Nat Commun: AP-1 and TGF beta co-mediate the resistance of non-classical Hedgehog signal transducting paths to induce substrate cell carcinoma.

Although cancer therapy targeting cancer genes has made great progress, the efficacy of monotherapy is limited by the heterogeneity of tumors.
skin substrate cell carcinoma (BCC) is one of the most common cancers in the United States, and because of its repeated exposure to ultraviolet light and high mutation burden, as well as easy access to clinical samples, BCC is an excellent model for tumor evolution and heterogeneity research.
previous studies have shown that BCC occurs due to the overactivation of the Hedgehog (Hh) signaling path, making it a promising candidate for targeted therapies.
, however, the initial response rate with SMO inhibitor therapy was only a disappointing 40 per cent, and the recurrence rate in the first year was 20 per cent.
LYPD3/TACSTD2/LY6D marker NMRTF subpopulation researchers in BCCs patients have previously discovered a cardiomyocrine-related transcription factor (nMRTF) drug-resistant pathline that amplifies atypical Gli1 activity, but the characteristics and drivers of nMRTF cell state are still unknown.
the transcription of RHoGEFs induced by AP-1 and Smad3, the researchers identified three prognostic surface markers (LYPD3, TACSTD2, and LY6D) associated with nMRTF and SMO inhibitor resistance by sequencing single-cell RNA in patient tumor tissue.
study found that the cell state of nMRTF is similar to that of hair follicle substation transfer-amplified cells in which AP-1 and TGF beta can co-drive nMRTF activation.
JNK/AP-1 signal can induce the transcription of RhoGEFs by combining chromatin openness with Smad3 pairs of DNA, ultimately facilitating the activation of nMRTF.
important, small molecule AP-1 inhibitors are able to selectively target LYPD3 plus/TACSTD2 plus/LY6D-nMRTF path, opening the way for improved combination therapy for the disease.
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