HBEGF

Study offers first in-depth analysis of the microenvironment of neuroblastoma and its response to chemotherapy PHILADELPHIA, April 14, 2025 /PRNewswire/ -- Researchers at Children's Hospital of Philadelphia (CHOP) developed a longitudinal atlas of neuroblastoma, a common and potentially deadly childhood cancer, to gain deeper understanding into precise molecular mechanisms underlying why and how certain treatments eventually become ineffective. The findings, which offer insights that could potentially lead to new personalized medicine approaches in neuroblastoma treatment, were published today in the journal Nature Genetics. Despite significant advances in the standard of care, the 5-year survival rate of high-risk neuroblastoma after diagnosis remains less than 50%. Neuroblastoma cells within the same tumor can vary greatly, which creates challenges in treatment efficacy. Until now, the scientific community lacked understanding of how the tumor microenvironment changes during treatment. In this study, researchers created a cell atlas that afforded the first in-depth look at how different cell types, like malignant cells and immune cells, interact and change within their natural environment, which led to valuable new insights. "Our atlas provides a crucial foundation for developing novel treatments by mapping the complex interactions between malignant cells and surrounding cells that support tumor growth," said senior study author Kai Tan, PhD, a professor in the Department of Pediatrics at Children's Hospital of Philadelphia who spearheads CHOP's participation in the National Cancer Institute (NCI) Human Tumor Atlas Network (HTAN). "As researchers, we look to use these insights to tailor therapies to target unique characteristics of a patient's tumor. Overall, we are optimistic about the doors our research and techniques are opening." In this study, CHOP researchers used advanced single cell sequencing and spatial omics techniques to analyze the transcriptional, epigenetic and proteomic profiles of tumor samples from 22 pediatric patients with high-risk neuroblastoma before and after induction chemotherapy. This multidimensional dataset can be accessed from the HTAN data portal. The authors uncovered diverse tumor and non-tumor cell characteristics, as well as major changes in these characteristics following chemotherapy. They found that patients had worse outcomes when cancer cells were multiplying more actively and became more metabolically active. Conversely, tumors that developed more mature, neuron-like features resulted in better outcomes in patients. Additionally, researchers found that an increase in a type of mesenchymal-like tumor cells was linked to poorer responses in chemotherapy. Certain immune cells (e.g. macrophages) became more active in ways that led to tumor growth by enabling blood vessel growth while suppressing the immune response. Researchers also discovered a specific communication pathway (HB-EGF/ERBB4) between macrophages and cancer cells that triggered signals promoting tumor growth. These findings highlight the importance of identifying new factors inside the tumor's microenvironment that influence how high-risk neuroblastoma responds to treatment. Using preclinical models, the researchers are further testing this pathway with the goal of eventually translating the findings to novel therapeutic strategies. "Studies of this magnitude are only made possible by monumental team efforts," said Wenbao Yu, PhD, a lead author of the study and a Research Assistant Professor at Children's Hospital of Philadelphia. "With the collaboration of biologists, clinicians, and computational scientists, we were able to gain new insights into the complex ecosystem of neuroblastoma."   The research was supported by the National Cancer Institute (NCI) Human Tumor Atlas Network grant under award (#U2C CA233285). Additional support includes National Institutes of Health (NIH) grant (U54 HL165442), American Cancer Society Institutional Research Grant (IRG-22-150- 41-IRG) and NIH grant (T32 CA009140). Yu et al. "Longitudinal single-cell multiomic atlas of high-risk neuroblastoma reveals chemotherapy-induced tumor microenvironment rewiring. Nature Genetics. Online April 14, 2025. DOI: 10.1038/s41588-025-02158-6. About Children's Hospital of Philadelphia: A non-profit, charitable organization, Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, the hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. The institution has a well-established history of providing advanced pediatric care close to home through its CHOP Care Network, which includes more than 50 primary care practices, specialty care and surgical centers, urgent care centers, and community hospital alliances throughout Pennsylvania and New Jersey. CHOP also operates the Middleman Family Pavilion and its dedicated pediatric emergency department in King of Prussia, the Behavioral Health and Crisis Center (including a 24/7 Crisis Response Center) and the Center for Advanced Behavioral Healthcare, a mental health outpatient facility. Its unique family-centered care and public service programs have brought Children's Hospital of Philadelphia recognition as a leading advocate for children and adolescents. For more information, visit . Contact: Jennifer Lee Children's Hospital of Philadelphia (267) 426-6084 [email protected] SOURCE Children's Hospital of Philadelphia WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

Thanks to laboratory produced human mini-retinas, researchers were able to observe complex changes in the retina as they occur in macular degeneration. This enabled them to discover the so-called cell extrusion as a potential mechanism for neurodegenerative diseases. Visual cells in the human retina may not simply die in some diseases, but are mechanically transported out of the retina beforehand. Scientists from the Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) and the Center for Regenerative Therapies Dresden (CRTD) at TU Dresden have now discovered this. For their research, they used miniature human retinas produced in the laboratory, so-called organoids. In the new issue of the journal Nature Communications, they report on their discovery, which paves the way for completely new research approaches, especially in connection with age-related macular degeneration (AMD). "This principle, known as cell extrusion, has not yet been studied in neurodegenerative diseases," says Prof. Mike Karl, who heads the research group. AMD is the main cause of blindness and severe visual impairment in Germany. It is estimated that a quarter of people over the age of 60 suffer from AMD. The macula is a special region within the human retina that is needed, among other things, for high resolution color vision. In AMD, thousands of light-sensitive visual cells, the so-called photoreceptor cells, are lost in the macula. "This was the starting point for our research project: we observed that photoreceptors are lost, but we could not detect any cell death in the retina," explains Mike Karl, who conducts research at the Dresden site of the DZNE and the CRTD at TU Dresden. "Half of all photoreceptors disappeared from the retinal organoid within ten days, but obviously they did not die in the retina. That made us curious." For the researchers -- the DZNE and the CRTD were involved, as well as the Helmholtz Centre for Environmental Research (UFZ) -- an elaborate search for the causes began. This led them to a study from 2012 (doi: 10.1038/nature10999): Jody Rosenblatt from King's College in London was the first to describe the extrusion of living cells -- the mechanical ejection of cells from epithelia. The thereby extruded cells then only die in succession. She demonstrated this mechanism in simple epithelial cells of the kidney. Mike Karl and his team now showed in their pioneering work that this extrusion can also be triggered in the much more complex retina, consisting of several different cell types, and leads to neurodegeneration. Interestingly, this cell extrusion could explain the outlying cells that have been previously reported in the ageing and diseased retina of patients with AMD and other diseases, but have not been studied in detail until now. The researchers made use of a technique they had previously developed: They worked with so-called retinal organoids -- an organ-like, three-dimensional model of the human retina grown from human stem cells in the laboratory. These organoids provide some characteristics of the human macula. The team found that two substances previously described in various neurodegenerative diseases -- the proteins HBEGF and TNF -- are sufficient to trigger degeneration in the retinal organoid. During this process, the researchers filmed the organoids in real time by so-called live imaging, considered as the gold standard for cell tracking. "We were able to capture the degeneration of photoreceptors through cell extrusion in the lab," says Mike Karl. The scientists found that this extrusion is triggered by activation of the protein PIEZO1, a sensor for biomechanical forces. That biomechanics may play a larger role in retinal degeneration is a new finding. "The retina is not known to be a biomechanically active tissue such as a muscle. It was known that diseases of the nervous system are associated with changes in the shape of cells, but to which extent biomechanical regulators are involved has not yet been studied in detail," says Karl. Thanks to the organoids, he and his team were able to observe the processes in an accelerated manner, so to speak: While it takes several years or even decades for photoreceptors to disappear in patients, such a process could now be reproduced in the laboratory in just 40 days. In the next step, the researchers now want to find out whether this mechanism occurs in human patients in the same way as in organoids. Initial findings suggest that this might be the same mechanism, but proof is still lacking. In their study, the Dresden researchers also found that pharmacological agents could prevent extrusion in an experimental setting in their model. They used a special snake venom to block the mechanosensor PIEZO1 on the cells. As a result, not only were the photoreceptors not ejected, but further pathological changes in the retina were prevented. "This gives hope for the development of future preventive and therapeutic treatments for complex neurodegenerative diseases such as AMD," Mike Karl sums up.