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Neural Network Deconvolution Method for Resolving Pathway-Level Progression of Tumor Clonal Expression Programs With Application to Breast Cancer Brain Metastases

Metastasis is the primary mechanism by which cancer results in mortality and there are currently no reliable treatment options once it occurs, making the metastatic process a critical target for new diagnostics and therapeutics. Treating metastasis before it appears is challenging, however, in part...

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Autores principales: Tao, Yifeng, Lei, Haoyun, Lee, Adrian V., Ma, Jian, Schwartz, Russell
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499245/
https://www.ncbi.nlm.nih.gov/pubmed/33013452
http://dx.doi.org/10.3389/fphys.2020.01055
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author Tao, Yifeng
Lei, Haoyun
Lee, Adrian V.
Ma, Jian
Schwartz, Russell
author_facet Tao, Yifeng
Lei, Haoyun
Lee, Adrian V.
Ma, Jian
Schwartz, Russell
author_sort Tao, Yifeng
collection PubMed
description Metastasis is the primary mechanism by which cancer results in mortality and there are currently no reliable treatment options once it occurs, making the metastatic process a critical target for new diagnostics and therapeutics. Treating metastasis before it appears is challenging, however, in part because metastases may be quite distinct genomically from the primary tumors from which they presumably emerged. Phylogenetic studies of cancer development have suggested that changes in tumor genomics over stages of progression often result from shifts in the abundance of clonal cellular populations, as late stages of progression may derive from or select for clonal populations rare in the primary tumor. The present study develops computational methods to infer clonal heterogeneity and dynamics across progression stages via deconvolution and clonal phylogeny reconstruction of pathway-level expression signatures in order to reconstruct how these processes might influence average changes in genomic signatures over progression. We show, via application to a study of gene expression in a collection of matched breast primary tumor and metastatic samples, that the method can infer coarse-grained substructure and stromal infiltration across the metastatic transition. The results suggest that genomic changes observed in metastasis, such as gain of the ErbB signaling pathway, are likely caused by early events in clonal evolution followed by expansion of minor clonal populations in metastasis, a finding that may have translational implications for early detection or prevention of metastasis.
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spelling pubmed-74992452020-10-02 Neural Network Deconvolution Method for Resolving Pathway-Level Progression of Tumor Clonal Expression Programs With Application to Breast Cancer Brain Metastases Tao, Yifeng Lei, Haoyun Lee, Adrian V. Ma, Jian Schwartz, Russell Front Physiol Physiology Metastasis is the primary mechanism by which cancer results in mortality and there are currently no reliable treatment options once it occurs, making the metastatic process a critical target for new diagnostics and therapeutics. Treating metastasis before it appears is challenging, however, in part because metastases may be quite distinct genomically from the primary tumors from which they presumably emerged. Phylogenetic studies of cancer development have suggested that changes in tumor genomics over stages of progression often result from shifts in the abundance of clonal cellular populations, as late stages of progression may derive from or select for clonal populations rare in the primary tumor. The present study develops computational methods to infer clonal heterogeneity and dynamics across progression stages via deconvolution and clonal phylogeny reconstruction of pathway-level expression signatures in order to reconstruct how these processes might influence average changes in genomic signatures over progression. We show, via application to a study of gene expression in a collection of matched breast primary tumor and metastatic samples, that the method can infer coarse-grained substructure and stromal infiltration across the metastatic transition. The results suggest that genomic changes observed in metastasis, such as gain of the ErbB signaling pathway, are likely caused by early events in clonal evolution followed by expansion of minor clonal populations in metastasis, a finding that may have translational implications for early detection or prevention of metastasis. Frontiers Media S.A. 2020-09-04 /pmc/articles/PMC7499245/ /pubmed/33013452 http://dx.doi.org/10.3389/fphys.2020.01055 Text en Copyright © 2020 Tao, Lei, Lee, Ma and Schwartz. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Physiology
Tao, Yifeng
Lei, Haoyun
Lee, Adrian V.
Ma, Jian
Schwartz, Russell
Neural Network Deconvolution Method for Resolving Pathway-Level Progression of Tumor Clonal Expression Programs With Application to Breast Cancer Brain Metastases
title Neural Network Deconvolution Method for Resolving Pathway-Level Progression of Tumor Clonal Expression Programs With Application to Breast Cancer Brain Metastases
title_full Neural Network Deconvolution Method for Resolving Pathway-Level Progression of Tumor Clonal Expression Programs With Application to Breast Cancer Brain Metastases
title_fullStr Neural Network Deconvolution Method for Resolving Pathway-Level Progression of Tumor Clonal Expression Programs With Application to Breast Cancer Brain Metastases
title_full_unstemmed Neural Network Deconvolution Method for Resolving Pathway-Level Progression of Tumor Clonal Expression Programs With Application to Breast Cancer Brain Metastases
title_short Neural Network Deconvolution Method for Resolving Pathway-Level Progression of Tumor Clonal Expression Programs With Application to Breast Cancer Brain Metastases
title_sort neural network deconvolution method for resolving pathway-level progression of tumor clonal expression programs with application to breast cancer brain metastases
topic Physiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499245/
https://www.ncbi.nlm.nih.gov/pubmed/33013452
http://dx.doi.org/10.3389/fphys.2020.01055
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