GSE132215
The secretome of skin cancer cells activates the mTOR/MYC pathway in healthy keratinocytes and converts them into tumorigenic cells
Cutaneous squamous cell carcinoma (cSCC) is the most aggressive tumor among non-melanoma skin cancers (NMSC), showing a high potential for local invasion and metastasis. In recent years, the incidence of cSCC has increased tremendously due to increased UV exposure. The secretome of cancer cells is currently the focus of many studies in order to identify new marker proteins for different types of cancer and to investigate its influence on the tumor microenvironment. In our study we evaluated whether the secretome of cSCC cells has an impact on keratinocytes, the surrounding tissue cells of cSCC. Therefore, we analyzed and compared the secretome of human A431 cancer cells and of HaCaT keratinocytes by mass spectrometry. In a second experiment, keratinocytes were exposed to the secretome of A431 cells and the transcriptome was analyzed by next-generation sequencing. Several proto-oncogenes including MYC and EGFR were up-regulated and tumor suppressor genes such as CDKN2A and TP53 were down-regulated in keratinocytes treated with A431 conditioned medium (CM). HaCaT cells incubated with A431-CM revealed a significantly activated mTOR pathway with a concomitant increase in proliferation and migration. In contrast, the inhibition of mTOR by rapamycin led to a decreased proliferation- and migration-rate of A431-CM treated keratinocytes, which demonstrated the relevance of the mTOR complex in these processes. In conclusion, our data demonstrate the impact of the secretome of cancer cells on the transcription machinery of the cells surrounding the tumor, leading to a tumorigenic cell fate. These observations underline the influence of mTOR on cSCC and might bear significance for novel strategies in cancer therapy. Overall design: Overall 12 samples were analyzed: two cell lines (A431, HACAT) with 1 treatment and 1 control and 3 replicates per condition.