The transcription factor FOSL1 is upregulated in human and mouse CCA, and is independently associated with patient survival. Genetic FOSL1 inhibition impairs cell proliferation and cell cycle progression in vitro, and tumor initiation and maintenance in vivo.The mevalonate pathway gene HMGCS1 is upregulated in human and mouse CCA, and its expression is controlled by direct FOSL1 promoter binding.Genetic HMGCS1 abrogation or pharmacological blockade with mTOR inhibitors phenocopies loss of FOSL1.
Locoregional failure (LRF) in breast cancer patients post-surgery and post-irradiation (IR) is linked to a dismal prognosis. In a refined new model, we identified Enpp1 (Ectonucleotide pyrophosphatase /phosphodiesterase 1/CD203a) to be closely associated with LRF. Enpp1 high circulating tumor cells (CTC) contribute to relapse by a self-seeding mechanism. This process requires the infiltration of PMN-MDSC and neutrophil extracellular traps (NET) formation. Genetic and pharmacological Enpp1 inhibition or NET blockade extend relapse-free survival. Furthermore, in combination with fractionated irradiation (FD), Enpp1 abrogation obliterates LRF.Mechanistically, Enpp1-generated adenosinergic metabolites enhance Haptoglobin (Hp) expression.This inflammatory mediator elicits myeloid invasiveness and promotes NET formation. Accordingly, a significant increase in ENPP1 and NET formation is detected in relapsed human breast cancer tumors. Moreover, high ENPP1 or HP levels are associated with poor prognosis. These findings unveil the ENPP1/HP axis as an unanticipated mechanism exploited by tumor cells linking inflammation to immune remodeling favoring local relapse.
ENPP1 (Ecto-nucleotide pyrophosphatase/ phosphodiesterase) participates in the hydrolysis of different purine nucleotides in an array of physiological processes. However, ENPP1 is frequently overexpressed in local relapses, and tumor metastases, which associates with poor prognosis and survival in a range of solid tumors. ENPP1 promotes an immunosuppressive tumor microenvironment (TME) by tilting the balance of ATP/Adenosine (Ado) in conjunction with other components (CD38, CD39/ENTPD1 and CD73/NT5E). Moreover, ENPP1 intersects the stimulator of interferon genes (STING), impairing its robust immune response through the hydrolysis of the effector 2´,3´-cyclic-GMP-AMP (cGAMP). Thus, ENPP1 blockade emerges as a unique target eliciting immune remodeling and leveraging the STING pathway. Several ENPP1 inhibitors have shown an immunostimulatory effect and their combination with other therapeutic modalities such as immune checkpoint blockade (ICB), STING activation, DNA damage response (DDR) inhibitors and radiotherapy (RT), represents a promising avenue to boost anti-tumor immune responses and to improve current clinical outcomes in several tumors. This comprehensive review summarizes the current state-of-the art and opens new perspectives for novel treatment strategies.
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