Oral ENPP1 inhibitor designed using generative AI as next generation STING modulator for solid tumorse solid tumors
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1164192 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR30771512_1.fastq.gz | Fastqsanger.gz | |||
| SRR30771512_2.fastq.gz | Fastqsanger.gz | |||
| SRR30771514_1.fastq.gz | Fastqsanger.gz | |||
| SRR30771514_2.fastq.gz | Fastqsanger.gz |
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Project description:Through variation in the cancer cell and their immune infiltrates each tumor represents a unique problem, but therapeutic targets can be found in the shared features. Radiation therapy can change the interaction between the cancer cells and the stroma through release of innate adjuvants including the STING agonist cGAMP. Enpp1 is a phosphodiesterase that can be expressed by cancer cells and can degrade cGAMP. Enpp1 can therefore limit innate adjuvant availability following radiation therapy. We observed that many cancer cells lack Enpp1 expression, but that Enpp1 expression is retained in cells of the tumor stroma and this expression in the tumor stroma limits tumor control by radiation therapy. We demonstrate the efficacy of a novel Enpp1 inhibitor and show that this inhibitor improves tumor control by radiation even where the cancer cells lack Enpp1. We show that the mechanism requires STING and type I IFN receptor expression by non-cancer cells, and is dependent on CD8 T cells as a final effector mechanism of tumor control. This suggests that Enpp1 inhibition may be an effective partner for radiation therapy regardless of whether cancer cells express Enpp1, and identifies a novel therapeutic Enpp1 inhibitor suitable for combination therapies in immuno-oncology.
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Project description:ENPP1 expression correlates with poor prognosis in many cancers, and we previously discovered that ENPP1 is the dominant hydrolase of extracellular cGAMP: a cancer-cell-produced immunotransmitter that activates the anticancer STING pathway. However, ENPP1 has other catalytic activities and the molecular and cellular mechanisms contributing to its tumorigenic effects remain unclear. Here, using single cell RNA-seq (scRNA-seq), we show that ENPP1 overexpression drives primary tumor growth and metastasis by synergistically dampening extracellular cGAMP-STING mediated antitumoral immunity and activating immunosuppressive extracellular adenosine (eADO) signaling. In addition to cancer cells, stromal and immune cells in the tumor microenvironment (TME) also express ENPP1 which functions as a gate keeper to block cGAMP sensing in these cells. Enpp1 knockout in both cancer cells and normal tissues slowed primary tumor growth and prevented metastasis in an extracellular cGAMP- and STING-dependent manner. Lastly, an ENPP1 knock-in mutation that selectively abolishes ENPP1’s cGAMP hydrolysis activity phenocopied total ENPP1 knockout, demonstrating that restoration of paracrine cGAMP-STING signaling is the dominant anti-cancer mechanism of ENPP1 inhibition. In summary, selectively blocking ENPP1’s cGAMP hydrolysis activity is a promising therapeutic approach for treating cancer.
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Project description: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. Enpp1high 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.
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