美国纪念斯隆-凯特琳癌症中心Christine A. Iacobuzio-Donahue课题组取得一项新突破。他们的最新研究提出了单细胞分辨率下胰腺癌的基因组进化。该研究于2026年1月22日发表于国际一流学术期刊《自然—遗传学》杂志上。

研究人员以单核DNA测序为主题，研究了来自24个胰腺肿瘤的137491个单核，反映了不同的临床情况。大量研究表明，研究小组发现驱动基因的体细胞改变频率更高；许多表现为拷贝数的改变，占空间异质性的大部分。在具有典型KRAS致癌突变的胰腺癌中，课题组研究人员发现可能对基因型的不同依赖可能表明对KRAS抑制的不同反应。在具有种系杂合子BRCA2突变的胰腺癌中，该课题组发现了野生型等位基因失活的不同机制和时间，这些机制和时间塑造了不同的进化轨迹。肿瘤对转化生长因子-β的内在反应失活通过多种机制发生，发生在肿瘤发生后，与侵袭和转移相吻合，反映了胰腺导管腺癌发展后期表型的选择压力增加。

研究人员表示，大多数胰腺癌的进化研究依赖于批量测序，但克隆进化发生在单细胞水平。

附：英文原文

Title: Genomic evolution of pancreatic cancer at single-cell resolution

Author: Zhang, Haochen, Sashittal, Palash, Karnoub, Elias-Ramzey, Jakatdar, Akhil, Umeda, Shigeaki, Hong, Jungeui, Noronha, Anne Marie, Cardenas, Agustin, Erakky, Amanda, McIntyre, Caitlin A., Hayashi, Akimasa, Lecomte, Nicolas, Hilmi, Marc, Park, Wungki, Pang, Nan, OReilly, Eileen M., Wei, Alice C., Raphael, Benjamin J., Iacobuzio-Donahue, Christine A.

Issue&Volume: 2026-01-22

Abstract: Most evolutionary studies on pancreatic cancer rely on bulk sequencing, yet clonal evolution happens at the single-cell level. We used single-nucleus DNA sequencing to study 137,491 single nuclei from 24 pancreatic neoplasms reflecting various clinical scenarios. We found higher frequencies of somatic alterations to driver genes that bulk studies indicate; many manifest as copy number alterations and account for the majority of spatial heterogeneity. In pancreatic cancers with canonical KRAS oncogenic mutations, we found likely varied dependence on the genotype that may signify differential response to KRAS inhibition. In pancreatic cancers with germline heterozygous BRCA2 mutations, we discovered varied mechanisms and timing of inactivation of the wild-type allele that sculpted differential evolutionary trajectories. Inactivation of tumor-intrinsic response to transforming growth factor-β happens through various mechanisms, takes place after oncogenesis and coincides with invasion and metastasis, reflecting increasing selective pressure for the phenotype later in pancreatic ductal adenocarcinoma development.

DOI: 10.1038/s41588-025-02468-9

Source: https://www.nature.com/articles/s41588-025-02468-9