Metabolic Processes in Cancer Cells Studied via Pharmaco-Metabolomics Approach

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Graduate student Jiajun Du takes a stimulated Raman image of melanoma cancer cells in the lab. [Caltech]

One of the biggest challenges to the development of cancer therapies is the fact that there is no single kind of cancer. As a result, researchers are trying to learn more about how specific cancers function in order to create effective treatments for those types of cancer.

Scientists from Caltech and collaborators published an article “Raman-guided subcellular pharmaco-metabolomics for metastatic melanoma cells” in Nature Communications showing that a framework they developed, using a specialized type of microscopy, allows them to probe the metabolic processes inside cancer cells.

“The question we are interested in is why all the cancer cells we look at have very different behaviors. Because some cells have higher reliance on some metabolic pathways, they are more susceptible to disruption of those pathways,” says Lu Wei, PhD, assistant professor of chemistry, Caltech, whose team worked with researchers from the Institute for Systems Biology in Seattle and the University of California, Los Angeles (UCLA).

The scientists used Raman spectroscopy in conjunction with its advanced version, stimulated Raman scattering (SRS) microscopy. Raman spectroscopy takes advantage of the natural vibrations that occur in the bonds between the atoms that make up a molecule.

In this method, a molecule is bombarded with laser light. As the laser light’s photons bounce off the molecule, they gain or lose energy as a result of their interaction with the vibrations in the molecule’s bonds. Because each kind of bond in a molecule affects photons in a unique and predictable way, the structure of the molecule can be deduced by how the photons “look” after they bounce off of it.

By mapping the distribution of targeted chemical bonds, SRS microscopy then provides imagery of these molecular structures.

Using those combined techniques, Wei and her fellow researchers examined the metabolites present in five cell lines of melanoma commonly used in research. The melanoma cells were chosen, according to Wei, because they have a wide spectrum of metabolic characteristics that can be studied.

“Non-invasively probing metabolites within single live cells is highly desired but challenging. Here we utilize Raman spectro-microscopy for spatial mapping of metabolites within single cells, with the specific goal of identifying druggable metabolic susceptibilities from a series of patient-derived melanoma cell lines. Each cell line represents a different characteristic level of cancer cell de-differentiation,” write the investigators.

“First, with Raman spectroscopy, followed by stimulated Raman scattering (SRS) microscopy and transcriptomics analysis, we identify the fatty acid synthesis pathway as a druggable susceptibility for differentiated melanocytic cells. We then utilize hyperspectral-SRS imaging of intracellular lipid droplets to identify a previously unknown susceptibility of lipid mono-unsaturation within de-differentiated mesenchymal cells with innate resistance to BRAF inhibition. Drugging this target leads to cellular apoptosis accompanied by the formation of phase-separated intracellular membrane domains.”

“The integration of subcellular Raman spectro-microscopy with lipidomics and transcriptomics suggests possible lipid regulatory mechanisms underlying this pharmacological treatment. Our method should provide a general approach in spatially-resolved single cell metabolomics studies.”

By studying the cells’ metabolites, the researchers can begin to deduce how their metabolisms work, and how they could be targeted by drugs. Wei says the team uncovered a few new metabolic susceptibilities in cancer cells, including fatty acid synthesis and mono-unsaturation, but adds that right now, the primary purpose of the research is to do fundamental science.

“We’ve introduced a framework of pushing Raman spectroscopy into systems biology,” she says. “And we’re using sub-cellular information we’ve gathered with it to guide our study into pharmacometabolomics—the study of how metabolism affects drugs.”

James R. Heath, PhD, of the Institute for Systems Biology in Seattle and co-author on the paper, says this new technology allows researchers to obtain a more detailed look inside cancer cells than ever before.

“The chemical imaging methods developed in Lu’s lab allowed us to identify druggable metabolic susceptibilities in some very aggressive cancer models. These metabolic weaknesses would be missed by any other analytical approach,” notes Heath.

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