Schwarz Franziska M, Schniewind Iñaki, Besso Maria J, Lange Steffen, Linge Annett, Patil Shivaprasad G, Löck Steffen, Klusa Daria, Dietrich Antje, Voss-Böhme Anja, Nowrouzi Ali, Krause Mechthild, Dubrovska Anna, Kurth Ina, Peitzsch Claudia
Institute of Radiooncology - OncoRay, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany.
OncoRay - National Center for Radiation Research in Oncology, National Center for Radiation Oncology (NCRO), Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.
Mol Cancer Res. 2022 May 4;20(5):794-809. doi: 10.1158/1541-7786.MCR-21-0806.
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 current study, we analyzed irradiation-induced plasticity within the aldehyde dehydrogenase (ALDH)-positive (ALDH+) population in prostate cancer. The radiosensitivity of xenograft tumors derived from ALDH+ and ALDH-negative (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 10 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 with ALDH- cells. Phenotypic conversion and clonal competition were analyzed with fluorescence protein-labeled cells to distinguish cellular origins in competitive three-dimensional 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 prostate cancer cells and may be responsible for radiotherapy failure.
The increase of ALDH+ cells with stem-like features in prostate xenograft tumors after local irradiation represents a putative cellular escape mechanism inducing tumor radioresistance.
肿瘤异质性和细胞可塑性是由癌症干细胞（CSC）群体驱动的肿瘤进展、转移扩散和治疗反应的关键决定因素。在本研究中，我们分析了前列腺癌中醛脱氢酶（ALDH）阳性（ALDH+）群体内辐射诱导的可塑性。通过局部肿瘤控制分析确定了源自ALDH+和ALDH阴性（ALDH-）细胞的异种移植肿瘤的放射敏感性，并证明了不同的剂量反应曲线、复发时间和粘着斑信号传导。通过多重基因表达分析在10个DU145和PC3细胞群体中分析转录异质性，结果表明ALDH+群体内的异质性程度更高，与ALDH-细胞相比，辐射后这种异质性甚至会增加。使用荧光蛋白标记的细胞分析表型转化和克隆竞争，以区分竞争性三维培养物和异种移植肿瘤中的细胞来源。我们发现，ALDH+群体在竞争中胜过ALDH-细胞并驱动肿瘤生长，尤其是在辐射后。通过结合细胞可塑性、克隆竞争和表型特异性放射敏感性的概率马尔可夫区室模型再现了肿瘤照射前后体内ALDH+和ALDH-细胞之间细胞状态组成的观察动态。转录分析表明，在治疗压力下异种移植肿瘤内从ALDH-细胞向ALDH+细胞的细胞转化部分是通过转录抑制因子SNAI2的诱导介导的。总之，辐射诱导的细胞转化事件存在于源自前列腺癌细胞的异种移植肿瘤中，可能是放疗失败的原因。
局部照射后前列腺异种移植肿瘤中具有干细胞样特征的ALDH+细胞增加代表了一种可能的诱导肿瘤放射抗性的细胞逃逸机制。
