed resistance to gefitinib or erlotinib. We find that amplification of MET causes gefitinib resistance by driving ERBB3 (HER3)–dependent activation of PI3K, a pathway thought to be specific to EGFR/ERBB family receptors. Thus, we propose that MET amplification may promote drug resistance in other ERBB-driven cancers as well.

4,218 citations