Structural variants drive context-dependent oncogene activation in cancer.

Higher-order chromatin structure is important for the regulation of genes by distal regulatory sequences1,2. Structural variants (SVs) that alter three-dimensional (3D) genome organization can lead to enhancer-promoter rewiring and human disease, particularly in the context of cancer3. However, only a small minority of SVs are associated with altered gene expression4,5, and it remains unclear why certain SVs lead to changes in distal gene expression and others do not. To address these questions, we used a combination of genomic profiling and genome engineering to identify sites of recurrent changes in 3D genome structure in cancer and determine the effects of specific rearrangements on oncogene activation. By analysing Hi-C data from 92 cancer cell lines and patient samples, we identified loci affected by recurrent alterations to 3D genome structure, including oncogenes such as MYC, TERT and CCND1. By using CRISPR-Cas9 genome engineering to generate de novo SVs, we show that oncogene activity can be predicted by using 'activity-by-contact' models that consider partner region chromatin contacts and enhancer activity. However, activity-by-contact models are only predictive of specific subsets of genes in the genome, suggesting that different classes of genes engage in distinct modes of regulation by distal regulatory elements. These results indicate that SVs that alter 3D genome organization are widespread in cancer genomes and begin to illustrate predictive rules for the consequences of SVs on oncogene activation.

LARP4 is an RNA-binding protein that binds nuclear-encoded mitochondrial mRNAs to promote mitochondrial function.

Mitochondria-associated RNA-binding proteins (RBPs) have emerged as key contributors to mitochondrial biogenesis and homeostasis. With few examples known, we set out to identify RBPs that regulate nuclear-encoded mitochondrial mRNAs (NEMmRNAs). Our systematic analysis of RNA targets of 150 RBPs identified RBPs with a preference for binding NEMmRNAs, including LARP4, a La RBP family member. We show that LARP4's targets are particularly enriched in mRNAs that encode respiratory chain complex proteins (RCCPs) and mitochondrial ribosome proteins (MRPs) across multiple human cell lines. Through quantitative proteomics, we demonstrate that depletion of LARP4 leads to a significant reduction in RCCP and MRP protein levels. Furthermore, we show that LARP4 depletion reduces mitochondrial function, and that LARP4 re-expression rescues this phenotype. Our findings shed light on a novel function for LARP4 as an RBP that binds to and positively regulates NEMmRNAs to promote mitochondrial respiratory function.

Laparoscopic cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: a prospective clinical trial and comparative analysis.

BACKGROUND: Open cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is associated with high morbidity, which limits the degree to which patients may benefit from this therapy. This study aimed to determine the feasibility of laparoscopic CRS/HIPEC. METHODS: This was a single institution prospective clinical trial and comparative study using historical controls. Patients with histologically confirmed peritoneal surface malignancy (PSM) of appendiceal, colorectal, ovarian, or primary peritoneal origin, peritoneal carcinomatosis index (PCI) [Formula: see text] 10 were eligible. RESULTS: Clinical trial: 18 patients (median age 57 years, 39% female) with appendiceal (15) or colorectal (3) primary PSM underwent laparoscopic CRS/HIPEC. Median and range outcomes were: operative time 219 min (134-378), EBL 10 mL (0-100), time to return to bowel function 3 days (1-7), duration IV narcotic use 3 days (1-8), length of stay 6 days (3-11). All patients had a complete cytoreduction (CC-score 0). Three (17%) experienced minor morbidity, with no major morbidity or mortality. Median DFS and OS were not reached with median follow-up of 48 months. Comparative analysis: Laparoscopic approach associated with reduced time to return of bowel function (3 versus 4 days, p = 0.001), length of stay (8 versus 5 days, p < 0.001), and morbidity (16% versus 42%, p = 0.008). Independent predictors of DFS included prior chemotherapy (HR 5.07, 95% CI 1.85, 13.89; p = 0.002), and CC-score > 0 (HR 3.31, 95% CI 1.19, 9.41; p = 0.025), but not surgical approach. CC-score > 0 was the only independent predictor of OS (HR 10.12, 95% CI 2.16, 47.30, p = 0.003). CONCLUSIONS AND RELEVANCE: Laparoscopic CRS/HIPEC should be considered for patients with PSM with low-volume disease, including those with adenocarcinoma histology. TRIAL REGISTRATION: Clinicaltrials.gov; NCT02463877.

Claudin 7 suppresses invasion and metastasis through repression of a smooth muscle actin program.

Metastasis initiates when cancer cells escape from the primary tumor, which requires changes to intercellular junctions. Claudins are transmembrane proteins that form the tight junction, and their expression is reduced in aggressive breast tumors. However, claudins' roles during breast cancer metastasis remain unclear. We used gain- and loss-of-function genetics in organoids isolated from murine breast cancer models to establish that Cldn7 suppresses invasion and metastasis. Transcriptomic analysis revealed that Cldn7 knockdown induced smooth muscle actin (SMA)-related genes and a broader mesenchymal phenotype. We validated our results in human cell lines, fresh human tumor tissue, bulk RNA-seq, and public single-cell RNA-seq data. We consistently observed an inverse relationship between Cldn7 expression and expression of SMA-related genes. Furthermore, knockdown and overexpression of SMA-related genes demonstrated that they promote breast cancer invasion. Our data reveal that Cldn7 suppresses breast cancer invasion and metastasis through negative regulation of SMA-related and mesenchymal gene expression.