Mechanism Of GPRC5A Deficiency In Lung Tumorigenesis And Metastasis

Driver mutation is a key factor in tumorigenesis and an ideal therapeutic target.However,about half of lung cancer patients have no specific therapeutic schedule due to the lack of driver mutations.GPRC5A is a newly identified lung tumor suppressor gene which is widely suppressed in lung cancer patients.Gprc5a-ko mice can spontaneously develop lung cancers which show very similar pathogenesis and pathological characteristics to human lung cancers,indicating that Gprc5a-ko mouse is an ideal model for studying the mechanism of lung tumorigenesis and metastasis.Tumorigenesis and metastasis are complex and multi-step process.Tumor microenvironment or niche is the key factor of metastasis which can not only maintain the stemness of cancer cells,support the survival and development of metastatic cancer cells,but also enable cancer cells to evade immune surveillance through reprogramming.In the first part,we showed that lung metastasis,via tumor cells,was greatly increased in Gprc5a-ko mice compared to that in wild-type(WT)mice,which is associated with upregulated IL6 in tissue microenvironment,combined deletion of Il6 and Gprc5a almost completely eliminated lung metastasis in Gprc5a-ko/Il6-ko mice.Mechanistically,1)IL6/STAT3 signaling reprogrammed immune escape pathway in cancer cells,repression of STAT3 signaling in tumor cells endowed the susceptibility to T cell-mediated cytotoxicity;2)High level of IL6promoted the formation of pre-metastatic niche,induced the recruitment of myeloid derived suppressor cells(MDSC)and the polarization of type II macrophage,inhibited the infiltration of T cell and NK cell,and enabled cancer cells to evade host immunity.All of these can be reversed by knocking out IL6 or targeting IL6.Consistently,activated IL6/STAT3 was negatively correlated with CD8~+T cells infiltration in non-small cell lung cancer(NSCLC)patients.Therefore,IL6 plays a key role in lung metastasis by inducing the formation of pre-metastasis niche and immunosuppression.The cell-of-origin of lung cancer and related procedures are still unclear.In the second part,we found that the bronchoalveolar stem cell(BASC)of Gprc5a-ko mice exhibited greatly enhanced self-renewal,stemness,and dedifferentiation compared to WT,suggesting that KO-BASC is activated and is a potential cell-of-origin of lung cancer.Single-cell analysis showed that,the stem-related genes,EGFR and NF-?B signaling were highly upregulated in KO-BASC compared to WT-BASC.Meanwhile,inflammatory stimulation induced drastic expansion of KO-BASC compared to WT-BASC,blockade of NF-?B in pulmonary epithelial cells can significantly suppressed BASC expansion and almost abolished lung tumorigenesis.Therefore,the expansion of BASC and the occurrence of lung cancer depend on the activation of NF-?B signaling.In summary,with Gprc5a-ko mouse models,we found that:1)IL6/STAT3promotes lung metastasis by orchestrating pre-metastatic niche formation and immunosuppression;2)Gprc5a deficiency induces,via EGFR and NF-?B signaling,expansion of BASC,the cell-of-origin,for lung tumorigenesis.Our study provides a reasonable explanation for the role of GPRC5A in lung tumorigenesis and metastasis,and also provides a new opinion for the prevention and treatment of lung cancer.