A spatial model predicts that dispersal and cell turnover limit intratumour heterogeneity

Waclaw, Bartłomiej; Božić, Ivana; Pittman, Meredith E.; Hruban, Ralph H.; Vogelstein, Bert; Nowak, Martin A.

doi:10.1038/nature14971

Cited by 459 publications

(552 citation statements)

References 96 publications

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“…S9). 14) Simulation of Genetic Diversity in Growing Populations. To simulate the clonal diversity in a tumor and to compare with the theoretical predictions, we designed cellular automata models (55,56) to simulate tumor expansion and mutation accumulation in 3D space.…”

Section: ) Computermentioning

confidence: 99%

Extremely high genetic diversity in a single tumor points to prevalence of non-Darwinian cell evolution

Ling

Yang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

324

410

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The prevailing view that the evolution of cells in a tumor is driven by Darwinian selection has never been rigorously tested. Because selection greatly affects the level of intratumor genetic diversity, it is important to assess whether intratumor evolution follows the Darwinian or the non-Darwinian mode of evolution. To provide the statistical power, many regions in a single tumor need to be sampled and analyzed much more extensively than has been attempted in previous intratumor studies. Here, from a hepatocellular carcinoma (HCC) tumor, we evaluated multiregional samples from the tumor, using either whole-exome sequencing (WES) (n = 23 samples) or genotyping (n = 286) under both the infinite-site and infinite-allele models of population genetics. In addition to the many single-nucleotide variations (SNVs) present in all samples, there were 35 “polymorphic” SNVs among samples. High genetic diversity was evident as the 23 WES samples defined 20 unique cell clones. With all 286 samples genotyped, clonal diversity agreed well with the non-Darwinian model with no evidence of positive Darwinian selection. Under the non-Darwinian model, MALL (the number of coding region mutations in the entire tumor) was estimated to be greater than 100 million in this tumor. DNA sequences reveal local diversities in small patches of cells and validate the estimation. In contrast, the genetic diversity under a Darwinian model would generally be orders of magnitude smaller. Because the level of genetic diversity will have implications on therapeutic resistance, non-Darwinian evolution should be heeded in cancer treatments even for microscopic tumors.

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Section: ) Computermentioning

confidence: 99%

Extremely high genetic diversity in a single tumor points to prevalence of non-Darwinian cell evolution

Ling

Yang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

324

410

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“…This technology could provide new pathways for 3D bioprinting, because the technology addresses the central challenge of replicating tissue structures or even fabricating artificial organs that are made up of multiple cell types and complex geometries, but with singlecell control resolution (4). In addition, we expect this technology to rebuild the 3D architecture of a tumor, which will aid in the investigation of heterogeneous genetic alterations during tumor growth and metastasis process (22). The ability to precisely transport single cells along three axes using our 3D acoustic tweezers may facilitate investigations of a number of challenging problems in biology, particularly those involved in the spatial regulation of cells in 2D or 3D environments (23).…”

Section: Discussionmentioning

confidence: 99%

Three-dimensional manipulation of single cells using surface acoustic waves

Guo

Mao

Chen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

468

356

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The ability of surface acoustic waves to trap and manipulate micrometer-scale particles and biological cells has led to many applications involving "acoustic tweezers" in biology, chemistry, engineering, and medicine. Here, we present 3D acoustic tweezers, which use surface acoustic waves to create 3D trapping nodes for the capture and manipulation of microparticles and cells along three mutually orthogonal axes. In this method, we use standing-wave phase shifts to move particles or cells in-plane, whereas the amplitude of acoustic vibrations is used to control particle motion along an orthogonal plane. We demonstrate, through controlled experiments guided by simulations, how acoustic vibrations result in micromanipulations in a microfluidic chamber by invoking physical principles that underlie the formation and regulation of complex, volumetric trapping nodes of particles and biological cells. We further show how 3D acoustic tweezers can be used to pick up, translate, and print single cells and cell assemblies to create 2D and 3D structures in a precise, noninvasive, label-free, and contact-free manner.3D acoustic tweezers | cell printing | 3D cell manipulation | cell assembly | 3D particle manipulationT he ability to precisely manipulate living cells in three dimensions, one cell at a time, offers many possible applications in regenerative medicine, tissue engineering, neuroscience, and biophysics (1-3). However, current bioprinting methods are generally hampered by the need to reconstruct and mimic 3D cellto-cell communications and cell-environment interactions. Because of this constraint, bioprinting requires accurate reproduction of multicellular architecture (4, 5). Several approaches have been developed to produce complex cell patterns, clusters, assembled arrays, and even tissue structures. These approaches use many disparate technologies which include optics, magnetic and electrical fields, injection printing, physical or geometric constraints, or surface engineering (6-11). However, there is currently a paucity of a single method that can facilitate the formation of complex multicellular structures with high precision, high versatility, multiple dimensionality, and single-cell resolution, while maintaining cell viability, integrity, and function. As a result, there is a critical need to develop new methods that seek to overcome these limitations."Acoustic tweezers," which manipulate biological specimens using sound waves, offer several unique advantages (12, 13) in comparison with other techniques. First, the acoustic tweezers technology is the only active cell-manipulation method using gentle mechanical vibrations that do not alter cell characteristics. Acoustic vibrations create a pressure gradient in the medium to move suspended microobjects and cells, thereby resulting in a contaminationfree, contact-less, and label-free method for cell manipulation. Sound waves are preferred for cell manipulation for the following reasons: (i) cells maintain their native state (e.g., shape, size, reflective index,...

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“…However, although heterogeneity is required for Darwinian evolution, positive selection does not necessarily lead to heterogeneity (Waclaw et al, 2015). As such, the extent to which positive selection can account for the degree of ITH in tumors has been called into question (Ling et al, 2015;Williams et al, 2016).…”

Section: Processes Of Cancer Genome Evolution and Evolutionary Debatesmentioning

confidence: 99%

Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future

McGranahan

Swanton

2017

Cell

2,030

1,694

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Intratumor heterogeneity, which fosters tumor evolution, is a key challenge in cancer medicine. Here we review data and technologies that have revealed intra-tumor heterogeneity across cancer types, and the dynamics, constraints and contingencies inherent to tumor evolution. We emphasize the importance of macro-evolutionary leaps, often involving large-scale chromosomal alterations, in driving tumor evolution and metastasis, and consider the role of the tumor microenvironment in engendering heterogeneity and drug-resistance. We suggest that bold approaches to drug development, harnessing the adaptive properties of the immunemicroenvironment whilst limiting those of the tumor, combined with advances in clinical trial-design, will improve patient outcome.

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A spatial model predicts that dispersal and cell turnover limit intratumour heterogeneity

Cited by 459 publications

References 96 publications

Extremely high genetic diversity in a single tumor points to prevalence of non-Darwinian cell evolution

Extremely high genetic diversity in a single tumor points to prevalence of non-Darwinian cell evolution

Three-dimensional manipulation of single cells using surface acoustic waves

Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future

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