Alshaker Heba, Hunter Ewan, Salter Matthew, Ramadass Aroul, Westra Willem, Winkler Mathias, Green Jayne, Akoulitchev Alexandre, Pchejetski Dmitri
School of Medicine, University of East Anglia, Norwich, United Kingdom.
Oxford BioDynamics Limited, Oxford, United Kingdom.
Front Oncol. 2022 Aug 19;12:990842. doi: 10.3389/fonc.2022.990842. eCollection 2022.
Three-dimensional chromosome loop conformations are powerful regulators of gene expression. These chromosome conformations can be detected both in tumour and in circulating cells and have significant disease biomarker potential. We have recently detected specific chromosome conformations in circulating cells of patients with prostate cancer (PCa) which were similar to ones found in their primary tumours, however, the possibility of horizontal transfer of chromosome conformations was not studied previously.
Human monocytes (U937) were co-cultured in Boyden chambers through 0.4 uM membrane with or without PC-3 human PCa cells or their conditioned media and a custom DNA microarray for 900,000 chromosomal loops covering all coding loci and non-coding RNA genes was performed on each part of the co-culture system.
We have detected 684 PC-3 cell-specific chromosome conformations across the whole genome that were absent in naïve monocytes but appeared in monocytes co-cultured with PC-3 cells or with PC-3-conditioned media. Comparing PC3-specific conformations to the ones we have previously detected in systemic circulation of high-risk PCa patients revealed 9 positive loops present in both settings.
Our results demonstrate for the first time a proof of concept for horizontal transfer of chromosome conformations without direct cell-cell contact. This carries high clinical relevance as we have previously observed chromatin conformations in circulating cells of patients with melanoma and PCa similar to ones in their primary tumours. These changes can be used as highly specific biomarkers for diagnosis and prognosis. Further studies are required to elucidate the specific mechanism of chromosome conformations transfer and its clinical significance in particular diseases.
三维染色体环构象是基因表达的有力调节因子。这些染色体构象在肿瘤细胞和循环细胞中均可检测到，具有作为重要疾病生物标志物的潜力。我们最近在前列腺癌（PCa）患者的循环细胞中检测到了特定的染色体构象，这些构象与在其原发肿瘤中发现的构象相似，然而，此前尚未研究染色体构象水平转移的可能性。
将人单核细胞（U937）通过0.4μm的膜在Boyden小室中与PC-3人前列腺癌细胞或其条件培养基共培养，并对共培养系统的每个部分进行定制的DNA微阵列检测，该微阵列可覆盖900,000个染色体环，涵盖所有编码基因座和非编码RNA基因。
我们在全基因组中检测到684种PC-3细胞特异性染色体构象，这些构象在未处理的单核细胞中不存在，但在与PC-3细胞或PC-3条件培养基共培养的单核细胞中出现。将PC3特异性构象与我们之前在高危PCa患者的体循环中检测到的构象进行比较，发现两种情况下均存在9个阳性环。
我们的结果首次证明了在没有直接细胞间接触的情况下染色体构象水平转移的概念验证。这具有高度的临床相关性，因为我们之前在黑色素瘤和PCa患者的循环细胞中观察到的染色质构象与其原发肿瘤中的相似。这些变化可作为诊断和预后的高度特异性生物标志物。需要进一步研究以阐明染色体构象转移的具体机制及其在特定疾病中的临床意义。
