Susceptibility in the immune response to metastases

Scientists led by Sabine Taschner-Mandl, PhD, St. Anna Children’s Cancer Research Institute, and Nikolaus Fortelny, PhD, Paris Lodron University of Salzburg, were the first to analyze bone marrow metastases from childhood tumors of the nervous system using modern single cells. sequence analysis. It turns out that cancer cells prevent cells in their environment from fighting the tumor – a process that can be reversed with drugs. The findings were published in a well-known journal Nature Communications.

Neuroblastoma is the most common solid tumor in infants and young children. Despite improving treatment options, more than half of patients with the very aggressive form (high-risk neuroblastoma) still experience relapse. “We specifically study bone marrow metastases because recurrences often originate there. Tumor cells seem to manipulate their environment so that it supports their growth instead of fighting it, ”explains Sabine Taschner-Mandl, Head of the Tumor Biology Group at St. Petersburg. Anna Children’s Cancer Research Institute (St. Anna CCRI).

How cancer cells manipulate neighboring cells
Therefore, a recently published study investigated the cell architecture and cell-cell communication of metastatic neuroblastoma of two major genetic subtypes (MYCN amplification or ATRX mutations) and those without such changes using single-cell transcriptomics and epigenomics. “To date, only primary tumors have been studied in detail, but not metastatic neuroblastoma,” said Irfete Fetahu, PhD, first co-author and study co-author and postdoc in the Tumor Biology Group.

The team investigated the interaction of metastatic tumor cells with healthy bone marrow cells in greater detail. “We developed an algorithm that allows us to analyze different cells in the bone marrow and model their interactions,” emphasizes Fortelny, head of the Computational Systems Biology Group, University of Lodron Paris Salzburg. “Our analyzes have shown that certain cells, called monocytes, react to unwanted invaders. During this time, they encourage the growth process and release cytokines that stimulate tumor growth,” said Fetahu. Interestingly, investigations at the epigenetic level demonstrated that although monocytes in the tumor microenvironment are activated to attack cancer cells, they are unable to respond appropriately to this signal. “These monocytes are receiving contradictory messages. As a result, they are no longer able to fight the tumor,” Fetahu explained this dilemma.

Interfere with the state of pathological immune cells
Communication between neuroblastoma cells and bone marrow or monocytes is largely regulated by MK proteins (midkine), MIF (macrophage migration inhibiting factor) and related molecules. The signaling pathways controlled by these proteins are regulated in immune cells. “Drugs targeting MK and MIF interfere with this pathological interaction and are currently being investigated. Through selective inhibition, it may be possible to return these pathologically altered monocytes to their original state,” said Taschner-Mandl.

Metastases act differently
Scientists have also found that cellular plasticity, that is, the ability of cells to change depending on environmental influences, is maintained during metastasis. In addition, metastatic tumor cell gene expression is dependent on the neuroblastoma genetic subtype. For example, neuroblastoma cells that have a MYCN amplification changes only slightly when they metastasize from the primary tumor to the bone marrow, whereas tumor cells with ATRX mutations show marked differences in metastases. “Tumor genetics leads to characteristic signals and thus highly specific changes in the bone marrow microenvironment, which are expressed in individual signatures,” said Taschner-Mandl. “This could explain why patients with neuroblastoma ATRX mutations often respond poorly to therapy.”

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Publication
Single-cell transcriptomics and epigenomics unraveled the role of monocytes in neuroblastoma bone marrow metastasis
Irfete S. Fetahu ^#,*, Wolfgang Esser scale^#Rohit Dnyansagar^#Samuel Sindelar, Fikret Rifatbegovic, Andrea Bileck, Lukas Skos, Eva Bozsaky, Daria Lazic, Lisa Shaw, Marcus Tötzl, Dora Tarlungeanu, Marie Bernkopf, Magdalena Rados, Wolfgang Weninger, Eleni M. Tomazou, Christoph Bock, Christopher Gerner, Ruth Ladenstein , Matthias Farlik, Nikolaus Fortelny*^,§Sabine Taschner-Mandl*^,§

# co-contributing as the first author

*corresponding author

§ jointly supervise this work

Nature Communications, June 26, 2023
DOI: 10.1038/s41467-023-39210-0
https://www.nature.com/articles/s41467-023-39210-0

Funding
This study was supported by the Vienna Science and Technology Fund (WWTF), the Austrian Science Fund FWF, and the Transcan-2/ERA-NET initiative.

About Sabine Taschner-Mandl, PhD
Sabine Taschner-Mandl, PhD has been head of the Tumor Biology group at St. Anna Children’s Cancer Research since 2018, where she has been working as a scientist since 2008. In addition, she is a lecturer at the Medical University of Vienna and the Vienna University of Technology. Dr. Taschner-Mandl completed his biology studies at the University of Vienna with a diploma thesis in vaccine development at Intercell. This was followed by a PhD thesis and a post-doctoral position at the Institute of Immunology at the Medical University of Vienna. Apart from his research at St. Anna Children’s Cancer Research Institute, Dr. Taschner-Mandl is a visiting scientist at Significo and the University of Helsinki as part of the Marie Curie Program EC-FP7.
For his research, Dr. Taschner-Mandl has received numerous grants, including from the Austrian Research Promotion Agency, the Vienna Science, Research and Technology Fund, and the European Commission’s ERA-NET initiative.

About the St. Anna, CCRI
St. Anna CCRI is an internationally recognized multidisciplinary research institute with the goal of developing and optimizing diagnostic, prognostic and therapeutic strategies for the treatment of children and adolescents with cancer. To achieve this goal, it combines basic research with translational and clinical research and focuses on the specific characteristics of childhood tumor disease to provide young patients with the best and most innovative therapies. Specialized research groups in tumor genomics and epigenomics, immunology, molecular biology, cell biology, bioinformatics, and clinical research work together to align scientific findings with the clinical needs of clinicians to ultimately improve the well-being of our patients.
www.ccri.at

About Dr. Nikolaus Fortelny (PhD)
Dr. Fortelny is an assistant professor in the Department of Biosciences and Medical Biology at Paris Lodron University of Salzburg. In his work, he focuses on the analysis and modeling of complex biological processes using methods from artificial intelligence and statistics. Dr. Fortelny studied molecular biology in Vienna and then bioinformatics in Geneva. He completed his dissertation in Vancouver, Canada. Dr. Fortelny later joined the Center for Molecular Medicine (CeMM) in Vienna, where he developed deep learning algorithms that simulate biological networks. His research group at the Paris Lodron University of Salzburg further develops models of biological processes, focusing on the application of complex, robust and interpretable algorithms.

About the University of Paris Lodron Salzburg
Paris Lodron University Salzburg (PLUS, www.plus.ac.at) has six faculties with 34 departments and around 90 curricula in digital and analytical subjects, natural and life sciences, social sciences, cultural studies, theology, law and economics. Founded in 1622 and rebuilt in 1962, PLUS is now the largest educational and research institution in Salzburg. Research is driven by three research areas of focus and interaction between scientists from all disciplines promotes interdisciplinary collaboration. In biomedical research, research at PLUS focuses on tumor biology, particularly in the interaction of the immune system with cancer.