Characterizing the ecological and evolutionary dynamics of cancer.


Journal

Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904

Informations de publication

Date de publication:
08 2020
Historique:
received: 29 08 2019
accepted: 22 06 2020
pubmed: 29 7 2020
medline: 27 10 2020
entrez: 29 7 2020
Statut: ppublish

Résumé

Tumor initiation and progression are somatic evolutionary processes driven by the accumulation of genetic alterations, some of which confer selective fitness advantages to the host cell. This gene-centric model has shaped the field of cancer biology and advanced understanding of cancer pathophysiology. Importantly, however, each genotype encodes diverse phenotypic traits that permit acclimation to varied microenvironmental conditions. Epigenetic and transcriptional changes also contribute to the heritable phenotypic variation required for evolution. Additionally, interactions between cancer cells and surrounding stromal and immune cells through autonomous and non-autonomous signaling can influence competition for survival. Therefore, a mechanistic understanding of tumor progression must account for evolutionary and ecological dynamics. In this Perspective, we outline technological advances and model systems to characterize tumor progression through space and time. We discuss the importance of unifying experimentation with computational modeling and opportunities to inform cancer control.

Identifiants

pubmed: 32719518
doi: 10.1038/s41588-020-0668-4
pii: 10.1038/s41588-020-0668-4
doi:

Types de publication

Journal Article Research Support, N.I.H., Extramural Review

Langues

eng

Sous-ensembles de citation

IM

Pagination

759-767

Subventions

Organisme : NCI NIH HHS
ID : DP1 CA238296
Pays : United States

Références

Seth, S. et al. Pre-existing functional heterogeneity of tumorigenic compartment as the origin of chemoresistance in pancreatic tumors. Cell Rep. 26, 1518–1532.e9 (2019).
pubmed: 30726735
Bhang, H. E. et al. Studying clonal dynamics in response to cancer therapy using high-complexity barcoding. Nat. Med. 21, 440–448 (2015).
pubmed: 25849130
Pogrebniak, K. L. & Curtis, C. Harnessing tumor evolution to circumvent resistance. Trends Genet. 34, 639–651 (2018).
pubmed: 29903534 pmcid: 6368975
Schulz, D. et al. Simultaneous multiplexed imaging of mRNA and proteins with subcellular resolution in breast cancer tissue samples by mass cytometry. Cell Syst. 6, 25–36.e5 (2018).
pubmed: 29289569 pmcid: 5791659
Nowell, P. C. The clonal evolution of tumor cell populations. Science 194, 23–28 (1976).
pubmed: 959840
Greaves, M. & Maley, C. C. Clonal evolution in cancer. Nature 481, 306–313 (2012).
pubmed: 22258609 pmcid: 22258609
Bailey, M. H. et al. Comprehensive characterization of cancer driver genes and mutations. Cell 173, 371–385.e18 (2018).
pubmed: 29625053 pmcid: 29625053
Gatenby, R. A. & Brown, J. Mutations, evolution and the central role of a self-defined fitness function in the initiation and progression of cancer. Biochim Biophys. Acta Rev. Cancer 1867, 162–166 (2017).
pubmed: 28341421
Gerlinger, M. et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366, 883–892 (2012).
pubmed: 22397650 pmcid: 22397650
Sottoriva, A. et al. A Big Bang model of human colorectal tumor growth. Nat. Genet. 47, 209–216 (2015).
pubmed: 25665006 pmcid: 4575589
Boutros, P. C. et al. Spatial genomic heterogeneity within localized, multifocal prostate cancer. Nat. Genet. 47, 736–745 (2015).
pubmed: 26005866
Gao, R. et al. Punctuated copy number evolution and clonal stasis in triple-negative breast cancer. Nat. Genet. 48, 1119–1130 (2016).
pubmed: 27526321 pmcid: 5042845
McPherson, A. et al. Divergent modes of clonal spread and intraperitoneal mixing in high-grade serous ovarian cancer. Nat. Genet. 48, 758–767 (2016).
pubmed: 27182968
Turajlic, S. et al. Deterministic evolutionary trajectories influence primary tumor growth: TRACERx Renal. Cell 173, 595–610.e11 (2018).
pubmed: 5938372 pmcid: 5938372
Shlush, L. I. et al. Tracing the origins of relapse in acute myeloid leukaemia to stem cells. Nature 547, 104–108 (2017).
pubmed: 28658204
Maley, C. C. et al. Classifying the evolutionary and ecological features of neoplasms. Nat. Rev. Cancer 17, 605–619 (2017).
pubmed: 28912577 pmcid: 5811185
Yaffe, M. B. Why geneticists stole cancer research even though cancer is primarily a signaling disease. Sci. Signal. 12, eaaw3483 (2019).
pubmed: 30670634
Chen, K. H., Boettiger, A. N., Moffitt, J. R., Wang, S. & Zhuang, X. Spatially resolved, highly multiplexed RNA profiling in single cells. Science 348, aaa6090 (2015).
pubmed: 4662681 pmcid: 4662681
Keren, L. et al. A structured tumor-immune microenvironment in triple negative breast cancer revealed by multiplexed ion beam imaging. Cell 174, 1373–1387.e19 (2018).
pubmed: 6132072 pmcid: 6132072
Tsao, J. L. et al. Genetic reconstruction of individual colorectal tumor histories. Proc. Natl Acad. Sci. USA 97, 1236–1241 (2000).
pubmed: 10655514
Martincorena, I. et al. High burden and pervasive positive selection of somatic mutations in normal human skin. Science 348, 880–886 (2015).
pubmed: 25999502 pmcid: 4471149
Martincorena, I. et al. Somatic mutant clones colonize the human esophagus with age. Science 362, 911–917 (2018).
pubmed: 30337457 pmcid: 6298579
Yokoyama, A. et al. Age-related remodelling of oesophageal epithelia by mutated cancer drivers. Nature 565, 312–317 (2019).
pubmed: 30602793
Jaiswal, S. & Ebert, B. L. Clonal hematopoiesis in human aging and disease. Science 366, eaan4673 (2019).
pubmed: 31672865
Srivastava, S., Ghosh, S., Kagan, J. & Mazurchuk, R. The PreCancer Atlas (PCA). Trends Cancer 4, 513–514 (2018).
pubmed: 30064657
Uchi, R. et al. Integrated multiregional analysis proposing a new model of colorectal cancer evolution. PLoS Genet. 12, e1005778 (2016).
pubmed: 26890883 pmcid: 4758664
Cross, W. et al. The evolutionary landscape of colorectal tumorigenesis. Nat. Ecol. Evol. 2, 1661–1672 (2018).
pubmed: 6152905 pmcid: 6152905
Turajlic, S. et al. Tracking cancer evolution reveals constrained routes to metastases: TRACERx Renal. Cell 173, 581–594.e12 (2018).
pubmed: 29656895 pmcid: 5938365
Hu, Z. et al. Quantitative evidence for early metastatic seeding in colorectal cancer. Nat. Genet. 51, 1113–1122 (2019).
pubmed: 31209394 pmcid: 6982526
Hu, Z., Li, Z., Ma, Z. & Curtis, C. Multi-cancer analysis of clonality and the timing of systemic spread in paired primary tumors and metastases. Nat. Genet. 52, 701–708 (2020).
pubmed: 32424352
Gerstung, M. et al. The evolutionary history of 2,658 cancers. Nature 578, 122–128 (2020).
pubmed: 7054212 pmcid: 7054212
Werner, B. et al. Measuring single cell divisions in human tissues from multi-region sequencing data. Nat. Commun. 11, 1035 (2020).
pubmed: 32098957 pmcid: 7042311
Sun, R. et al. Between-region genetic divergence reflects the mode and tempo of tumor evolution. Nat. Genet. 49, 1015–1024 (2017).
pubmed: 5643198 pmcid: 5643198
Williams, M. J. et al. Quantification of subclonal selection in cancer from bulk sequencing data. Nat. Genet. 50, 895–903 (2018).
pubmed: 6475346 pmcid: 6475346
Gruber, M. et al. Growth dynamics in naturally progressing chronic lymphocytic leukaemia. Nature 570, 474–479 (2019).
pubmed: 31142838 pmcid: 6630176
Bozic, I. et al. Evolutionary dynamics of cancer in response to targeted combination therapy. eLife 2, e00747 (2013).
pubmed: 23805382 pmcid: 3691570
Landau, D. A. et al. Mutations driving CLL and their evolution in progression and relapse. Nature 526, 525–530 (2015).
pubmed: 26466571 pmcid: 4815041
Landau, D. A. et al. The evolutionary landscape of chronic lymphocytic leukemia treated with ibrutinib targeted therapy. Nat. Commun. 8, 2185 (2017).
pubmed: 29259203 pmcid: 5736707
Rueda, O. M. et al. Dynamics of breast-cancer relapse reveal late-recurring ER-positive genomic subgroups. Nature 567, 399–404 (2019).
pubmed: 30867590 pmcid: 6647838
Van Allen, E. M. et al. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science 350, 207–211 (2015).
pubmed: 26359337 pmcid: 5054517
Rizvi, N. A. et al. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124–128 (2015).
pubmed: 25765070 pmcid: 4993154
Łuksza, M. et al. A neoantigen fitness model predicts tumour response to checkpoint blockade immunotherapy. Nature 551, 517–520 (2017).
pubmed: 29132144 pmcid: 6137806
Yost, K. E. et al. Clonal replacement of tumor-specific T cells following PD-1 blockade. Nat. Med. 25, 1251–1259 (2019).
pubmed: 6689255 pmcid: 6689255
Zhang, A. W. et al. Interfaces of malignant and immunologic clonal dynamics in ovarian cancer. Cell 173, 1755–1769.e22 (2018).
pubmed: 29754820
Failmezger, H. et al. Topological tumor graphs: a graph-based spatial model to infer stromal recruitment for immunosuppression in melanoma histology. Cancer Res. 80, 1199–1209 (2020).
pubmed: 31874858
Lloyd, M. C. et al. Darwinian dynamics of intratumoral heterogeneity: not solely random mutations but also variable environmental selection forces. Cancer Res. 76, 3136–3144 (2016).
pubmed: 27009166 pmcid: 5384728
Carmona-Fontaine, C. et al. Metabolic origins of spatial organization in the tumor microenvironment. Proc. Natl Acad. Sci. USA 114, 2934–2939 (2017).
pubmed: 28246332
Northcott, J. M., Dean, I. S., Mouw, J. K. & Weaver, V. M. Feeling stress: the mechanics of cancer progression and aggression. Front. Cell Dev. Biol. 6, 17 (2018).
pubmed: 29541636 pmcid: 5835517
Cassereau, L., Miroshnikova, Y. A., Ou, G., Lakins, J. & Weaver, V. M. A 3D tension bioreactor platform to study the interplay between ECM stiffness and tumor phenotype. J. Biotechnol. 193, 66–69 (2015).
pubmed: 25435379
Wang, F. et al. RNAscope: a novel in situ RNA analysis platform for formalin-fixed, paraffin-embedded tissues. J. Mol. Diagn. 14, 22–29 (2012).
pubmed: 22166544 pmcid: 3338343
Angelo, M. et al. Multiplexed ion beam imaging of human breast tumors. Nat. Med. 20, 436–442 (2014).
pubmed: 4110905 pmcid: 4110905
Lubeck, E., Coskun, A. F., Zhiyentayev, T., Ahmad, M. & Cai, L. Single-cell in situ RNA profiling by sequential hybridization. Nat. Methods 11, 360–361 (2014).
pubmed: 4085791 pmcid: 4085791
Lee, J. H. et al. Fluorescent in situ sequencing (FISSEQ) of RNA for gene expression profiling in intact cells and tissues. Nat. Protoc. 10, 442–458 (2015).
pubmed: 25675209 pmcid: 4327781
Goltsev, Y. et al. Deep profiling of mouse splenic architecture with codex multiplexed imaging. Cell 174, 968–981.e15 (2018).
pubmed: 30078711 pmcid: 6086938
Wang, X. et al. Three-dimensional intact-tissue sequencing of single-cell transcriptional states. Science 361, eaat5691 (2018).
pubmed: 29930089 pmcid: 6339868
Eng, C. L. et al. Transcriptome-scale super-resolved imaging in tissues by RNA seqFISH. Nature 568, 235–239 (2019).
pubmed: 30911168 pmcid: 6544023
Lundberg, E. & Borner, G. H. H. Spatial proteomics: a powerful discovery tool for cell biology. Nat. Rev. Mol. Cell Biol. 20, 285–302 (2019).
pubmed: 30659282
Giesen, C. et al. Highly multiplexed imaging of tumor tissues with subcellular resolution by mass cytometry. Nat. Methods 11, 417–422 (2014).
Chevrier, S. et al. An immune atlas of clear cell renal cell carcinoma. Cell 169, 736–749.e18 (2017).
pubmed: 5422211 pmcid: 5422211
Decalf, J., Albert, M. L. & Ziai, J. New tools for pathology: a user’s review of a highly multiplexed method for in situ analysis of protein and RNA expression in tissue. J. Pathol. 247, 650–661 (2019).
pubmed: 30570141
Jackson, H. W. et al. The single-cell pathology landscape of breast cancer. Nature 578, 615–620 (2020).
pubmed: 31959985
Marusyk, A. et al. Non-cell-autonomous driving of tumour growth supports sub-clonal heterogeneity. Nature 514, 54–58 (2014).
pubmed: 25079331 pmcid: 4184961
Merritt, C. R. et al. Multiplex digital spatial profiling of proteins and RNA in fixed tissue. Nat. Biotechnol. 38, 586–599 (2020).
pubmed: 32393914
Moffitt, J. R. et al. High-performance multiplexed fluorescence in situ hybridization in culture and tissue with matrix imprinting and clearing. Proc. Natl Acad. Sci. USA 113, 14456–14461 (2016).
pubmed: 27911841
Ståhl, P. L. et al. Visualization and analysis of gene expression in tissue sections by spatial transcriptomics. Science 353, 78–82 (2016).
pubmed: 27365449
Vickovic, S. et al. High-definition spatial transcriptomics for in situ tissue profiling. Nat. Methods 16, 987–990 (2019).
pubmed: 31501547 pmcid: 6765407
Rodriques, S. G. et al. Slide-seq: a scalable technology for measuring genome-wide expression at high spatial resolution. Science 363, 1463–1467 (2019).
pubmed: 30923225 pmcid: 6927209
Gawad, C., Koh, W. & Quake, S. R. Single-cell genome sequencing: current state of the science. Nat. Rev. Genet. 17, 175–188 (2016).
pubmed: 26806412
Navin, N. et al. Tumour evolution inferred by single-cell sequencing. Nature 472, 90–94 (2011).
pubmed: 21399628 pmcid: 4504184
Casasent, A. K. et al. Multiclonal invasion in breast tumors identified by topographic single cell sequencing. Cell 172, 205–217.e12 (2018).
pubmed: 29307488 pmcid: 5766405
Zahn, H. et al. Scalable whole-genome single-cell library preparation without preamplification. Nat. Methods 14, 167–173 (2017).
pubmed: 28068316
Laks, E. et al. Clonal decomposition and DNA replication states defined by scaled single-cell genome sequencing. Cell 179, 1207–1221.e22 (2019).
pubmed: 31730858 pmcid: 6912164
Buenrostro, J. D. et al. Single-cell chromatin accessibility reveals principles of regulatory variation. Nature 523, 486–490 (2015).
pubmed: 26083756 pmcid: 4685948
Cusanovich, D. A. et al. Multiplex single cell profiling of chromatin accessibility by combinatorial cellular indexing. Science 348, 910–914 (2015).
pubmed: 25953818 pmcid: 4836442
Cao, J. et al. Joint profiling of chromatin accessibility and gene expression in thousands of single cells. Science 361, 1380–1385 (2018).
pubmed: 30166440 pmcid: 6571013
Jackson, E. L. & Lu, H. Three-dimensional models for studying development and disease: moving on from organisms to organs-on-a-chip and organoids. Integr. Biol. (Camb.) 8, 672–683 (2016).
Tsherniak, A. et al. Defining a cancer dependency map. Cell 170, 564–576.e16 (2017).
pubmed: 28753430 pmcid: 5667678
Ghandi, M. et al. Next-generation characterization of the Cancer Cell Line Encyclopedia. Nature 569, 503–508 (2019).
pubmed: 31068700 pmcid: 6697103
Bolan, P. O. et al. Genotype-fitness maps of EGFR-mutant lung adenocarcinoma chart the evolutionary landscape of resistance for combination therapy optimization. Cell Syst. 10, 52–65.e7 (2020).
pubmed: 31668800
Stowers, R. S. et al. Matrix stiffness induces a tumorigenic phenotype in mammary epithelium through changes in chromatin accessibility. Nat. Biomed. Eng. 3, 1009–1019 (2019).
pubmed: 31285581 pmcid: 6899165
Bissell, M. J. & Radisky, D. Putting tumours in context. Nat. Rev. Cancer 1, 46–54 (2001).
pubmed: 11900251 pmcid: 2975572
Han, K. et al. CRISPR screens in cancer spheroids identify 3D growth-specific vulnerabilities. Nature 580, 136–141 (2020).
pubmed: 32238925
Sato, T. et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459, 262–265 (2009).
pubmed: 19329995
Sachs, N. et al. A living biobank of breast cancer organoids captures disease heterogeneity. Cell 172, 373–386.e10 (2018).
pubmed: 29224780
van de Wetering, M. et al. Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell 161, 933–945 (2015).
pubmed: 25957691 pmcid: 6428276
Neal, J. T. et al. Organoid modeling of the tumor immune microenvironment. Cell 175, 1972–1988.e16 (2018).
pubmed: 30550791 pmcid: 6656687
Clevers, H. & Tuveson, D. A. Organoid models for cancer research. Annu. Rev. Cancer Biol. 3, 223–234 (2019).
Albritton, J. L. & Miller, J. S. 3D bioprinting: improving in vitro models of metastasis with heterogeneous tumor microenvironments. Dis. Model. Mech. 10, 3–14 (2017).
pubmed: 28067628 pmcid: 5278522
Hu, M. et al. Facile engineering of long-term culturable ex vivo vascularized tissues using biologically derived matrices. Adv. Healthc. Mater. 7, e1800845 (2018).
pubmed: 30369101 pmcid: 6478398
Katt, M. E., Placone, A. L., Wong, A. D., Xu, Z. S. & Searson, P. C. In vitro tumor models: advantages, disadvantages, variables, and selecting the right platform. Front. Bioeng. Biotechnol. 4, 12 (2016).
pubmed: 26904541 pmcid: 4751256
Kersten, K., de Visser, K. E., van Miltenburg, M. H. & Jonkers, J. Genetically engineered mouse models in oncology research and cancer medicine. EMBO Mol. Med. 9, 137–153 (2017).
pubmed: 28028012
Winters, I. P., Murray, C. W. & Winslow, M. M. Towards quantitative and multiplexed in vivo functional cancer genomics. Nat. Rev. Genet. 19, 741–755 (2018).
pubmed: 30267031
Bruna, A. et al. A biobank of breast cancer explants with preserved intra-tumor heterogeneity to screen anticancer compounds. Cell 167, 260–274.e22 (2016).
pubmed: 27641504 pmcid: 5037319
Echeverria, G. V. et al. High-resolution clonal mapping of multi-organ metastasis in triple negative breast cancer. Nat. Commun. 9, 5079 (2018).
pubmed: 30498242 pmcid: 6265294
Sánchez-Rivera, F. J. et al. Rapid modelling of cooperating genetic events in cancer through somatic genome editing. Nature 516, 428–431 (2014).
pubmed: 25337879 pmcid: 4292871
Walther, V. et al. Can oncology recapitulate paleontology? Lessons from species extinctions. Nat. Rev. Clin. Oncol. 12, 273–285 (2015).
pubmed: 25687908 pmcid: 4569005
Rogers, Z. N. et al. Mapping the in vivo fitness landscape of lung adenocarcinoma tumor suppression in mice. Nat. Genet. 50, 483–486 (2018).
pubmed: 29610476 pmcid: 6061949
McPherson, A. W., Chan, F. C. & Shah, S. P. Observing clonal dynamics across spatiotemporal axes: a prelude to quantitative fitness models for cancer. Cold Spring Harb. Perspect. Med. 8, a029603 (2018).
pubmed: 28630229 pmcid: 5793737
Russo, M. et al. Adaptive mutability of colorectal cancers in response to targeted therapies. Science 366, 1473–1480 (2019).
pubmed: 31699882
Gatenby, R. A., Silva, A. S., Gillies, R. J. & Frieden, B. R. Adaptive therapy. Cancer Res. 69, 4894–4903 (2009).
pubmed: 19487300 pmcid: 3728826
Enriquez-Navas, P. M. et al. Exploiting evolutionary principles to prolong tumor control in preclinical models of breast cancer. Sci. Transl. Med. 8, 327ra24 (2016).
pubmed: 26912903 pmcid: 4962860
West, J. et al. Towards multidrug adaptive therapy. Cancer Res. 80, 1578–1589 (2020).
pubmed: 31948939
Zhang, J., Cunningham, J. J., Brown, J. S. & Gatenby, R. A. Integrating evolutionary dynamics into treatment of metastatic castrate-resistant prostate cancer. Nat. Commun. 8, 1816 (2017).
pubmed: 29180633 pmcid: 5703947
Zhang, J., Fishman, M. N., Brown, J. S. & Gatenby, R. A. Integrating evolutionary dynamics into treatment of metastatic castrate-resistant prostate cancer (mCRPC): updated analysis of the adaptive abiraterone (abi) study (NCT02415621). J. Clin. Oncol. 37, 5041 (2019).
Zhao, B. et al. Exploiting temporal collateral sensitivity in tumor clonal evolution. Cell 165, 234–246 (2016).
pubmed: 26924578 pmcid: 5152932
Lin, K. H. et al. Using antagonistic pleiotropy to design a chemotherapy-induced evolutionary trap to target drug resistance in cancer. Nat. Genet. 52, 408–417 (2020).
pubmed: 32203462
Anderson, A. R. & Quaranta, V. Integrative mathematical oncology. Nat. Rev. Cancer 8, 227–234 (2008).
pubmed: 18273038
Sharp, J. A. et al. Designing combination therapies using multiple optimal controls. J. Theor. Biol. 497, 110277 (2020).
pubmed: 32294472
Gluzman, M., Scott, J. G. & Vladimirsky, A. Optimizing adaptive cancer therapy: dynamic programming and evolutionary game theory. Proc. Biol. Sci. 287, 20192454 (2020).
pubmed: 32315588
Lind, P. A., Libby, E., Herzog, J. & Rainey, P. B. Predicting mutational routes to new adaptive phenotypes. eLife 8, e38822 (2019).
pubmed: 30616716 pmcid: 6324874
Rozenblatt-Rosen, O. et al. The Human Tumor Atlas Network: charting tumor transitions across space and time at single-cell resolution. Cell 181, 236–249 (2020).
pubmed: 32302568
Metzcar, J., Wang, Y., Heiland, R. & Macklin, P. A review of cell-based computational modeling in cancer biology. JCO Clin. Cancer Inform. 3, 1–13 (2019).
pubmed: 30715927

Auteurs

Nastaran Zahir (N)

Division of Cancer Biology, National Cancer Institute, Rockville, MD, USA.

Ruping Sun (R)

Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.

Daniel Gallahan (D)

Division of Cancer Biology, National Cancer Institute, Rockville, MD, USA.

Robert A Gatenby (RA)

Departments of Radiology and Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

Christina Curtis (C)

Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. cncurtis@stanford.edu.
Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, CA, USA. cncurtis@stanford.edu.
Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. cncurtis@stanford.edu.

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