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Cell Studies on Pancreatic Cancer, Double-Strand Break Repair Profiling, Mitochondrial Gene Silencing

A team from Canada and Germany looks at pancreatic ductal adenocarcinoma (PDAC) tumor microenvironments. Using clinical data, tissue phenotypes, multi-omic profiling, and laser capture microdissection methods, the researchers detected distinct "sub-tumor microenvironments" (subTMEs) in samples from 210 advanced PDAC cases. Those "deserted," "reactive," and intermediate subTMEs were subsequently assessed with three-dimensional experimental models and in the context of PDAC patient outcomes, they report. In particular, chemoprotective "deserted" subTMEs were marked by lower-than-usual tumor-suppressive immune features and activated fibroblast cells, becoming more common after chemotherapy, the authors note, while immune-rich "reactive" subTMEs contained more complex communities of activated fibroblasts cells, pro-growth features, and aggressive tumor cell features. "The intra-tumoral co-occurrence of subTMEs produced patient-specific phenotypic and computationally predictable heterogeneity tightly linked to malignant biology," they write, noting that the pancreatic cancer TME "is not random, but marks fundamental tissue organizational units."

Researchers at the University of California, San Francisco, the Massachusetts Institute of Technology, and Princeton University describe a high-throughput, CRISPR interference-based sequencing strategy called "Repair-seq" for profiling DNA double-strand break (DSB) repair. The team applied Repair-seq to cells subjected to systematic DSB-related gene knockdown, following the effects of DSBs introduced by Cas9 or Cas12a nuclease enzyme in cells with or without the addition of oligonucleotides involved in homology-directed repair. "Systematic interrogation of this data uncovered unexpected relationships among DSB repair genes and demonstrated that repair outcomes with superficially similar sequence architectures can have markedly different genetic dependencies," the authors report. "This work provides a foundation for mapping DNA repair pathways and for optimizing genome editing across diverse modalities."

Finally, a University Medical Center Gottingen-led team outlines an in vitro method for blocking specific mitochondrial messenger RNA translation with chemically synthesized precursor morpholino chimeras in purified mitochondria. The researchers used this approach to investigate translation, ribosome assembly, and ribosome interaction patterns for components of the mitochondria-encoded oxidative phosphorylation system, including bicistronic messenger RNAs such as the ATP8/ATP6 transcript that code for two proteins. "Our data show that this in vitro system to target mitochondrial gene expression at the level of translation provides a powerful approach to dissect the mechanism of translation but also the biology of mitochondrial transcripts at large," the authors conclude.