{'fraction_non_alphanumeric': 0.020602218700475437, 'fraction_numerical': 0.003169572107765452, 'mean_word_length': 6.04089219330855, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Plasticity within aldehyde dehydrogenase-positive cells determines prostate cancer radiosensitivity.

Tumor heterogeneity and cellular plasticity are key determinants of tumor progression, metastatic spread and therapy response driven by the cancer stem cell (CSC) population. Within the present study, we analyzed irradiation-induced plasticity within the aldehyde dehydrogenase (ALDH)-positive population in prostate cancer (PCa). The radiosensitivity of xenograft tumors derived from ALDH+ and ALDH- cells was determined with local tumor control analyses and demonstrated different dose-response profiles, time to relapse and focal adhesion signaling. The transcriptional heterogeneity was analyzed in pools of ten DU145 and PC3 cells with multiplex gene expression analyses and illustrated a higher degree of heterogeneity within the ALDH+ population that even increases upon irradiation in comparison to ALDH- cells. Phenotypic conversion and clonal competition were analyzed with fluorescence protein-labeled cells to distinguish cellular origins in competitive 3D cultures and xenograft tumors. We found that the ALDH+ population outcompetes ALDH- cells and drives tumor growth, in particular upon irradiation. The observed dynamics of the cellular state compositions between ALDH+ and ALDH- cells in vivo before and after tumor irradiation was reproduced by a probabilistic Markov compartment model that incorporates cellular plasticity, clonal competition and phenotype-specific radiosensitivities. Transcriptional analyses indicate that the cellular conversion from ALDH- into ALDH+ cells within xenograft tumors under therapeutic pressure was partially mediated through induction of the transcriptional repressor SNAI2. In summary, irradiation-induced cellular conversion events are present in xenograft tumors derived from PCa cells and may be responsible for radiotherapy failure.