Dataset Information

Defining Cancer Subpopulations by Adaptive Strategies Rather Than Molecular Properties Provides Novel Insights into Intratumoral Evolution.

ABSTRACT: Ongoing intratumoral evolution is apparent in molecular variations among cancer cells from different regions of the same tumor, but genetic data alone provide little insight into environmental selection forces and cellular phenotypic adaptations that govern the underlying Darwinian dynamics. In three spontaneous murine cancers (prostate cancers in TRAMP and PTEN mice, pancreatic cancer in KPC mice), we identified two subpopulations with distinct niche construction adaptive strategies that remained stable in culture: (i) invasive cells that produce an acidic environment via upregulated aerobic glycolysis; and (ii) noninvasive cells that were angiogenic and metabolically near-normal. Darwinian interactions of these subpopulations were investigated in TRAMP prostate cancers. Computer simulations demonstrated invasive, acid-producing (C2) cells maintain a fitness advantage over noninvasive, angiogenic (C3) cells by promoting invasion and reducing efficacy of immune response. Immunohistochemical analysis of untreated tumors confirmed that C2 cells were invariably more abundant than C3 cells. However, the C2 adaptive strategy phenotype incurred a significant cost due to inefficient energy production (i.e., aerobic glycolysis) and depletion of resources for adaptations to an acidic environment. Mathematical model simulations predicted that small perturbations of the microenvironmental extracellular pH (pHe) could invert the cost/benefit ratio of the C2 strategy and select for C3 cells. In vivo, 200 mmol/L NaHCO3 added to the drinking water of 4-week-old TRAMP mice increased the intraprostatic pHe by 0.2 units and promoted proliferation of noninvasive C3 cells, which remained confined within the ducts so that primary cancer did not develop. A 0.2 pHe increase in established tumors increased the fraction of C3 cells and signficantly diminished growth of primary and metastatic tumors. In an experimental tumor construct, MCF7 and MDA-MB-231 breast cancer cells were coinjected into the mammary fat pad of SCID mice. C2-like MDA-MB-231 cells dominated in untreated animals, but C3-like MCF7 cells were selected and tumor growth slowed when intratumoral pHe was increased. Overall, our data support the use of mathematical modeling of intratumoral Darwinian interactions of environmental selection forces and cancer cell adaptive strategies. These models allow the tumor to be steered into a less invasive pathway through the application of small but selective biological force. Cancer Res; 77(9); 2242-54. ©2017 AACR.

SUBMITTER: Ibrahim-Hashim A

PROVIDER: S-EPMC6005351 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Defining Cancer Subpopulations by Adaptive Strategies Rather Than Molecular Properties Provides Novel Insights into Intratumoral Evolution.

Ibrahim-Hashim Arig A Robertson-Tessi Mark M Enriquez-Navas Pedro M PM Damaghi Mehdi M Balagurunathan Yoganand Y Wojtkowiak Jonathan W JW Russell Shonagh S Yoonseok Kam K Lloyd Mark C MC Bui Marilyn M MM Brown Joel S JS Anderson Alexander R A ARA Gillies Robert J RJ Gatenby Robert A RA

Cancer research 20170301 9

Ongoing intratumoral evolution is apparent in molecular variations among cancer cells from different regions of the same tumor, but genetic data alone provide little insight into environmental selection forces and cellular phenotypic adaptations that govern the underlying Darwinian dynamics. In three spontaneous murine cancers (prostate cancers in TRAMP and PTEN mice, pancreatic cancer in KPC mice), we identified two subpopulations with distinct niche construction adaptive strategies that remain ...[more]

PMID: 28249898

Similar Datasets

Project description:BackgroundPorcine deltacoronavirus (PDCoV) is one of the emerging swine enteric coronaviruses (SECoVs), which has been widely prevalent in the North America and Asia. In addition to causing severe diarrhea in piglets, PDCoV also shows the potential to infect diverse host species, including calves, chickens, turkey poults, and humans. However, the clinical pathogenicity and genetic evolution of PDCoV is still not fully understood.ResultsHere, we recorded an outbreak of a novel recombinant PDCoV strain (CHN-HeN06-2022) in a large nursery fattening pig farm. Genomic analysis showed that the CHN-HeN06-2022 strain shared 98.3-98.7% sequence identities with the Chinese and American reference strains. To clarify the evolutionary relationships, phylogenetic analysis was performed using the PDCoV genome sequences available in the GenBank database. Based on genetic distance and geographical distribution, the phylogenetic tree clearly showed that all the PDCoV sequences could be divided into lineage 1 and lineage 2, which were further classified into sublineage 1.1 (Chinese strains), 1.2 (the North American strains), 2.1 (the Southeast Asian strains), and 2.2 (Chinese strains). Corresponding to the evolutionary tree, we found that, compared to lineage 1, lineage 2 strains usually contain a continuous 6-nt deletion in Nsp2 and a 9-nt deletion in Nsp3, respectively. Furthermore, recombination analysis suggested that the CHN-HeN06-2022 occurred segments exchange crossed Nsp2 and Nsp3 region between sublineage 1.1 and sublineage 2.1. Combined with previously reported recombinant strains, the highest recombination frequency occurred in Nsp2, Nsp3, and S gene. Additionally, we identified a total of 14 amino acid sites under positive selection in spike protein, most of which are located in the regions related with the viral attachment, receptor binding, and membrane fusion.ConclusionsTaken together, our studies provide novel insights into the genetic diversity and adaptive evolution of PDCoV. It would be helpful to the development of vaccine and potential antiviral agent.

Project description:Orchidaceae is the 3rd largest family of angiosperms, an evolved young branch of monocotyledons. This family contains a number of economically-important horticulture and flowering plants. However, the limited availability of genomic information largely hindered the study of molecular evolution and phylogeny of Orchidaceae. In this study, we determined the evolutionary characteristics of whole chloroplast (cp) genomes and the phylogenetic relationships of the family Orchidaceae. We firstly characterized the cp genomes of four orchid species: Cremastra appendiculata, Calanthe davidii, Epipactis mairei, and Platanthera japonica. The size of the chloroplast genome ranged from 153,629 bp (C. davidi) to 160,427 bp (E. mairei). The gene order, GC content, and gene compositions are similar to those of other previously-reported angiosperms. We identified that the genes of ndhC, ndhI, and ndhK were lost in C. appendiculata, in that the ndh I gene was lost in P. japonica and E. mairei. In addition, the four types of repeats (forward, palindromic, reverse, and complement repeats) were examined in orchid species. E. mairei had the highest number of repeats (81), while C. davidii had the lowest number (57). The total number of Simple Sequence Repeats is at least 50 in C. davidii, and, at most, 78 in P. japonica. Interestingly, we identified 16 genes with positive selection sites (the psbH, petD, petL, rpl22, rpl32, rpoC1, rpoC2, rps12, rps15, rps16, accD, ccsA, rbcL, ycf1, ycf2, and ycf4 genes), which might play an important role in the orchid species' adaptation to diverse environments. Additionally, 11 mutational hotspot regions were determined, including five non-coding regions (ndhB intron, ccsA-ndhD, rpl33-rps18, ndhE-ndhG, and ndhF-rpl32) and six coding regions (rps16, ndhC, rpl32, ndhI, ndhK, and ndhF). The phylogenetic analysis based on whole cp genomes showed that C. appendiculata was closely related to C. striata var. vreelandii, while C. davidii and C. triplicate formed a small monophyletic evolutionary clade with a high bootstrap support. In addition, five subfamilies of Orchidaceae, Apostasioideae, Cypripedioideae, Epidendroideae, Orchidoideae, and Vanilloideae, formed a nested evolutionary relationship in the phylogenetic tree. These results provide important insights into the adaptive evolution and phylogeny of Orchidaceae.

Dataset Information

Defining Cancer Subpopulations by Adaptive Strategies Rather Than Molecular Properties Provides Novel Insights into Intratumoral Evolution.

Publications

Defining Cancer Subpopulations by Adaptive Strategies Rather Than Molecular Properties Provides Novel Insights into Intratumoral Evolution.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets