Abstract
Heterogeneity is an intrinsic characteristic of cancer. Even in isogenic tumors, cell populations exhibit differential cellular programs that overall supply malignancy and decrease treatment efficiency. In this study, we investigated the functional relationship among cell subtypes and how this interdependency can promote tumor development in a cancer cell line. To do so, we performed single-cell RNA-seq of MCF7 Multicellular Tumor Spheroids as a tumor model. Analysis of single-cell transcriptomes at two-time points of the spheroid growth, allowed us to dissect their functional relationship. As a result, three major robust cellular clusters, with a non-redundant complementary composition, were found. Meanwhile, one cluster promotes proliferation, others mainly activate mechanisms to invade other tissues and serve as a reservoir population conserved over time. Our results provide evidence to see cancer as a systemic unit that has cell populations with task stratification with the ultimate goal of preserving the hallmarks in tumors.
Highlights
Cancer studies have established that tumors are complex and heterogeneous systems
Multicellular tumor spheroids (MCTS) are scaffold-free self-assembled aggregates of isogenic cancer cells displaying an intermediate complexity between monolayer cell cultures and in vivo solid tumors[14]
MCF7 multicellular tumor spheroids (MCTS) were cultured for 19 days, and their diameter distribution was measured by image analysis of photos taken to the culture flask at three independent culture kinetics in different days of progression
Summary
Cancer studies have established that tumors are complex and heterogeneous systems. These properties are grounded on genetic variations and diverse microenvironmental conditions that induce sizable differences in gene expression profiles, surface biomarkers, metabolism, growth rates, morphology, metastatic potential and response to therapy at a single cell level[1,2]. Gold standard to build a comprehensive assessment of cancer development They are one of the best options to perform longitudinal studies. MCTS develop a heterogeneous microenvironment that leads to the generation of proliferative, quiescent, and necrotic/ apoptotic subpopulations[15,16] This in vitro cancer model is valuable as they mimic the first avascular stages of tumor formation, and exhibit aggressiveness features such as multicellular resistance, migration, and invasion[17]. The similarities between MCTS and tumors, plus their experimental advantages, such as reproducibility and evaluations at several time points, makes them an appealing model to unravel their heterogeneous composition of clonal subpopulations at different stages of growth and figure out their functional interrelationship
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