McConnell Alicia M, Chassé Maggie H, Noonan Haley R, Mito Jeffrey K, Barbano Julia, Weiskopf Erika, Gosselink Irene F, Prasad Meera, Yang Song, Abarzua Phammela, Lian Christine G, Murphy George F, Trapnell Cole, Zon Leonard I
Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston, Howard Hughes Medical Institute, Boston, MA 02115, USA.
Harvard Stem Cell Institute, Boston, MA 02115, USA.
bioRxiv. 2024 Oct 25:2024.10.22.618007. doi: 10.1101/2024.10.22.618007.
The field cancerization theory suggests that a group of cells containing oncogenic mutations are predisposed to transformation. We previously identified single cells in zebrafish that reactivate an embryonic neural crest state before initiating melanoma. Here we show that single cells reactivate the neural crest fate from within large fields of adjacent abnormal melanocytes, which we term the "cancer precursor zone." These cancer precursor zone melanocytes have an aberrant morphology, dysplastic nuclei, and altered gene expression. Using single cell RNA-seq and ATAC-seq, we defined a distinct transcriptional cell attractor state for cancer precursor zones and validated the stage-specific gene expression initiation signatures in human melanoma. We identify the cancer precursor zone driver, ID1, which binds to TCF12 and inhibits downstream targets important for the maintenance of melanocyte morphology and cell cycle control. Examination of patient samples revealed precursor melanocytes expressing ID1, often surrounding invasive melanoma, indicating a role for ID1 in early melanomagenesis. This work reveals a surprising field effect of melanoma initiation in which tumors arise from within a zone of morphologically distinct, but clinically covert, precursors with altered transcriptional fate. Our studies identify novel targets that could improve early diagnosis and prevention of melanoma.
场癌化理论表明，一组含有致癌突变的细胞易于发生转化。我们之前在斑马鱼中鉴定出了在引发黑色素瘤之前重新激活胚胎神经嵴状态的单细胞。在此我们表明，单细胞在相邻异常黑素细胞的大区域内重新激活神经嵴命运，我们将该区域称为“癌症前体区”。这些癌症前体区的黑素细胞具有异常形态、发育异常的细胞核以及改变的基因表达。利用单细胞RNA测序和ATAC测序，我们为癌症前体区定义了一种独特的转录细胞吸引子状态，并在人类黑色素瘤中验证了阶段特异性基因表达起始特征。我们鉴定出癌症前体区驱动因子ID1，它与TCF12结合并抑制对维持黑素细胞形态和细胞周期控制很重要的下游靶点。对患者样本的检查发现表达ID1的前体黑素细胞，通常围绕侵袭性黑色素瘤，表明ID1在早期黑色素瘤发生中起作用。这项工作揭示了黑色素瘤起始过程中一种惊人的场效应，即肿瘤源自形态上不同但临床上隐匿的、转录命运改变的前体区域。我们的研究确定了可改善黑色素瘤早期诊断和预防的新靶点。
