Sahoo Sarthak, Ramu Soundharya, Nair Madhumathy G, Pillai Maalavika, San Juan Beatriz P, Milioli Heloisa Zaccaron, Mandal Susmita, Naidu Chandrakala M, Mavatkar Apoorva D, Subramaniam Harini, Neogi Arpita G, Chaffer Christine L, Prabhu Jyothi S, Somarelli Jason A, Jolly Mohit Kumar
Department of Bioengineering, Indian Institute of Science, Bangalore 560012, India.
Division of Molecular Medicine, St. John's Research Institute, St. John's Medical College, Bangalore 560012, India.
iScience. 2024 May 27;27(7):110116. doi: 10.1016/j.isci.2024.110116. eCollection 2024 Jul 19.
Intra-tumoral phenotypic heterogeneity promotes tumor relapse and therapeutic resistance and remains an unsolved clinical challenge. Decoding the interconnections among different biological axes of plasticity is crucial to understand the molecular origins of phenotypic heterogeneity. Here, we use multi-modal transcriptomic data-bulk, single-cell, and spatial transcriptomics-from breast cancer cell lines and primary tumor samples, to identify associations between epithelial-mesenchymal transition (EMT) and luminal-basal plasticity-two key processes that enable heterogeneity. We show that luminal breast cancer strongly associates with an epithelial cell state, but basal breast cancer is associated with hybrid epithelial/mesenchymal phenotype(s) and higher phenotypic heterogeneity. Mathematical modeling of core underlying gene regulatory networks representative of the crosstalk between the luminal-basal and epithelial-mesenchymal axes elucidate mechanistic underpinnings of the observed associations from transcriptomic data. Our systems-based approach integrating multi-modal data analysis with mechanism-based modeling offers a predictive framework to characterize intra-tumor heterogeneity and identify interventions to restrict it.
肿瘤内表型异质性促进肿瘤复发和治疗抗性，仍然是一个尚未解决的临床挑战。解码可塑性的不同生物学轴之间的相互联系对于理解表型异质性的分子起源至关重要。在这里，我们使用来自乳腺癌细胞系和原发性肿瘤样本的多模态转录组数据——批量、单细胞和空间转录组学，来确定上皮-间质转化（EMT）和管腔-基底可塑性之间的关联，这两个关键过程导致了异质性。我们表明，管腔型乳腺癌与上皮细胞状态密切相关，但基底型乳腺癌与混合的上皮/间质表型以及更高的表型异质性相关。代表管腔-基底和上皮-间质轴之间串扰的核心潜在基因调控网络的数学模型阐明了从转录组数据中观察到的关联的机制基础。我们基于系统的方法将多模态数据分析与基于机制的建模相结合，提供了一个预测框架，以表征肿瘤内异质性并确定限制它的干预措施。
