Conversion of prostate adenocarcinoma to small cell carcinoma-like by reprogramming

Abstract

The lineage relationship between prostate adenocarcinoma and small cell carcinoma was studied by using the LuCaP family of xenografts establishedfrom primary neoplasm to metastasis. Expression of four stem cell transcription factor (TF) genes, LIN28A, NANOG, POU5F1, SOX2, were analyzedin the LuCaP lines. These genes, when force expressed in differentiated cells, can reprogram the recipients into stem-like induced pluripotent stem(iPS) cells. Most LuCaP lines expressed POU5F1, while LuCaP 145.1, representative of small cell carcinoma, expressed all four. Through transcriptomedatabase query, many small cell carcinoma genes were also found in stem cells. To test the hypothesis that prostate cancer progression from“differentiated” adenocarcinoma to “undifferentiated” small cell carcinoma could involve re-expression of stem cell genes, the four TF genes weretransduced via lentiviral vectors into five adenocarcinoma LuCaP lines—70CR, 73CR, 86.2, 92, 105CR—as done in iPS cell reprogramming. Theresultant cells from these five transductions displayed a morphology of small size and dark appearing unlike the parentals. Transcriptome analysis ofLuCaP 70CR (“ ” to denote transfected progeny) revealed a unique gene expression close to that of LuCaP 145.1. In a prostate principal componentsanalysis space based on cell-type transcriptomes, the different LuCaP transcriptome datapoints were aligned to suggest a possible ordered sequence ofexpression changes from the differentiated luminal-like adenocarcinoma cell types to the less differentiated, more stem-like small cell carcinoma types,and LuCaP 70CR . Prostate cancer progression can thus be molecularly characterized by loss of differentiation with re-expression of stem cell genes.