The genomic landscape of metastasis in treatment-naïve breast cancer models

Abstract

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.

Insights from transgenic mouse models of PyMT-induced breast cancer: recapitulating human breast cancer progression in vivo

“…While these tumors maintain their diploid status, amplifications and deletions have been reported [13]. For example, amplifications of chromosome 11 are common in these tumors [13][14][15][16][17]. Chromosome 11 is orthologous to chromosome 17 in humans, which is commonly amplified and associated with increased PI3K activity due to amplification of the ErbB2 locus [15][16][17][18].…”

“…Several subsequent studies revealed that the expression of the PyMT oncogene is coupled to additional biochemical and genetic events that drive tumorigenesis and metastasis [ 12 ]. To that end, genomic analysis and whole exome sequencing was performed on the arising tumors [ 13 , 14 ]. While these tumors maintain their diploid status, amplifications and deletions have been reported [ 13 ].…”

“…Although less common, deletions have been detected in chromosome 4, which codes for several tumor suppressors [ 13 , 15 ]. Single nucleotide variants and activating mutations were detected through whole-exome studies and were found to be very common in naïve PyMT tumors and drive tumor progression and metastasis [ 14 ]. Moreover, whole genome sequencing detected several mutations in PyMT tumors [ 19 ].…”

Metastasis-Specific Gene Expression in Autochthonous and Allograft Mouse Mammary Tumor Models: Stratification and Identification of Targetable Signatures

“…These pathways were subsequently validated as key metastasis-modifying pathways in allograft transplantation models, using therapeutically relevant dosing schemas. These gene expression pathways are also enriched in lung metastases from three breast cancer patient-derived xenograft models generated by Alzubi and colleagues (29,42), providing further support of their relevance to human breast cancer metastasis. The molecular target of sildenafil, phosphodiesterase type 5 (PDE5) has been identified as a tumor biomarker in several human cancers (43,44), and work with human cancer cell lines has revealed that expression and activation of PDE5 stimulates invasive, migratory, and cancer stem cell phenotypes (44).…”

Methodological Advancements for Investigating Intra-tumoral Heterogeneity in Breast Cancer at the Bench and Bedside

“…A study that conducted WES of paired primary tumors and lung metastases from the MMTV-PyMT and MMTV - Her2 models identified metastasis-enriched and metastasis-specific mutations and CNAs in known oncogenes, including Kras. Orthotopic engraftment of cells expressing the Kras G12D mutation led to increased metastatic burden while knock down of Kras reduced metastasis to the lungs [ 126 ].…”