Biology subjects

Hunter, K.

Publications and source records attributed to Hunter, K..

3 recordsLinked to original sources

bioRxiv2018

Integrated sequence and gene expression analysis of mouse models of breast cancer reveals critical events with human parallels

Mouse models have an essential role in cancer research, yet little is known about how various models resemble human cancer at a genomic level. However, the shared genomic alterations in each model and corresponding human cancer are critical for translating findings in mice to the clinic. We have completed whole genome sequencing and transcriptome profiling of two widely used mouse models of breast cancer, MMTV-Neu and MMTV-PyMT. This genomic information was integrated with phenotypic data and CRISPR/Cas9 studies to understand the impact of key events on tumor biology. Despite the engineered initiating transgenic event in these mouse models, they contain similar copy number alterations, single nucleotide variants, and translocation events as human breast cancer. Through integrative in vitro and in vivo studies, we identified 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. Importantly this amplification is also found in 25% of HER2+ human breast cancer and is associated with increased metastasis. In addition to copy number alterations, we observed a propensity of the tumors to modulate tyrosine kinase mediated signaling through mutation of phosphatases. Specifically, we found that 81% of MMTV-PyMT tumors have a mutation in the EGFR regulatory phosphatase, PTPRH. Mutation in PTPRH led to increased phospho-EGFR levels and decreased latency. Moreover, PTPRH mutations increased response to EGFR kinase inhibitors. Analogous PTPRH mutations are present in lung cancer patients and together this data suggests that a previously unidentified population of human lung cancer patients may respond to EGFR targeted therapy. 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.

cancer biology↗

bioRxiv2018

Analysis of head and neck carcinoma progression reveals novel and relevant stage-specific genetic changes associated with immortalisation and malignancy.

Head and neck squamous cell carcinoma (HNSCC) is a widely prevalent cancer globally with high mortality and morbidity. We report here changes in the genomic landscape in the development of HNSCC from potentially premalignant lesions (PPOLS) to malignancy and lymph node metastases. Frequent likely pathological mutations are restricted to a relatively small set of genes including TP53, CDKN2A, FBXW7, FAT1, NOTCH1 and KMT2D; these arise early in tumour progression and are present in PPOLs with NOTCH1 mutations restricted to cell lines from lesions that subsequently progressed to HNSCC. The most frequent genetic changes are of consistent somatic copy number alterations (SCNA). The earliest SCNAs involved deletions of CSMD1 (8p23.2), FHIT (3p14.2) and CDKN2A (9p21.3) together with gains of chromosome 20. CSMD1 deletions or promoter hypermethylation were present in all of the immortal PPOLs and occurred at high frequency in the immortal HNSCC cell lines (promoter hypermethylation ~63%, hemizygous deletions ~75%, homozygous deletions ~18%). Forced expression of CSMD1 in the HNSCC cell line H103 showed significant suppression of proliferation (p=0.0053) and invasion in vitro (p=5.98X10-5) supporting a role for CSMD1 inactivation in early head and neck carcinogenesis. In addition, knockdown of CSMD1 in the CSMD1-expressing BICR16 cell line showed significant stimulation of invasion in vitro (p=1.82 x 10-5) but not cell proliferation (p=0.239). HNSCC with and without nodal metastases showed some clear differences including high copy number gains of CCND1, hsa-miR-548k and TP63 in the metastases group. GISTIC peak SCNA regions showed significant enrichment (adj P<0.01) of genes in multiple KEGG cancer pathways at all stages with disruption of an increasing number of these involved in the progression to lymph node metastases. Sixty-seven genes from regions with statistically significant differences in SCNA/LOH frequency between immortal PPOL and HNSCC cell lines showed correlation with expression including 5 known cancer drivers.\n\nLay SummaryCancers affecting the head and neck region are relatively common. A large percentage of these are of one particular type; these are generally detected late and are associated with poor prognosis. Early detection and treatment dramatically improve survival and reduces the damage associated with the cancer and its treatment. Cancers arise and progress because of changes in the genetic material of the cells. This study focused on identifying such changes in these cancers particularly in the early stages of development, which are not fully known. Identification of these changes is important in developing new treatments as well as markers of behaviour of cancers and also the early or premalignant lesions. We used a well-characterised panel of cell lines generated from premalignant lesions as well as cancers, to identify mutations in genes, and an increase or decrease in number of copies of genes. We mapped new and previously identified changes in these cancers to specific stages in the development of these cancers and their spread. We additionally report here for the first time, alterations in CSMD1 gene in early premalignant lesions; we further show that this is likely to result in increased ability of the cells to spread and possibly, multiply faster as well.

cancer biology↗

bioRxiv2018

RCD1 Coordinates Chloroplastic and Mitochondrial Electron Transfer through Interaction with ANAC Transcription Factors

Signaling from chloroplasts and mitochondria, both dependent on reactive oxygen species (ROS), merge at the nuclear protein RADICAL-INDUCED CELL DEATH1 (RCD1). ROS produced in the chloroplasts affect the abundance, thiol redox state and oligomerization of RCD1. RCD1 directly interacts in vivo with ANAC013 and ANAC017 transcription factors, which are the mediators of the ROS-related mitochondrial complex III retrograde signa and suppresses activity of ANAC013 and ANAC017. Inactivation of RCD1 leads to increased expression of ANAC013 and ANAC017-regulated genes belonging to the mitochondrial dysfunction stimulon (MDS), including genes for mitochondrial alternative oxidases (AOXs). Accumulating AOXs and other MDS gene products alter electron transfer pathways in the chloroplasts, leading to diminished production of chloroplastic ROS and increased protection of photosynthetic apparatus from ROS damage. RCD1-dependent regulation affects chloroplastic and mitochondrial retrograde signaling including chloroplast signaling by 3-phosphoadenosine 5-phosphate (PAP). Sensitivity of RCD1 to organellar ROS provides feedback control of nuclear gene expression.

plant biology↗