PLUS: Pediatric Cancer: Vulnerabilities in the Immune Response against Metastases DiscoveredScientists led by Nikolaus Fortelny, Paris Lodron University Salzburg, and Sabine Taschner-Mandl, St. Anna Children’s Cancer Research, have gained new insights into the cell architecture and cell-cell communication of neuroblastoma metastases in a groundbreaking study. Using modern single cell analysis, bone marrow metastases from childhood tumors of the nervous system were analyzed for the first time. The results show that cancer cells prevent certain cells in their environment from fighting the tumor - a process that could be reversed by drugs. The results were published in the renowned journal Nature Communications.
Neuroblastoma is the most common solid tumor in infants and young children. Despite constantly improving treatment options, more than half of patients still experience relapses with a very aggressive form (high-risk neuroblastoma). "The reason we looked at bone marrow metastases is that recurrences often originate there. The tumor cells seem to manipulate their environment so that it supports them in their growth instead of fighting them," explains Sabine Taschner-Mandl, head of the Tumor Biology Group at St. Anna Children’s Cancer Research.
How cancer cells manipulate their neighboring cellsThe study now published therefore investigated the cell architecture and cell-cell communication of neuroblastoma metastases from two major genetic subtypes (MYCN amplification and ATRX mutations, respectively) and those without such changes using single-cell transcriptomics and epigenomics.
"Until now, only primary tumors have been studied in such a detailed manner. The simultaneous use of these methods has not been done before in neuroblastoma metastases," said Irfete Fetahu, co-first author as well as co-corresponding author of the study and postdoctoral fellow in the Tumor Biology Group.
Among other things, the team examined the interaction of the metastasized tumor cells with the healthy bone marrow cells in more detail.
"Specially developed algorithms enabled us to analyze different cells in the bone marrow and also to model their interactions," emphasizes Fortelny, head of the Computational Systems Biology Group, Paris Lodron University Salzburg. "Here, our analysis revealed that certain cells, so-called monocytes, react particularly strongly to the unwanted invaders. In the course of this, they stimulate growth processes and release cytokines that boost tumor growth," Fetahu elaborates.
Interestingly, studies at the epigenetic level showed that although monocytes in the tumor microenvironment are activated to act against cancer cells, they cannot respond appropriately to these signals under the influence of tumor messengers. "The monocytes receive conflicting messages and, so to speak, no longer know what exactly they are supposed to do. As a result, they can no longer perform their normal function of fighting tumors," Fetahu explains the dilemma.
Overcoming manipulation with drugsMuch of the communication between neuroblastoma cells and bone marrow or monocytes occurs via the proteins MK (midkine) and MIF (macrophage migration inhibitory factor) and associated molecules. Signaling pathways controlled by these proteins are upregulated not only on the tumor side but also on the immune cell side.
"Therapeutics directed against MK and MIF interrupt this pathological interaction and are already being tested in other types of cancer. In the future, selective inhibition could make it possible to return the pathologically altered monocytes to their original normal state," says Taschner-Mandl confidently.
Metastases behave differentlyThe researchers also found that cellular plasticity, i.e. the ability of cells to change depending on environmental influences, is preserved during metastasis. In addition, the gene expression of metastasized tumor cells is dependent on the particular neuroblastoma subtype. Thus, neuroblastoma cells that have MYCN amplification generally differ only slightly whether they are present in the primary tumor or metastasize, whereas the opposite is true for tumor cells with ATRX mutation.
"The genetics of the tumor lead to characteristic signals and thus very specific changes in the bone marrow microenvironment, which translates into individual signatures," Taschner-Mandl said. "This could explain why neuroblastoma patients* with ATRX mutation usually tend to respond poorly to their therapy."
About high-risk neuro blastomaNeuroblastomas are the most common solid tumors outside the brain in children. High-risk neuroblastomas are those tumors that have MYCN amplification or metastatic tumors from eighteen months of age. Unfortunately, the prognosis is still unsatisfactory, with only about half of children with high-risk neuroblastoma surviving the disease long-term. Current standard treatment includes chemotherapy, surgery, autologous stem cell transplantation, and isotretionin in combination with immunotherapy.
About Dr. Nikolaus Fortelny (PhD)Dr. Nikolaus Fortelny is an Assistant Professor at the Department of Biosciences and Medical Biology at Paris Lodron University Salzburg. His work is dedicated to the analysis and modeling of complex, biological processes using artificial intelligence and statistical methods. Fortelny studied molecular biology in Vienna and then bioinformatics in Geneva. He received his doctoral degree in Vancouver, Canada. Fortelny then conducted research at the Center for Molecular Medicine (CeMM) in Vienna, including the development of artificial intelligence algorithms that mimic biological networks. His research group at Paris Lodron University Salzburg continues to develop models of biological processes, focusing on the robust and interpretable application of complex algorithms.
about Dr. Sabine Taschner-Mandl (PhD)Dr. Sabine Taschner-Mandl has been leading the Tumor Biology group at St. Anna Children’s Cancer Research since 2018, where she has been working scientifically since 2008. In addition, the researcher holds a teaching position at the Medical University of Vienna as well as the Vienna University of Technology. Taschner-Mandl completed her biology studies at the University of Vienna with a diploma thesis in vaccine development at Intercell. This was followed by a dissertation and a post-doctoral position at the Institute of Immunology at the Medical University of Vienna. In addition to her work at St. Anna Children’s Cancer Research, Taschner-Mandl was a visiting scientist at Significo and the University of Helsinki as part of the EC-FP7 Marie Curie Program. Taschner-Mandl has received numerous grants for her research, including from the Austrian Research Promotion Agency, the Vienna Science Research and Technology Fund, and the European Commission’s ERA-NET initiative.
Irfete S. Fetahu #,*, Wolfgang Esser-Skala#, 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*,§
Nature Communications, June 26, 2023
DOI: 10.1038/s41467’023 -39210-0
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