Metabolism as a driver of tumour phenotypic and genetic heterogeneity

Metabolism as a driver of tumour phenotypic and genetic heterogeneity

Dr Maria Rodriguez Colman; UMC Utrecht

Maria Rodriguez Colman is originally from Argentina and obtained her PhD at the Institute of Biomedical Sciences, IRB Lleida (Catalunya, Spain). During her postdoc in Utrecht, the Netherlands she started a research line using organoids to disclose the role of metabolism in stem cell function and differentiation. She showed that intestinal cell types have distinct metabolic phenotypes, and that a ‘metabolic teamwork’ between these cell types supports intestinal homeostasis(1).

Importantly, she pioneered the application of organoid technology to metabolic studies by adapting and developing numerous techniques, such as live imaging, metabolomics and bioenergetics measurements. Since 2020 she is appointed Associate Professor at the Center for Molecular Medicine (CMM) at UMC Utrecht. The Rodriguez Colman Lab investigates the “Metabolism of Stem Cells and Cancer” and is on the front of investigating metabolism at the subcellular, cellular and tissue scale. To that end, they use organoids models, a multicellular and hetero-cellular system able to recapitulate the complexity of stem cell and differentiation dynamics(2).

They perform cutting-edge 4-D live imaging coupled to machine learning that allows single cell tracking and lineage reconstruction. Fluorescent based genetic reporters are applied to monitor metabolites and metabolic fluxes. These sensors are combined with reporters for cell types, such as stem cells and differentiated cells. We investigate the impact of metabolic changes on cell fate decisions in the context of tissue development, homeostasis and in cancer. 1. Interplay between metabolic identities in the intestinal crypt supports stem cell function. Rodríguez-Colman MJ, et al., Nature, 2017 doi: 10.1038/nature21673 2. Mitochondria define intestinal stem cell differentiation downstream of a FOXO/Notch axis. M.C. Ludikhuize, …, M.J. Rodríguez Colman. Cell Metabolism, 2020. doi: 10.1016/j.cmet.2020.10.005.

Cancer is a heterogeneous disease owing to variations in genotypes and phenotypes among and within tumours. This diversity is an important contributor to therapy resistance and tumour recurrence. Derailed metabolism is one of the hallmarks of cancer. The Warburg effect is one of the most conserved phenotypes of cancer cells. Remarkably, the advantages conferred by such reprogramming remain debated. Our investigations aim to dissect the influence of metabolites on tumour developmental dynamics. For this research, we employ human derived organoids, that faithfully recapitulate the native tissue architecture and cellular dynamics. By genetically introducing fluorescent reporters into tumour organoids, we use 4D live imaging to simultaneously monitor cell type specification and metabolic changes occurring during tumour organoid development with high temporal and single-cell resolution.

I will present our recent advances in unravelling the intricate role of lactate in delineating intratumoural phenotypic and genetic heterogeneity. We find that lactate orchestrates epigenetic modifications, leading to MYC-driven transcriptional reprogramming that fosters cancer (stem) cell plasticity, thereby shaping tumour development. Next to that, we investigate the impact of energy and redox metabolism in regulating chromosome   mitosis, and their alteration in cancer, thus contributing to the genetic evolution of the tumour.

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