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Single-cell RNAseq uncovers involution mimicry as an aberrant development pathway during breast cancer metastasis

View ORCID ProfileFatima Valdes-Mora, View ORCID ProfileRobert Salomon, View ORCID ProfileBrian Gloss, Andrew MK. Law, View ORCID ProfileKendelle Murphy, View ORCID ProfileDaniel L. Roden, View ORCID ProfileLesley Castillo, View ORCID ProfileYolanda Colino-Sanguino, View ORCID ProfileZoya Kikhtyak, View ORCID ProfileNona Farbehi, View ORCID ProfileJames RW. Conway, View ORCID ProfileSamantha R. Oakes, View ORCID ProfileThomas Cox, View ORCID ProfilePaul Timpson, View ORCID ProfileChristopher J. Ormandy, View ORCID ProfileDavid Gallego-Ortega
doi: https://doi.org/10.1101/624890
Fatima Valdes-Mora
Histone Variant Laboratory, Genomics and Epigenetics Division, Garvan Institute of Medical Research. Sydney, NSW AustraliaSt. Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, NSW, Australia
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  • ORCID record for Fatima Valdes-Mora
Robert Salomon
Garvan-Weizmann Centre for Cellular Genomics. Garvan Institute of Medical Research. Sydney, NSW, AustraliaInstitute for Biomedical Materials and Devices, University of Technology Sydney. Sydney, NSW, Australia
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Brian Gloss
Tumour Development Laboratory, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW Australia
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  • ORCID record for Brian Gloss
Andrew MK. Law
Tumour Development Laboratory, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW Australia
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Kendelle Murphy
Invasion and Metastasis Laboratory, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW Australia
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  • ORCID record for Kendelle Murphy
Daniel L. Roden
St. Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, NSW, AustraliaGarvan-Weizmann Centre for Cellular Genomics. Garvan Institute of Medical Research. Sydney, NSW, Australia
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Lesley Castillo
Tumour Development Laboratory, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW AustraliaCancer Biology Laboratory, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW Australia
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Yolanda Colino-Sanguino
Histone Variant Laboratory, Genomics and Epigenetics Division, Garvan Institute of Medical Research. Sydney, NSW Australia
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  • ORCID record for Yolanda Colino-Sanguino
Zoya Kikhtyak
Tumour Development Laboratory, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW Australia
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  • ORCID record for Zoya Kikhtyak
Nona Farbehi
Garvan-Weizmann Centre for Cellular Genomics. Garvan Institute of Medical Research. Sydney, NSW, Australia
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  • ORCID record for Nona Farbehi
James RW. Conway
Invasion and Metastasis Laboratory, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW Australia
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  • ORCID record for James RW. Conway
Samantha R. Oakes
St. Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, NSW, AustraliaCancer Biology Laboratory, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW Australia
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Thomas Cox
St. Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, NSW, AustraliaMatrix and Metastasis Laboratory, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW Australia
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Paul Timpson
St. Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, NSW, AustraliaInvasion and Metastasis Laboratory, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW Australia
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Christopher J. Ormandy
St. Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, NSW, AustraliaCancer Biology Laboratory, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW Australia
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David Gallego-Ortega
St. Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, NSW, AustraliaTumour Development Laboratory, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW Australia
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  • For correspondence: d.gallego@garvan.org.au
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Abstract

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 the high-throughput microfluidic-based single-cell RNA-seq method Drop-seq to elucidate the cellular composition and functional diversity of breast tumours during the induction of metastatic disease in a transgenic model related to pregnancy-associated breast cancer (PABC). We characterised with unprecedented definition, how the activation of developmental programs associated to pregnancy results in the acquisition of an aggressive phenotype. We show 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 milk secretory cells, that in conjunction with cell types from the tumour microenvironment (TME), including cancer-associated fibroblasts (CAFs), 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 with the aggressive involution mimicry.

In conclusion, our study recapitulates developmental mechanisms that have gone awry during carcinogenesis in a model of PABC. We provide a large-scale single-cell transcriptional landscape of breast tumours that allows unprecedented understanding of breast heterogeneity and deep analysis of key molecular events that result in cancer malignancy.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 03, 2019.
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Single-cell RNAseq uncovers involution mimicry as an aberrant development pathway during breast cancer metastasis
Fatima Valdes-Mora, Robert Salomon, Brian Gloss, Andrew MK. Law, Kendelle Murphy, Daniel L. Roden, Lesley Castillo, Yolanda Colino-Sanguino, Zoya Kikhtyak, Nona Farbehi, James RW. Conway, Samantha R. Oakes, Thomas Cox, Paul Timpson, Christopher J. Ormandy, David Gallego-Ortega
bioRxiv 624890; doi: https://doi.org/10.1101/624890
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Single-cell RNAseq uncovers involution mimicry as an aberrant development pathway during breast cancer metastasis
Fatima Valdes-Mora, Robert Salomon, Brian Gloss, Andrew MK. Law, Kendelle Murphy, Daniel L. Roden, Lesley Castillo, Yolanda Colino-Sanguino, Zoya Kikhtyak, Nona Farbehi, James RW. Conway, Samantha R. Oakes, Thomas Cox, Paul Timpson, Christopher J. Ormandy, David Gallego-Ortega
bioRxiv 624890; doi: https://doi.org/10.1101/624890

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