Megino, C. | Search bioRxiv

bioRxiv2024

Multiple endocrine defects in adult-onset Sprouty1/2/4 triple knockout mice

Genes of the Sprouty family (Spry1-4) are feedback inhibitors of receptor tyrosine kinases, especially of Ret and the FGF receptors. As such, they play distinct and overlapping roles in embryo morphogenesis and are considered to be tumor suppressors in adult life. Genetic experiments in mice have defined in great detail the role of these genes during embryonic development, however their function in adult mice is less clearly established. Here we generate adult-onset, whole body Spry1/2/4 triple knockout mice. Tumor incidence in triple mutant mice is comparable to that of wild type littermates of up to one year of age, indicating that Sprouty loss per se is not sufficient to initiate tumorigenesis. On the other hand, triple knockout mice do not gain weight as they age, show less visceral fat, and have lower plasma glucose levels than wild type littermates, despite showing similar food intake and slightly reduced motor function. They also show alopecia, eyelid inflammation, and mild hyperthyroidism. Finally, triple knockout mice present phosphaturia and hypophosphatemia, suggesting exacerbated signaling downstream of FGF23. In conclusion, triple knockout mice develop a series of endocrine abnormalities but do not show increased tumor incidence.

physiology↗

bioRxiv2022

ARID1A-deficient cells promote endometrial carcinoma progression and dissemination by reprograming tumor microenvironment.

AT-rich interactive domain-containing protein 1A (ARID1A) loss-of-function mutation accompanied by a loss of ARID1A protein expression is frequently observed in endometrial carcinomas (EC). However, the mechanisms underlying this loss of ARID1A involved in the progression and dissemination of EC have been poorly studied and understood. Tumor microenvironment (TME) is reprogramed by cancer cells and have a high influence in aggressive behaviours of solid tumors. TME, and specially the stromal component, has a clear impact on the progression and aggressiveness of EC, but little is known about its activation, signalling and functions. Thus, the main aim of this study was to analyse the role of EC ARID1A loss in TME reprograming and its implication in endometrial tumor progression and aggressiveness. Here, using different endometrial in vitro and in vivo models, we show that endometrial tumor cells with altered expression of ARID1A promote the modulation and activation of the TME. We demonstrate that ARID1A depleted endometrial tumor cells induce aggressive behaviour in neighbouring endometrial tumor cells with wild-type ARID1A expression and the recruitment and activation of endometrial stromal cells (ESC). Interestingly, these pro-tumoral signals spread through the bloodstream supporting ARID1A wild-type EC cells aggressiveness. Finally, we show that ARID1A altered tumor cells display a different secretion profile and express significative high levels of chemokines in the TME. Taken together, our data demonstrate ARID1A depleted endometrial tumor cells reprograms TME promoting progression and dissemination of EC through chemokine secretion.

cancer biology↗