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

Fatima Valdes-Mora, et al.

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Sep 13, 2019

Received Date: 26th August 19

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, Neblina Sikta, Seán I. O’Donoghue, Thomas Cox, Paul Timpson, Christopher J. Ormandy and David Gallego-Ortega

Both luminal and basal breast cancer subtypes originate in the mammary luminal progenitor cell compartment. Basal breast cancer is associated with younger age, early relapse, and high mortality rate. Here we used unbiased droplet-based single-cell RNAseq to elucidate the cellular basis of tumour progression during the specification of the basal breast cancer subtype from the luminal progenitor population. Basal–like cancer cells resembled the alveolar lineage that is specified upon pregnancy and showed molecular features indicative of an interaction with the tumour microenvironment (TME) including EMT, hypoxia, lactation and involution. Involution signatures in luminal breast cancer tumours with alveolar lineage features were associated with worse prognosis and features of basal breast cancer. Our high-resolution molecular characterisation of the tumour ecosystem also revealed a highly interactive cell-cell network reminiscent of an involution process. This involution mimicry involves malignant education of cancer-associated fibroblasts and myeloid cell recruitment to support tissue remodelling and sustained inflammation. Our study shows how luminal breast cancer acquires a post-lactation developmental program to shift molecular subtype and promote tumour progression, with potential to explain the increased risk of cancer during the post-partum period.

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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

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