Oncology: Meet Hyperion

For the past two decades, malignant tumors have no longer been considered as simple clumps of tissue that develop chaotically, but as authentic miniature ecosystems. Within them, immune cells and cancer cells interact in a complex way, to the extent that the "social network" concept is sometimes used to describe their multiple relationships. However, an unfortunate phenomenon sometimes emerges from these reciprocal affinities, in that the body’s natural response for halting the progression of the cancer – the antitumor immune response – is inhibited. Elucidating the laws that govern the links between these cell populations will be necessary if we are to understand why so few patients respond favorably to immunotherapies and, ultimately, if we are to develop new treatments. This is the objective of the researchers at the Montpellier Cancer Research Institute (IRCM)*.

As explorers of the tumor microenvironment, the researchers know that such a little-known territory needs to be mapped. Helping them with this is the machine Hyperion, an intriguing presence in the laboratory.  Together with the mass spectrometer Hélios, this platform which is the first of its kind in France is capable of simultaneously analyzing some fifty cell markers from a solid-tumor biopsy – enabling detailed visualization of what communicates with what within the tissue – and of representing the famous cell social network. A network that the researchers have mischievously dubbed "Cellbook". With this spectacular tool, they hope to elucidate the ecological mysteries of the tumor and understand how it organizes treatment resistance.

Henri-Alexandre Michaud, Operational Manager of the platform, in front of Hyperion and its mass-spectrometry cytometer (CyTOF) sidekick, Helios. Montpellier Cancer Research Institute (unit 1194 Inserm/Université de Montpellier, Val d'Aurelle Regional Cancer Center). ©François Guénet

From the cell ecosystem to the research ecosystem

Yaël Glasson gets ready to slice a paraffin block, embedded in which is a tumor sample obtained by biopsy. In order to study the tumor microenvironment, certain preparations need to be made. Once the tumor biopsy has been performed in the operating theater, the sample is prepared by the Anatomical Pathology Department of the Montpellier Cancer Institute (ICM). Then, with the Translational Research Unit, it is aggregated with similar samples taken from other patients to form homogeneous "carrots", which are preserved in a block of paraffin. The choices of patient(s), tumor type, area of interest and type of tumor cells to analyze are decisive if Hyperion is to provide the researchers with useful data. ©François Guénet

Like the immune phenomena they are studying, the researchers at IRCM are evolving in an environment in which mutual dependence is the order of the day. Founded in 1997 and under the authority of Inserm since 2008, "the IRCM is currently in its adolescence, explains its Director, Claude Sardet. We seek to establish long-lasting working relationships with the ambitious young teams which have continued to join us since the unit was created, and to structure them according to the translational research model that is central to our organization."

Combining an Inserm unit, Montpellier University and a hospital (Montpellier Cancer Institute), as well as a translational research unit, clinical trial biometrics unit and tumor registry, the IRCM has done its utmost for its 220 members of staff to continue to work together to rapidly resolve complex problems and improve treatments. "The 17 teams, organized by theme, share everything: administrative services, stores, platforms, animal houses, biotechnologies... And sharing in this way is not just a principle of organization, it also has scientific effects. The blood and tissue samples used by our researchers are taken directly at the hospital, and the research results obtained enable them in turn to designate and clinically test therapeutic targets, specifies Sardet. The structure also hosts several biotechs created on the basis of Inserm researcher initiatives or patents, which participate in our establishment of links with industry. The idea is that they grow and then leave the Institute once they are mature."

A microtome cuts a paraffin block into thin sections. ©François Guénet
The section is placed in a water bath to smooth out any creases formed whilst being sliced. ©François Guénet
A sample is immunolabeled thanks to antibodies paired with stable metal isotopes. ©François Guénet
Pathologist Evelyne Crapez determines the most interesting area of the sample for Hyperion to analyze. For the time being, the team’s focus is on breast, ovarian, colon and gastro-esophageal cancers. ©François Guénet
Nathalie Bonnefoy, leader of the Immunity and Cancer team. In fine, analysis of the acquired data reveals three types of information. One, the cell types present in the tissue and their spatial distribution – from which the biological processes in which they are implicated can be deduced. Two, visualization of the "social network" of the cells – which cells communicate with which. And three, the occasional surprise findings: cell subtype phenotypes we were unaware of, or whose presence we would never have suspected! ©François Guénet

This single-site collaborative model, which embodies the concept of translational research in daily practice, is closely linked to the history of oncology. "We attract researchers who, despite working on fundamental subjects, know they need to find connections with the hospital and apply their fundamental findings, at least partially. This requirement is made clear right from recruitment", explains Nathalie Bonnefoy, leader of the Immunity and Cancer team. At present, 32 hospital clinicians are participating in the teams’ reflections and are truly implicated in developing research hypotheses on therapies, treatment-resistance phenomena, major programs in radiobiology and radiotherapy, as well as in immunotherapy and therapeutic antibody engineering. "This federative operating principle applies to all biology-health research conducted in Montpellier, even if it is particularly marked within the cancer research community, reinforced by the SIRIC certification," specifies Marc Ychou, Director of the Montpellier Cancer Institute.


An emblematic cancer research tool

The Integrated Cancer Research Sites (SIRICs) are centers certified for translational research in oncology. They have participated in codifying the laboratory-to-patient approach, with a continuum between fundamental and clinical research aimed at finding treatments rapidly and commencing personalized medical protocols. "In the Montpellier region, the major institutes all work together as harmoniously as possible. The staff move between the institutes so much that the town is seen as a giant biology-health campus, which comprises around 1,700 people, smiles Sardet. And because it is impossible for each institute to have its own high-tech equipment, we have created Biocampus – a system for sharing large equipment, in which Hyperion will play a major role." And this makes Hyperion an emblematic tool in cancer research: already open to the medical and scientific community in Montpellier, it will soon be available to teams from the wider region, followed by France as a whole, to academic and also private partners. The latter will be able to use it to test, for example, the effect of an antibody, gene or medicine on tumor growth.

Example visualization of immune cell occupation in a breast tumor. The T cells (in blue, pink and yellow) are found in abundance near the tumor foci (in red) and on the edges of the vascular structures (in green and white) or milk ducts (in green). This information, added to the data on cell function and phenotype, enables the accurate reconstitution of their social network within the tumor. © Henri-Alexandre Michaud

"We hope to decipher the immunosuppressant cellular and molecular mechanisms that help tumors evade immune system surveillance. Even if a lot of time is still needed before the immunotherapies are ready for a large number of patients, we are currently observing absolutely spectacular results in some patients – who were in a critical condition and were able to be saved thanks to a personalized approach", recaps Bonnefoy. "This new phenomenon increases the teams’ motivation and ambition in the face of the vast and complex continent that is immunity."

The IRCM Immunity and Cancer team. From left to right: Henri-Alexandre Michaud, Cécile Déjou, Virginie Lafont, Jonathan Vosgien, Nathalie Bonnefoy, Laurent Gros, Yaël Glasson, Aurélie Roussey and Naoill Abdellaoui. ©François Guénet

Note :
*unit 1194 Inserm/Université de Montpellier - Cancer Center (Val d'Aurelle)