Grana-Castro, O. | Search bioRxiv

bioRxiv2019

The GATA3 X308_Splice breast cancer mutation is a hormone context-dependent oncogenic driver

As the catalogue of oncogenic driver mutations is expanding, it is becoming clear that alterations in a given gene should not be lumped into one single class, since they might have different functions. The transcription factor GATA3 is a paradigm of this. Here, we address the functions of the most common GATA3 mutation (X308_Splice) which generates a neoprotein that we designate as neoGATA3, associated with good patient prognosis. Based on extensive analyses of molecular and clinical data from approximately 3000 breast cancer patients, supported by mechanistic studies in vitro, we show that neoGATA3 interferes with the transcriptional programs controlled by estrogen and progesterone receptors, without fully abrogating them. This has opposite outputs in the pre- or post-menopausal hormonal context, having pro- or anti-proliferative effects, respectively. NeoGATA3 is an example of a context- and stage-dependent driver mutation. Our data call for functional analyses of putative cancer drivers to guide clinical application.

cancer biology↗

bioRxiv2019

Dynamic interactions of lymphatic vessels at the hair follicle stem cell niche during hair regeneration

Lymphatic vessels (LV) are essential for skin fluid homeostasis and immune cell trafficking, but whether LV are associated with hair follicle (HF) regeneration is not known. Here, by using steady and live imaging approaches in mouse skin, we show that lymphatic capillaries distribute to the anterior permanent region of individual HF and interconnect neighboring HF at the level of the HF bulge, in a hair follicle stem cell (HFSC)-dependent manner. LV further connect individual HF in triads and dynamically flow across the skin. Interestingly, at the onset of the physiological HFSC activation, or upon pharmacological or genetic induction of HF growth, LV transiently expand their caliber suggesting an increased tissue drainage capacity. Interestingly, the physiological LV caliber increase is associated with a distinct gene expression correlated to ECM and cytoskeletal reorganization. Using mouse genetics, we show that the depletion of LV blocks the pharmacological induction of HF growth. Our findings define LV as components of the HFSC niche, coordinating HF connections at tissue-level, and provide insight into their functional contribution to HF regeneration.

cell biology↗