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Fluidigm Launches Hyperion Platform for Highly Multiplexed Molecular Imaging

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NEW YORK (GenomeWeb) - Fluidigm this week announced the broad commercial launch of its Hyperion Imaging Mass Cytometry platform, which allows researchers to add sample spatial and structural data to the multiplexed molecular analyses enabled by the company's traditional mass cytometry systems.

The platform has a number of potential applications within cancer research and other areas where cellular heterogeneity is a key concern, said Bernd Bodenmiller, assistant professor for quantitative biology at the University of Zurich and one of the original developers of imaging mass cytometry.

Bodenmiller was previously a postdoc in the lab of Stanford University researcher Garry Nolan, one of the earliest adopters of mass cytometry and a notable contributor to the technology's development. Bodenmiller continued his work with the system, sold by Fluidigm under the CyTOF name, when he established his own lab in Zurich. In 2014, he published a study in Nature Methods in which he and collaborators including Swiss Federal Institute of Technology Zurich researcher Detlef Günther coupled a laser ablation cell to a CyTOF and used it to simultaneously image 32 different proteins in breast cancer cells at subcellular resolution.

With this week's Hyperion launch, Fluidigm has brought this technology to market. At a press event this week, researchers including Bodenmiller; Matt Silver, principal scientist at drugmaker EMD Serono; and Akil Merchant, assistant professor of medicine at the University of Southern California's Keck School of Medicine presented on potential research applications for the device ranging from high-throughput drug screening to studies of circulating tumor cells and the tumor microenvironment.

Mass cytometry combines capabilities of flow cytometry and atomic mass spectrometry, allowing it to measure large numbers of proteins in single cells with high throughput. The technique detects proteins using antibodies linked to stable isotopes of elements, which can then be read with high resolution via mass spec.

The technology was developed by University of Toronto researchers including Scott Tanner who founded the mass cytometry firm DVS Sciences, which Fluidigm purchased in 2014. Mass cytometry has traditionally competed with single-cell technologies like flow cytometry, offering similar sorts of analyses but with higher multiplexing abilities.

The Hyperion is more analogous to a highly multiplexed immunohistochemistry workflow, allowing researchers to look at dozens of markers with sub-cellular resolution while retaining the spatial and structural information of a tissue sample. According to the company, the platform can currently look at 37 markers per sample simultaneously, with a theoretical maximum of 135 markers per samples. This compares to around 10 markers per sample for conventional IHC.

That makes it well suited to studies where cellular heterogeneity is an important factor, Bodenmiller told GenomeWeb this week, adding that it will likely be particularly popular for oncology research.

"Everything [in oncology] is so heterogeneous," he said. "There are so many cell types and they all act on each other. Because we can measure many different markers simultaneously we can now [distinguish between] many different cell types and study the interaction of these cell types in their spatial arrangements."

Bodenmiller said that his lab had managed to multiplex as many as 52 markers simultaneously using the instrument and can achieve a dynamic range of 105 with 1000-nm resolution.

In a paper published in August in Nature Methods, Bodenmiller and collaborators described the use of the Hyperion system to analyze cell phenotypes and interactions in 49 breast cancer samples along with three matched normal tissues and six additional normal tissue samples. Measuring markers of cell lineage along with markers of signaling pathway activation, proliferation, apoptosis, and known clinical protein markers, the researchers characterized the cellular phenotypes and microenvironments of these samples. 

Using the histoCAT data analysis tool developed by Bodenmiller's lab and licensed by Fluidigm in an agreement announced this week, the researchers identified, among other things, patterns of cellular interaction and organization associated with particular pathological grades as well as patterns of interaction between immune cells and stromal and tumor cells characteristic of tumor microenvironments.

Bodenmiller also presented research at this week's media event on a drug screening application his lab has developed using the platform in which they treat tumor samples with agents of interest and track changes in various cellular markers. He said that using a barcoding system to multiplex analysis of these samples, they collected data on 480 drug-tumor combinations in a day.

During the press event, EMD Serono's Silver said that his company is exploring the Hyperion as a tool for more highly multiplexed IHC-type applications. He noted that the drug maker is particularly interested in platforms like the Hyperion and other high-multiplex IHC systems for immune-oncology applications where such instruments could allow researchers to measure more biomarkers on what are often limited and expensive samples.

USC's Merchant presented on work he and his colleagues are doing using the Hyperion to analyze circulating tumor cells and characterize tumor microenvironments. He noted that the ability to look at multiple markers using Hyperion has allowed the researchers to uncover levels of heterogeneity in CTCs that had previously gone unobserved and to "really get a deep understanding of the biology of these tumor cells in circulation."

The USC team is also using the instrument to more deeply characterize the tumor microenvironment and immune response, Merchant said, noting that multiplexed marker analysis is essential to establish the actual function of immune cells observed in tumor microenvironments.

Imaging mass cytometry is one of several technologies that has emerged recently as a supplement and potential competitor to traditional IHC.

For instance, imaging mass spectrometry, which commonly uses MALDI combined with a TOF mass spec has recently advanced to the point where pathology applications are within reach. Bruker is working with commercial and academic pathology labs in Europe with the aim of developing MALDI imaging-based assays that could prove clinically useful.

Like imaging mass cytometry, MALDI imaging can provide large-scale spatial information on protein expression with cells and tissues, and could bring additional molecular information to traditional IHC-based experiments.

Bodenmiller said he sees the two technologies as complementary with MALDI imaging offering the potential for unbiased discovery and imaging mass cytometry enabling more targeted but deeper analyses.

"With MALDI imaging you don't need antibodies, so in this way it gives you the chance to discover novel things," he said. "The disadvantage is that you cannot measure the depth [of imaging mass cytometry]. If you want to look at phosphorylation sites or certain low-abundance markers you often cannot detect them by MALDI imaging, and that is why I think imaging mass cytometry is highly complementary. It is targeted, and that means we can repetitively measure a set of markers you are interested in, but, of course, you limit yourself to those markers."

Bodenmiller said he believes imaging mass cytometry has potential as a clinical tool, though he added that such applications remain a ways off. Shorter term, he said the technology could prove useful for clinical trials where "samples can be very expensive and you want to learn the maximum amount of information that you can from them."

The Hyperion launch comes as Fluidigm continues to shift from its focus on single-cell genomics to emphasize aspects of its business including its high-throughput genomics and mass cytometry offerings.

According to an analyst note from Cowen and Company, Fluidigm has installed more than 30 Hyperion systems to date with 11 placed in the first quarter of this year.

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