Biology subjects

Santoro, M. M.

Publications and source records attributed to Santoro, M. M..

3 recordsLinked to original sources

bioRxiv2026

THERAPY RESISTANCE IN MELANOMA DRIVES CILIOGENESIS AND GLUTAMINE/ASPARTATE METABOLISM DEPENDENCY

Despite the remarkable success of new therapeutic approaches, a considerable number of melanoma patients still relapse on conventional therapies within two years and develop resistance. Alterations in metabolism, including amino acid availability and regulation of metabolic processes, have been implicated in acquired drug resistance. In this study, we developed in vitro and in vivo models of target therapy resistance (TTR) and identified a translational program that supports primary ciliogenesis in drug-resistant BRAF melanoma. We established that drug resistance enhances primary ciliogenesis, which is needed to respond and survive to combination therapy (CT). Mechanistically, impairing cilia formation (IFT88KO) rewires glutamine and aspartate metabolism. Overall, we provide a new molecular mechanism underlying therapy resistance that should be considered to tailored therapeutic strategies.

cancer biology↗

bioRxiv2023

Sclerotome-derived vascular smooth muscle progenitors contribute to the hematopoietic stem cell specification niche

Haematopoietic stem cells (HSCs) are the self-renewing progenitors that continuously populate the haemato-immune cell lineages throughout life, and constitute the therapeutic component of bone marrow transplants. A major biomedical goal has been to understand the native specification of HSCs during embryonic development as a means to inform in vitro directed differentiation of pluripotent stem cells. Across vertebrate phyla, HSCs derive from haemogenic endothelium in the ventral floor of the primitive dorsal aorta (DA), also known as the descending aorta in mammals. Competent HSC-fated cells in the endothelium likely receive instructive signaling from neighbouring cells that constitute a "specification niche." We previously showed that experimental manipulations leading to defects in the most ventral compartment of the somite, the sclerotome, are correlated with HSC defects, raising the possibility that sclerotome patterning is required for HSC specification. Here we show that in zebrafish, specific sclerotome-derived cells contact the DA immediately prior to the emergence of HSCs. These cells subsequently give rise to vascular smooth muscle cells (VSMCs). When sclerotome patterning is disrupted, VSMCs are diminished, and HSC specification fails. We conclude that sclerotome-derived VSMC progenitors contribute to the embryonic HSC specification niche, most likely by providing unknown HSC inductive signals.

developmental biology↗

bioRxiv2020

Latrophilin 2 controls vascular morphogenesis and function by inhibiting endothelial cell adhesion and YAP/TAZ mechanosignaling

Dynamic modulation of endothelial cell-to-cell and cell-to-extracellular matrix (ECM) adhesion is essential for blood vessel patterning and functioning. Yet, the molecular mechanisms involved in this process have not been completely deciphered. We identify the adhesion G protein-coupled receptor (ADGR) Latrophilin 2 (LPHN2) as a novel determinant of endothelial cell (EC) adhesion and barrier function. In cultured ECs, endogenous LPHN2 localizes at ECM contacts, signals through cAMP/Rap1, and inhibits focal adhesion (FA) formation and nuclear localization of YAP/TAZ transcriptional regulators, while promoting tight junction (TJ) assembly. ECs also express an endogenous LPHN2 ligand, fibronectin-leucine-rich transmembrane 2 (FLRT2), that prevents ECM-elicited EC behaviors in a LPHN2-dependent manner. Vascular ECs of lphn2a knock-out zebrafish embryos become abnormally stretched, display a hyperactive YAP/TAZ pathway, and lack proper intercellular TJs. Consistently, blood vessels are hyperpermeable and intravascularly injected cancer cells extravasate more easily in lphn2a null animals. Thus, LPHN2 ligands, such as FLRT2, may be therapeutically exploited to interfere with cancer metastatic dissemination. SUMMARYCamillo et al. show that the LPHN2 receptor, upon activation by FLRT2 ligand, inhibits focal adhesion formation and promotes tight junction assembly in endothelial cells. Blood vessels of lphn2a null animals are hyperpermeable and injected cancer cells extravasate more easily.

cell biology↗