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Retinoblastoma from human stem cell-derived retinal organoids

Scientists have created a laboratory model for studying retinoblastoma driven by inherited mutations in the RB1 gene (Nat Commun 2021; doi: 10.1038/s41467-021-24781-7). The researchers created retinoblastoma organoid models that closely mimic the biology of tumors in patients. These models provide an important resource for studying the earliest stages of the disease, as well as screening new therapies. One particular problem for models created by knocking out, or eliminating, the RB1 gene has been that, while this mutation is a cornerstone for retinoblastoma in humans, mice with these abnormalities do not develop the disease. Previous research has shown that mouse models for retinoblastoma are not always reliable predictors for preclinical drug development studies. To create a better model for research, the scientists grew what are called retinal organoids. These models are 3D cultures of cells created from induced pluripotent stem cells (iPSCs). The cells were created using samples from retinoblastoma patients who had germline mutations in RB1. Grown and nurtured in the lab, iPSCs develop naturally into retinal tissue. The cells from the organoids were injected into mice, where retinoblastoma tumors eventually formed. The researchers conducted whole-genome sequencing, RNA sequencing, and methylation analysis of these retinoblastoma tumors and found that they were indistinguishable from patient samples. Through their work, the researchers created a large dataset of retinoblastoma single-cell analysis results. This data, alongside the researchers' other work with patient tumors, patient-derived xenografts and the organoid models, is freely available through the Childhood Solid Tumor Network. This resource is available to researchers anywhere, which offers the world's largest and most comprehensive collection of scientific resources for researchers studying pediatric solid tumors and related biology.



A proteogenomic portrait of lung squamous cell carcinoma

Patients with a subtype called lung adenocarcinoma (LUAD) have benefited from the development of new targeted medicines, but the search for effective new therapies for another subtype called lung squamous cell carcinoma (LSCC) has largely come up short. To learn more about the biological basis of LSCC, researchers from the Broad Institute of MIT and Harvard and the National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium (CPTAC), including collaborators from Baylor College of Medicine, have developed the largest and most comprehensive molecular map to date of LSCC. Their effort brings proteomic, transcriptomic, and genomic data together into a detailed "proteogenomic" view of LSCC (Cell 2021; Analysis of that data has revealed potential new drug targets, immune regulation pathways that might help the cancer evade immunotherapies, and even a new molecular subtype of LSCC. Data from the study is available on the CPTAC portal. In their study, the team analyzed DNA, RNA, proteins, and post-translational protein modifications (PTMs, i.e., phosphorylation, acetylation, and ubiquitylation) of 108 tumors before treatment, and compared them with normal tissue. Among the opportunities they saw for the development of new LSCC treatments, the researchers identified the gene NSD3 as a possible target for tumors harboring extra copies of FGFR1, another gene that is often duplicated or amplified in LSCC. Prior efforts have attempted, unsuccessfully, to target FGFR1 directly. The team's proteogenomic findings suggest that NSD3 could be a critical driver of tumor growth and survival in these tumors, making it a potential therapeutic target. They also noted a subset of patients whose tumors exhibited low expression of p63 but high expression of survivin, a protein that regulates cell proliferation and cell death and which is the target of clinical trials in other tumor types. Additionally, the team's data suggested that tumors driven by overexpression of the transcription factor SOX2 may be vulnerable to treatments directed against chromatin modifiers such as LSD1 and EZH2. SOX2 itself is generally considered an "undruggable" target; the team's observations point to an opportunity to develop a therapeutic workaround. Even though immunotherapy represents the greatest advance in LSCC therapy in decades, patient outcomes lag behind those seen with LUAD; only a minority of patients with LSCC exhibit long-term responses. Based on their proteogenomic data, the team presented a detailed picture of the immune landscape of LSCC, highlighting several immune regulation pathways that could serve as targetable points. In particular, their analysis highlighted a subset of tumors that exhibit markers associated with response to immune checkpoint inhibitors (such as PD-1/PD-L1 blockers), and with immune evasion, providing some clues as to why immunotherapy outcomes are so uneven across patients with LSCC. Ubiquitylation is a process by which the cell flags proteins with another small protein called ubiquitin (or its biochemical relatives) to target them for destruction. While this process is important in normal function, when dysregulated it can contribute or lead to disease. The Broad team previously developed UbiFast, a technology that enables deep-scale, high-throughput analysis of ubiquitylation in patient tissue samples. Applied to LSCC, UbiFast revealed complex regulation of metabolic pathways such as glycolysis and oxidative stress driven by molecular crosstalk based on ubiquitylation (or ubiquitin-like modifications) and two other forms of protein modification, phosphorylation (which changes a protein's enzymatic or catalytic activity) and acetylation (which can affect a protein's structure, activity, localization, and stability). Prior efforts have identified four molecular subtypes of LSCC using genomics, corresponding to distinct cell types and processes. With their proteomic perspective, the research team not only gained a deeper understanding of immune, metabolic, and proliferative signals associated with these subtypes, but also uncovered a new epithelial-to-mesenchymal transition subtype. The cells of this new type, they noted, may have greater potential for metastasis, but also feature active, kinase-driven molecular pathways that could be targeted therapeutically.



The exon-junction complex helicase eIF4A3 controls cell fate via coordinated regulation of ribosome biogenesis and translational output

In a new study, researchers have investigated the protein eIF4A3 and its role in the growth of cancer cells (Sci Adv 2021; doi: 10.1126/sciadv.abf7561). The study shows that by blocking or reducing the production of this protein, other processes arise that cause the growth and cell division of cancer cells to cease and eventually die. The research group investigated cultured cancer cells and cancer tissue where the eIF4A3 protein's expression was high compared to normal tissue. By adding synthetically produced small molecules that can later be further developed into finished drugs, the production of eIF4A3 can be checked. The researchers then discovered two distinct changes in the cancer cells. They reported the blocking of eIF4A3 activated the protein p53, which has an important role to play in fighting cancer cells. However, one challenge with many types of tumors is that the positive functions of the p53 protein are counteracted by another protein, MDM2. The researchers noted that blocking eIF4A3 also meant that the MDM2 protein changed. This change helps to maintain and strengthen p53 and can be beneficial in inhibiting the growth of cancer cells. The main conclusions of the study indicate that depletion or inhibition of eIF4A3 activates p53, alters the manufacturing process of proteins by disrupting ribosome biogenesis, and thereby inhibits the growth of cancer cells. Knowledge of the importance of the eIF4A3 protein opens up new opportunities for better and more effective treatment of cancer patients.