Department of Integrative Biology & Pharmacology, University of Texas Health Science Center at Houston, 6431 Fannin St, MSB 4.218, Houston, TX, 77030, USA.
Division of Molecular Pharmacology, Department of Medical Oncology & Clinical Therapeutics, City of Hope, Monrovia, CA, USA.
Sci Rep. 2023 Aug 8;13(1):12854. doi: 10.1038/s41598-023-39995-6.
Tumors are comprised of subpopulations of cancer cells that harbor distinct genetic profiles and phenotypes that evolve over time and during treatment. By reconstructing the course of cancer evolution, we can understand the acquisition of the malignant properties that drive tumor progression. Unfortunately, recovering the evolutionary relationships of individual cancer cells linked to their phenotypes remains a difficult challenge. To address this need, we have developed PhylinSic, a method that reconstructs the phylogenetic relationships among cells linked to their gene expression profiles from single cell RNA-sequencing (scRNA-Seq) data. This method calls nucleotide bases using a probabilistic smoothing approach and then estimates a phylogenetic tree using a Bayesian modeling algorithm. We showed that PhylinSic identified evolutionary relationships underpinning drug selection and metastasis and was sensitive enough to identify subclones from genetic drift. We found that breast cancer tumors resistant to chemotherapies harbored multiple genetic lineages that independently acquired high K-Ras and β-catenin, suggesting that therapeutic strategies may need to control multiple lineages to be durable. These results demonstrated that PhylinSic can reconstruct evolution and link the genotypes and phenotypes of cells across monophyletic tumors using scRNA-Seq.
肿瘤由具有不同遗传特征和表型的癌细胞亚群组成，这些特征和表型会随着时间的推移和治疗而演变。通过重建癌症的进化过程，我们可以了解导致肿瘤进展的恶性特性的获得。不幸的是，恢复与表型相关的单个癌细胞的进化关系仍然是一个具有挑战性的难题。为了解决这一需求，我们开发了 PhylinSic 方法，该方法可以从单细胞 RNA 测序 (scRNA-Seq) 数据中重建与基因表达谱相关的细胞之间的系统发育关系。该方法使用概率平滑方法调用核苷酸碱基，然后使用贝叶斯建模算法估计系统发育树。我们表明，PhylinSic 可以识别药物选择和转移的进化关系，并且足够敏感，可以从遗传漂移中识别亚克隆。我们发现，对化疗有抗药性的乳腺癌肿瘤中存在多个独立获得高 K-Ras 和 β-连环蛋白的遗传谱系，这表明治疗策略可能需要控制多个谱系才能持久。这些结果表明，PhylinSic 可以使用 scRNA-Seq 重建进化，并将单系肿瘤中细胞的基因型和表型联系起来。
