Dataset Information

Integrated analyses of murine breast cancer models reveal critical parallels with human disease.

ABSTRACT: Mouse models have an essential role in cancer research, yet little is known about how various models resemble human cancer at a genomic level. Here, we complete whole genome sequencing and transcriptome profiling of two widely used mouse models of breast cancer, MMTV-Neu and MMTV-PyMT. Through integrative in vitro and in vivo studies, we identify copy number alterations in key extracellular matrix proteins including collagen 1 type 1 alpha 1 (COL1A1) and chondroadherin (CHAD) that drive metastasis in these mouse models. In addition to copy number alterations, we observe a propensity of the tumors to modulate tyrosine kinase-mediated signaling through mutation of phosphatases such as PTPRH in the MMTV-PyMT mouse model. Mutation in PTPRH leads to increased phospho-EGFR levels and decreased latency. These findings underscore the importance of understanding the complete genomic landscape of a mouse model and illustrate the utility this has in understanding human cancers.

SUBMITTER: Rennhack JP

PROVIDER: S-EPMC6646342 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Integrated analyses of murine breast cancer models reveal critical parallels with human disease.

Rennhack Jonathan P JP To Briana B Swiatnicki Matthew M Dulak Caleb C Ogrodzinski Martin P MP Zhang Yueqi Y Li Caralynn C Bylett Evan E Ross Christina C Szczepanek Karol K Hanrahan William W Jayatissa Muthu M Lunt Sophia Y SY Hunter Kent K Andrechek Eran R ER

Nature communications 20190722 1

Mouse models have an essential role in cancer research, yet little is known about how various models resemble human cancer at a genomic level. Here, we complete whole genome sequencing and transcriptome profiling of two widely used mouse models of breast cancer, MMTV-Neu and MMTV-PyMT. Through integrative in vitro and in vivo studies, we identify copy number alterations in key extracellular matrix proteins including collagen 1 type 1 alpha 1 (COL1A1) and chondroadherin (CHAD) that drive metastas ...[more]

PMID: 31332182

Similar Datasets

Project description:Niemann-Pick Type C (NPC) disease is a rare, genetic, lysosomal disorder with progressive neurodegeneration. Poor understanding of the pathophysiology and a lack of blood-based diagnostic markers are major hurdles in the treatment and management of NPC and several additional, neurological lysosomal disorders. To identify disease severity correlates, we undertook whole genome expression profiling of sentinel organs, brain, liver, and spleen of Balb/c Npc1(-/-) mice relative to Npc1(+/-) at an asymptomatic stage, as well as early- and late-symptomatic stages. Unexpectedly, we found prominent up regulation of innate immunity genes with age-dependent change in their expression, in all three organs. We shortlisted a set of 12 secretory genes whose expression steadily increased with age in both brain and liver, as potential plasma correlates of neurological and/or liver disease. Ten were innate immune genes with eight ascribed to lysosomes. Several are known to be elevated in diseased organs of murine models of other lysosomal diseases including Gaucher's disease, Sandhoff disease and MPSIIIB. We validated the top candidate lysozyme, in the plasma of Npc1(-/-) as well as Balb/c Npc1(nmf164) mice (bearing a point mutation closer to human disease mutants) and show its reduction in response to an emerging therapeutic. We further established elevation of innate immunity in Npc1(-/-) mice through multiple functional assays including inhibition of bacterial infection as well as cellular analysis and immunohistochemistry. These data revealed neutrophil elevation in the Npc1(-/-) spleen and liver (where large foci were detected proximal to damaged tissue). Together our results yield a set of lysosomal, secretory innate immunity genes that have potential to be developed as pan or specific plasma markers for neurological diseases associated with lysosomal storage and where diagnosis is a major problem. Further, the accumulation of neutrophils in diseased organs (hitherto not associated with NPC) suggests their role in pathophysiology and disease exacerbation.

Dataset Information

Integrated analyses of murine breast cancer models reveal critical parallels with human disease.

Publications

Integrated analyses of murine breast cancer models reveal critical parallels with human disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets