PacRim7 7th PacRim Meeting Poster Presentations (1) (52 abstracts)
Characterisation of developmental pathways that drive metastatic progression of breast cancer at single cell resolution
Fatima Valdes-Mora 1, , Robert Salomon 3, , Brian Gloss 5 , Andrew MK Law 5 , Kendelle Murphy 6 , Daniel L Roden 2, , Lesley Castillo 5, , Yolanda Colino-Sanguino 1 , Nona Farbehi 3 , James Conway 6 , Paul Timpson 2, , Christopher J Ormandy 2, & David Gallego-Ortega 2,
1Histone Variant Group, Genomics and Epigenetics Division, Garvan Institute of Medical Research. Sydney, NSW Australia; 2St. Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia; 3Garvan-Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research, Sydney, NSW, Australia; 4Current: Institute for Biomedical Materials and Devices, University of Technology Sydney, Sydney, NSW, Australia; 5Tumour Development Group, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW, Australia; 6Invasion and Metastasis Laboratory, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW, Australia; 7Cancer Biology Laboratory, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW, Australia.
Tumour cell heterogeneity constitutes a challenge for cancer treatment and deeply impact the outcome of patients. A simultaneous overview of cancer cells and associated stromal cells is critical for the design of improved therapeutic regimes. Single-cell RNA-seq has emerged as a powerful method to unravel heterogeneity of complex biological systems; this has enabled in vivo characterization of cell type compositions through unsupervised sampling and modelling of transcriptional states in single cells. Here we used single-cell RNA-seq to elucidate the cellular composition and functional diversity of breast tumours during the induction of metastatic disease. We characterised with unprecedented definition, how the activation of developmental programs associated to pregnancy results in the acquisition of an aggressive phenotype. We use a transgenic model of alveolar cell differentiation to manipulate the lineage composition of the mammary epithelium in the MMTV-PyMT mouse mammary tumour model. We showed that cancer cells are classified in a structure comparable with the lineages of the epithelial mammary gland hierarchy, revealing high dynamics and plasticity of cancer cells during disease progression. This cancer progression program is orchestrated by alveolar cells, which in conjunction with cancer-associated fibroblasts and myeloid cells form a multi-cellular process that resembles an aberrant involution. Finally, we analysed the interactome of the tumour ecosystem to define a high-resolution landscape of the molecular pathways of cell-to-cell communication that underpins extra-cellular remodelling and inflammation associated to the aggressive involution mimicry. Our study recapitulates developmental mechanisms that have gone awry during carcinogenesis in a model of pregnancy-associated breast cancer, revealing breast heterogeneity and key molecular events that result in cancer progression. scRNA-seq technology is generating a paradigm-shift in our understanding of cancer biology, the simultaneous observation of the different cell species involved in metastatic programs will contribute to the development of novel drug combinations and more specific cancer therapies.
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Oncology Abstracts
ISSN 2631-4657 (online)
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