LY6D marks pre-existing resistant basosquamous tumor subpopulations.
LY6D marks pre-existing resistant basosquamous tumor subpopulations.
复制标题
DOI：
10.1038/s41467-022-35020-y
复制
发表时间：
2022-12-06
影响因子：
16.6
通讯作者：
Oro, Anthony E
中科院分区：
文献类型：
--
作者：
Haensel, Daniel;Gaddam, Sadhana;Li, Nancy Y;Gonzalez, Fernanda;Patel, Tiffany;Cloutier, Jeffrey M;Sarin, Kavita Y;Tang, Jean Y;Rieger, Kerri E;Aasi, Sumaira Z;Oro, Anthony E
要提高对规范治疗的反应，需要通过识别具有增强的细胞可塑性的离散细胞群来从机制上理解肿瘤的动态异质性。我们以前已经在皮肤基底细胞癌中展示了不同的耐药机制，但对与这些群体相关的细胞状态和标志物的全面了解仍然很少。在这里，我们确定了由表面标记LY6D标记的原始基底细胞癌肿瘤中预先存在的耐药细胞群。LY6D+肿瘤细胞在空间上具有局限性，具有基底细胞癌和鳞癌样细胞的特征。使用计算工具、器官和空间工具，我们表明LY6D+基底鳞状细胞代表了沿着皮肤谱系相关的上皮状态谱的中央节点上的持久种群，局部环境和应用治疗决定了蓄积的动力学。令人惊讶的是，LY6D+基鳞癌存在于许多上皮性肿瘤中，例如胰腺癌，这些肿瘤的预后很差。总体而言，我们的结果将耐药的LY6D+Basosquamy人群确定为重要的临床靶点，并为未来针对他们的治疗方法提供了策略建议。在皮肤基底细胞癌中识别具有细胞可塑性的不同细胞群对于理解治疗耐药机制是重要的。在这里，作者确定了与不良临床结果相关的耐药LY6D+碱鳞片人群。
Improved response to canonical therapies requires a mechanistic understanding of dynamic tumor heterogeneity by identifying discrete cellular populations with enhanced cellular plasticity. We have previously demonstrated distinct resistance mechanisms in skin basal cell carcinomas, but a comprehensive understanding of the cellular states and markers associated with these populations remains poorly understood. Here we identify a pre-existing resistant cellular population in naive basal cell carcinoma tumors marked by the surface marker LY6D. LY6D+ tumor cells are spatially localized and possess basal cell carcinoma and squamous cell carcinoma-like features. Using computational tools, organoids, and spatial tools, we show that LY6D+ basosquamous cells represent a persister population lying on a central node along the skin lineage-associated spectrum of epithelial states with local environmental and applied therapies determining the kinetics of accumulation. Surprisingly, LY6D+ basosquamous populations exist in many epithelial tumors, such as pancreatic adenocarcinomas, which have poor outcomes. Overall, our results identify the resistant LY6D+ basosquamous population as an important clinical target and suggest strategies for future therapeutic approaches to target them. The identification of distinct cell populations with cellular plasticity in skin basal cell carcinoma is important for understanding treatment resistance mechanisms. Here, the authors identify the resistant LY6D+ basosquamous population that correlates with poor clinical outcomes.