Prostate cancer reprogramming and dedifferentiation into induced pluripotent stem cells

Abstract This research concerns the biology of prostate cancer to understand the mechanisms underlying prostate cancer dedifferentiation. Dedifferentiation leads to nonadenocarcinoma and small cell carcinoma. Compared to well-differentiated adenocarcinoma, poorly differentiated small cell carcinoma is highly aggressive and lethal, associated with advanced disease, particularly after treatment failure. The presence of prostate cancer-specific TMPRSS2-ERG fusion in both adenocarcinoma and small cell carcinoma of the same tumor cases suggests a direct lineage, which we have shown experimentally by reprogramming of adenocarcinoma cells. Small cell carcinoma is stem-like and expresses stem cell transcription factors (scTFs). More importantly, like stem cells, small cell carcinoma can be induced to differentiate with stromal factors such as PENK. This research will delineate how stromal signaling can reverse or prevent prostate cancer dedifferentiation. Our hypothesis also postulates that all cancer undergo dedifferentiation to a stem-like state characterized by scTF + B2Mlo, which is represented by small cell carcinoma. That small cell carcinoma of many different tumor types is indistinguishable from each other and lends support to this view of cancer dedifferentiation/reprogramming. Exome sequencing data revealed no single thematic pattern for small cell carcinoma such as a particularly high number of DNA mutations. This is similar to what was found by exome sequencing analysis of prostate LuCaP small cell carcinoma versus LuCaP adenocarcinoma. It means that the prostate small cell carcinoma phenotype is not because of a specific accumulation of genomic mutations over the disease course. Our understanding of cancer dedifferentiation and therapy based on cancer differentiation induced by stromal factors could lead to a better management of prostate cancer.