Non-redundant roles of SOS1 and SOS2 RAS-GEFs in hepatocellular carcinoma and intestinal integrity
Andrea Olarte
Centro de Investigación del Cáncer (CSIC-Universidad de Salamanca)
SOS1 and SOS2 are ubiquitously expressed RAS guanine nucleotide exchange factors (RAS GEFs) that mediate signal transduction downstream of receptor tyrosine kinases. Despite their structural similarity, emerging evidence suggests that SOS1 and SOS2 exert distinct physiological and pathological functions. However, their specific contributions to metabolic homeostasis, tissue regeneration, and tumorigenesis remain poorly defined.
Our research reveals that SOS1 and SOS2 play non-redundant roles in maintaining systemic and tissue integrity. Using complementary in vivo models of hepatocellular carcinoma (HCC) induced by diethylnitrosamine (DEN) and hydrodynamic tail vein injection (HTVI), pharmacological SOS1 inhibition (BI-3406), and intestinal epithelial regeneration assays, we demonstrate that SOS1 functions as a major oncogenic driver in HCC, whereas SOS2 acts as a physiological brake that counterbalances SOS1-driven outputs. Genetic deletion or pharmacological inhibition of SOS1 markedly reduces hepatocellular carcinoma growth, metabolic rewiring, and ERK activation, while loss of SOS2 enhances lipid metabolism, inflammation, and proliferative signaling, thereby exacerbating tumor progression.
Beyond the liver, both SOS1 and SOS2 are essential for intestinal epithelial renewal, stem cell maintenance, and barrier function. Their combined disruption alters crypt architecture and induces systemic inflammation resembling sepsis, which can only be partially rescued through regenerative strategies such as organoid transplantation or growth-factor supplementation.
Together, these findings identify SOS1 and SOS2 as critical regulators of RAS-driven signaling networks that safeguard metabolic and epithelial homeostasis. Their imbalance leads to profound metabolic dysregulation, inflammatory stress, and enhanced tumorigenesis, highlighting the SOS1-SOS2 axis as a promising therapeutic target in cancer and tissue repair.