Speaker: Alessia Centonze
PhD student Cedric Blanpain's Lab, Laboratory of Stem Cells and Cancer, Université Libre de Bruxelles (ULB), Belgium
Host: Alejo Rodríguez-Fraticelli
Node: Cell Pathophysiology / Preclinical Models of Cancer
Date: Wednesday 26 January 2022, 12.00h
Glandular epithelia including the mammary gland (MG) and the prostate glands are composed of basal cells (BCs) and luminal cells (LCs). Many glandular epithelia develop from multipotent basal stem cells (BSCs) that are replaced in adult life by distinct pools of unipotent stem cells. However, adult unipotent BSCs can reactivate multipotency in regenerative conditions and upon oncogene expression. This suggests that an active mechanism restricts BSC multipotency during physiological conditions. We show that the ablation of LCs reactivates BSC multipotency from multiple epithelia both in vivo in mice and in vitro in organoids. Bulk and single-cell RNA sequencing revealed that, after LC ablation, BSCs activate a hybrid basal and luminal cell differentiation program before giving rise to LCs. By predicting ligand-receptor pairs from single-cell data, we found that TNF, which is secreted by LCs, restricts BC multipotency under normal physiological conditions. By contrast, the Notch, Wnt and EGFR pathways were activated in BSCs and their progeny after LC ablation; blocking these pathways, or stimulating TNF pathway, inhibited regeneration-induced BC multipotency. Our study demonstrates that the communication between LCs and BCs is essential to maintain lineage fidelity in glandular epithelial stem cells.
We have described different conditions in which BSC are multipotent, the comparison of the upregulated genes in BC in these conditions revealed an important role of the extracellular matrix (ECM) in the regulation of BSC multipotency. Using organoids, we show that Col1 and ECM stiffness are key to promote the switch from unipotency to multipotency of BSCs. Using single-cell RNA sequencing analysis, we are studying the contribution of Col1-signalling and ECM stiffness in the mechanisms leading to multipotency activation. The functional validation of these results will uncover the role of stroma-epithelia communication in BSC multipotency regulation and by which mechanisms the ECM stiffness and composition is controlling cell behaviour. Altogether, this study will reveal the complex regulation of cell fate maintenance in glandular epithelia, which can be lost in pathological conditions, such as cancer.