The genomic landscape of metastasis in treatment-naïve breast cancer models
| Autor: | Maxwell P. Lee, Jack D. Sanford, Karol Szczepanek, Tinghu Qiu, Howard H. Yang, Kent W. Hunter, Christina Ross |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Cancer Research DNA Mutational Analysis QH426-470 medicine.disease_cause Somatic evolution in cancer Metastasis Fusion gene Mice Sequencing techniques 0302 clinical medicine Basic Cancer Research Breast Tumors Medicine and Health Sciences Copy-number variation Neoplasm Metastasis Exome Cells Cultured Genetics (clinical) Exome sequencing Mice Inbred BALB C 0303 health sciences Mammalian Genomics High-Throughput Nucleotide Sequencing RNA sequencing Genomics Animal Models Primary tumor Oncology Experimental Organism Systems Disease Progression Heterografts Female KRAS Research Article Mice Nude Mouse Models Breast Neoplasms Mice Transgenic Biology Research and Analysis Methods Models Biological Clonal Evolution 03 medical and health sciences Model Organisms Breast cancer Breast Cancer Exome Sequencing Genetics medicine Animals Humans Molecular Biology Ecology Evolution Behavior and Systematics 030304 developmental biology business.industry Biology and Life Sciences Cancers and Neoplasms Computational Biology Comparative Genomics Genome Analysis medicine.disease Genome Annotation Mice Inbred C57BL Disease Models Animal Molecular biology techniques HEK293 Cells Metastatic Tumors Animal Genomics Mutation Animal Studies Cancer research business Carcinogenesis 030217 neurology & neurosurgery |
| Zdroj: | PLoS Genetics, Vol 16, Iss 5, p e1008743 (2020) PLoS Genetics |
| ISSN: | 1553-7404 |
| DOI: | 10.1371/journal.pgen.1008743 |
| Popis: | Metastasis remains the principle cause of mortality for breast cancer and presents a critical challenge because secondary lesions are often refractory to conventional treatments. While specific genetic alterations are tightly linked to primary tumor development and progression, the role of genetic alteration in the metastatic process is not well-understood. The theory of tumor evolution postulated by Peter Nowell in 1976 has yet to be proven in the context of metastasis. Therefore, in order to investigate how somatic evolution contributes to breast cancer metastasis, we performed exome, whole genome, and RNA sequencing of matched metastatic and primary tumors from pre-clinical mouse models of breast cancer. Here we show that in a treatment-naïve setting, recurrent single nucleotide variants and copy number variation, but not gene fusion events, play key metastasis-driving roles in breast cancer. For instance, we identified recurrent mutations in Kras, a known driver of colorectal and lung tumorigenesis that has not been previously implicated in breast cancer metastasis. However, in a set of in vivo proof-of-concept experiments we show that the Kras G12D mutation is sufficient to significantly promote metastasis using three syngeneic allograft models. The work herein confirms the existence of metastasis-driving mutations and presents a novel framework to identify actionable metastasis-targeted therapies. Author summary The majority of breast cancer-associated deaths are due to metastatic disease, the process where cancerous cells leave the primary tumor and spread to a new location in the body, because metastatic tumors often become insensitive to the same therapies that were successful in treating the primary tumor. To date, this complex process has been attributed to dynamic changes in tumor cell gene expression regulated by epigenetic factors. Interestingly, while genomic alterations are accepted drivers of neoplastic transformation, it is unknown if such events contribute to metastatic spread. One reason for this is the limited availability of matched and treatment-naïve primary tumor and metastatic tumor samples from patients for comparative genomic testing. Here we use two pre-clinical mouse models of metastatic breast cancer to test if genomic alterations can drive metastatic capacity. We identified metastasis-specific events of single nucleotide variation and gene amplification in well-known oncogenic genes, as well as lesser known factors. We also show that expression of these mutant factors can drive metastasis of weakly and non-metastatic mouse mammary cancer cell lines when implanted in mice. Crucially, by observing and reporting this untested etiology of metastatic disease, specific genomic events can now be included in efforts to develop targets for metastasis-specific therapies. |
| Databáze: | OpenAIRE |
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