Biology subjects

Blaas, L.

Publications and source records attributed to Blaas, L..

3 recordsLinked to original sources

bioRxiv2024

Tumour-derived LAMA5 is critical for tumour initiation and controls progression and phenotype in luminal breast cancer

Basement membrane (BM) supports and regulates the structural integrity, function and differentiation of epithelial tissues and protects against breast cancer invasion to stroma. Here we show that the BM component LAMA5 is critical for initiation of luminal mammary tumours, and controls tumour progression and phenotype development. LAMA5 is overexpressed in human breast carcinomas and LAMA5 downregulation attenuates growth of human breast cancer cells. Prepubertal luminal deletion of Lama5 in MMTV-PyMT mice results in marked reduction in emergence of early hyperplasias, along with a shift towards luminal progenitor-like phenotype. However, single allele deletion, but not biallelic deletion of Lama5 inhibits growth and progression towards advanced mammary carcinomas. Lama5 deficient luminal epithelial cells collectively display widespread alterations in Fibroblast growth factor (Fgf) signalling genes, including increased expression of Fgf receptor 2 (Fgfr2). Inhibition of Fgf receptors decreases growth and induces apoptosis also in biallelic-Lama5-deleted organoids without affecting wildtype organoids. Our results demonstrate a critical role for the BM component LAMA5 in mammary tumour initiation and reveal mechanisms of ECM-epithelial interplay in breast tumour progression and phenotype maintenance.

cancer biology↗

bioRxiv2019

Laminin alpha 5 is Necessary for Mammary Epithelial Growth and Function by Maintaining Luminal Epithelial Cell Identity

Epithelial attachment to the basement membrane (BM) is essential for mammary gland development, yet the exact roles of specific BM components remain unclear. Here, we demonstrate that expression of distinct laminin -isoforms by luminal and basal mammary epithelial cells enforces lineage identity that is necessary for normal mammary gland growth and function. Laminin 5 (LM5) is mainly expressed by the luminal epithelial cells, and it is necessary for pubertal mammary gland growth, pregnancy induced gland remodeling, and for alveolar function. Adhesion to LM5 containing laminin promotes luminal traits in both luminal and basal epithelial cells, and reduces progenitor activity of basal epithelial cells. Mechanistically, we show that Lama5 loss interferes with differentiation of hormone receptor positive luminal cells, which results in reduced Wnt4 expression and defective crosstalk between luminal and basal epithelial cells during gland remodeling. Our results reveal a novel BM-mediated mechanism, which regulates mammary gland remodeling and function via specification of luminal epithelial cells.

cell biology↗

bioRxiv2016

Mice deficient of Myc super-enhancer region reveal a differential control mechanism between normal and pathological growth

The gene desert upstream of the Myc oncogene on chromosome 8q24 contains susceptibility loci for several major forms of human cancer, including cancers of breast, prostate, and colon. The region shows high conservation between human and mouse and contains multiple MYC enhancers that are activated in tumor cells. However, the role of this region in normal development has not been addressed. Here we show that a 538 kb deletion of the entire MYC upstream super-enhancer region in mice results in 50 to 80% decrease in MYC expression in multiple tissues. The mice are viable and show no overt phenotype. However, they are resistant to tumorigenesis, and most normal cells isolated from them grow slowly in culture. Consistently, deletion of the 8q24 super-enhancer region perturbs Myc targets only in cultured cells, but not in vivo. These results reveal that only cells whose Myc activity is increased by serum or oncogenic driver mutations depend on the 8q24 super-enhancer region, and indicate that targeting the activity of this element is a promising strategy of cancer chemoprevention and therapy.

cancer biology↗