Danish Cancer Institute’s Post

Cancer isn't a single, straightforward disease. It's more akin to a collection of malevolent molecular adaptations used by cells to grow out of control. To effectively combat cancer, we need to understand these adaptations at the molecular level. MicroRNAs are tiny RNA molecules that act like orchestra conductors inside our cells. They have the remarkable ability to silence hundreds of genes in a coordinated manner, regulating crucial processes such as cell division and migration. When these processes go awry, it can lead to the aggressive behaviours exhibited by cancer cells. Recent discoveries have shed light on mutations in the proteins responsible for safeguarding the integrity of microRNAs in cancer patients. These mutations cause microRNAs loaded into these defective proteins to degrade much faster, potentially contributing to tumor formation. With the support of a grant from the NEYE Fonden, our research aims to delve into the intricate molecular mechanisms underlying microRNA regulation in tumours. This project will be lead by Dr. Nina Nelson, a Walter Benjamin Postdoctoral fellowship awarded by Deutsche Forschungsgemeinschaft (DFG) - German Research Foundation, who recently joined out team. Together, we will investigate what factors cause microRNAs to degrade over time and explore the mechanisms cells employ to repair damaged microRNAs. By gaining a deeper understanding of these molecular processes, we hope to pave the way for the development of therapies that prevent the decay of microRNAs, even when loaded into defective proteins. Ultimately, our goal is to harness these insights to develop more effective therapeutic strategies. #MicroRNAs #CancerResearch #NEYEFoundation #DFG

Pinning down answers to fight cancer with groundbreaking research. Published in Molecular Cell, Dr. Rina Rosenzweig and her lab in the Department of Chemical and Structural Biology, Weizmann Institute of Science, have uncovered new information with the possibility to develop new and targeted cancer treatments. Some proteins (“guardian proteins”) work hard to protect the body from cancerous growths, they have accompanying “chaperone proteins” to help the proteins in their folding. Unfortunately, sometimes, the proteins succumb to genetic mutations and the chaperones do not detect the change of work. That is where Dr. Rosenzweig’s team comes in. They discovered a mechanism in which the chaperone can help the protein out and help protect a protein with a cancerous mutation. Dr. Rosenzweig says, “Our study presents the potential target of such treatments, which would reduce DNAJA2’s cancer-supporting activity.” Read more in the article below. https://lnkd.in/dBWyJhx9 #cancer #research #protein #Weizmann

Honored to contribute my scientific expertise to such a groundbreaking project addressing prostate cancer in Africa. This study is particularly close to my heart, as I belong to the demographic with the highest global incidence and mortality rates for prostate cancer (men of African descent). I hope that through increased awareness, routine screening will become a reality across the continent, helping to save lives. A heartfelt thank you to the Men of African Descent and Carcinoma of the Prostate (MADCaP) network for their incredible work and dedication to this cause. Together, we are making strides toward a healthier future. The link to the research briefing for this study: https://lnkd.in/dGVHscRx The full paper is published in Nature Genetics: https://lnkd.in/dZTs4UPa

🔬 Researchers from the University of Sheffield and St. Anna CCRI have created a model designed to investigate the origins of neuroblastoma, a cancer primarily affecting infants and young children. 🔗: https://shorturl.at/jxABU 👉 A new model developed by researchers at the The University of Sheffield (Anestis Tsakiridis), working closely with colleagues from St. Anna Children's Cancer Research Institute (CCRI) (Florian Halbritter), replicates the emergence of early neuroblastoma cancer-like cells giving an insight into the genetic pathway of the disease. 📌 The research, published in Nature Communications, sheds light on the intricate genetic pathways which initiate neuroblastoma. An international team found that specific mutations in chromosomes 17 and 1, combined with overactivation of the MYCN gene, play a pivotal role in the development of aggressive neuroblastoma tumors. 👉 Childhood cancer is often diagnosed and detected late in the process, leaving researchers with very little idea of the conditions that led to tumor initiation, which occurs very early during foetal development. In order to understand tumor initiation, models which truthfully recreate the conditions that lead to the appearance of a tumor are needed. 📸 ©Dr. Ingrid Saldana

Among the thousands of DNA mutations that can be detected in cancer, how to identify the few mutations that matter most? Soufyan Lakbir offers a solution, by developing the tool CIBRA: Computational Identification of Biologically Relevant Alterations. Our study demonstrates that there are still many oncogenes and tumor suppressor genes to be discovered, which deserve to be studied in more detail for their putative impact on treatment of cancer and patient survival. Want to know more? Our paper was just published online in #Bioinformatics, Proceedings of #ECCB2024 https://lnkd.in/e48x5BcU Many thanks to the team: Soufyan Lakbir, Caterina Buranelli, Gerrit Meijer, Jaap Heringa, Sanne Abeln   The Netherlands Cancer Institute, Vrije Universiteit Amsterdam (VU Amsterdam), Utrecht University This work was funded a.o. by Health~Holland #cancer #biomarkers

A new study led by The University of Texas Health Science Center at San Antonio (UT Health San Antonio) is shedding light on a novel role of breast cancer gene 1 (BRCA1) in tumor suppression. Individuals with inherited mutations in BRCA1 are predisposed to breast, ovarian and other cancers. BRCA1 helps prevent cancer by repairing damaged DNA, but how it does so is yet to be determined. The damage in question is the DNA double-strand break, where both strands of DNA are broken and can lead to cancer if not repaired or if repaired inaccurately. The new research led by UT Health San Antonio shows that BRCA1 not only pushes a DNA break toward an accurate DNA repair mechanism called homologous recombination (HR) but also promotes subsequent steps by spurring the activity of "end resection enzymes" that process DNA ends to prepare them for HR. "Our biochemical analysis with purified BRCA1 protein helps illuminate its role in DNA end processing," said Patrick Sung, DPhil, associate dean for research at UT Health San Antonio and director of its Greehey Children's Cancer Research Institute. He is a senior author of the new study titled, "Promotion of DNA end resection by BRCA1-BARD1 in homologous recombination," published Sept. 11 in the journal Nature.

What drives aggressive bone cancer? New research, published in the journal Cell, solves the mystery of what drives the genomic rearrangements causing the aggressive development and evolution of osteosarcoma tumors. By analysing the largest collection of whole-genome data from osteosarcoma patients, the researchers identified a new mutation mechanism, called loss-translocation-amplification (LTA) chromothripsis, which is present in approximately 50% of high-grade osteosarcoma cases. By analysing genomic data from a large cohort of osteosarcoma patients, the researchers uncovered the prevalence of LTA chromothripsis in approximately 50% of both paediatric and adult high-grade osteosarcomas. However, it very rarely occurs in other cancer types, thus highlighting the need for large-scale analysis of rare cancers to identify the distinct mutations that underpin their evolution. Predicting the prognosis – the likely course of the disease – for osteosarcoma patients remains a major unmet need. As part of this study, the team also presented a novel prognostic biomarker for osteosarcoma: loss of heterozygosity (LOH). LOH occurs when one copy of a genomic region is lost. In osteosarcoma, a high degree of LOH across the genome predicts a lower survival probability. #ScienceMission #sciencenewshighlights https://lnkd.in/giNRqV4w

It is with great excitement that I am pleased to announce that our latest research paper has been published today in Nature Cell Biology. Here we show that delays in mitosis, indicative that a cell has encountered problems in aligning and segregating its chromosomes, are accompanied by time-dependent autocatalytic destruction of the p53 E3 ubiquitin ligase MDM2. If a cell completes cell division in a normal time frame, G1 daughter cells still retain sufficient MDM2 to limit p53 activity in early G1, and the cell continues into the next cell cycle. If, however, a cell spends longer than a threshold time in mitosis (60-90 minutes in hTERT-RPE1 cells), MDM2 levels fall below the level required to restrain p53 signalling in early G1. Now unopposed, p53 is stabilised and triggers transcription of its downstream target gene p21, leading to CDK inhibition and sustained G1 cell cycle arrest. This protective mitotic timer pathway is lost in cancer cells harbouring mutations in p53 or its downstream effector p21. Cancer cells often have more chromosomes due to ploidy changes, and consequently spend more time in mitosis to align and segregate these supernumerary chromosomes. Loss of the mitotic timer pathway allows these cancer cells to circumvent this protective response and carry on proliferating despite the mitotic delays. Thus, our study sheds new light on the role of the p53 pathway in detecting and responding to potentially harmful stresses, and uncovers a new role for MDM2 in detecting mitotic delays and in doing so, protecting against genome instability and aneuploidy. This has been a fantastic project to work on in the lab and I would like to thank my incredibly talented colleagues who have collectively driven this project forward. My thanks also go to our funding body Cancer Research UK who funded the work. Please read the full story here: https://lnkd.in/e9eRe3ga

Dr. Nir Ben Chetrit highlighted the dual roles of macrophages in tumor biology: pro-inflammatory that reside mostly in the tumor nest, and anti-inflammatory that can be found mostly in the stroma. He emphasized the need to reprogramming anti-inflammatory phenotype macrophage into inflammatory ones in the context of I-O and especially PD1 blockade strategy. 📈To improve anti-PD1 based treatment outcomes, two approaches are mainly proposed: targeting macrophage abundance and addressing their immunosuppressive functions. Using a novel ex vivo organotypic tumor microenvironment (oTME) model and murine studies, they mapped the functional heterogeneity of tumor-associated macrophages (TAMs), highlighting that spatial information is the main key to understand macrophage heterogeneity. 🔑Key findings revealed that Notch4 mediates self-renewal of TAMs; its inhibition reduced tumor growth and lung dissemination in triple-negative breast cancer models. Dr. Ben Chetrit stressed the need for developing innate immune strategies, particularly targeting Notch4 to reverse macrophage-related immunosuppression.

It's been a distinct pleasure working on an exciting international project that was just published today in the Journal of Clinical Investigation, between my group at the British Columbia Cancer Research Institute and my OICR colleagues (Valentina Evdokimova, Peter Ruzanov, Lincoln Stein, Laszlo Radvanyi, and others), the Stefan Burdach group at Technical University Munich, and the Michael Cox group at the Vancouver Prostate Centre. In this study, we show that driver oncoproteins in Ewing sarcoma and prostate carcinoma cause tumor cells to express distinct types of RNA known as repeat element RNAs, and then to package these RNAs into structures called extracellular vesicles. What is surprising is that these types of RNA, including HERVK and HSAT2,3 RNAs, are typically not expressed in normal cells, as they are encoded in regions of DNA that are transcriptionally silent, or turned off; i.e. so-called heterochromatic DNA. These vesicles then go out into the tumor microenvironment (TME), where they interact with normal stromal cells, including immune cells. This effectively causes inflammation and DNA damage in the surrounding normal cells, leading to immunosuppression within the local environment, or in the neighborhoods that the tumor cells might spread to. We are excited about how further studies could lead to strategies to prevent this process, which may have profound implications for therapies directed against these diseases.