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PNAS Papers on Mosquito Gene Drive, Head and Neck Cancer, Precancerous Lesions in Lung

Editor's Note: Some of the articles described below are not yet available at the PNAS site, but they are scheduled to be posted this week.

A team from the UK, US, and Italy explores off-target edits in an Anopheles gambiae malaria mosquito model subjected to a CRISPR-Cas9-based gene drive, using a germline-incorporated version of the Cas9 nuclease enzyme designed to prompt "super-Mendelian inheritance of the transgene by homology-directed repair." Based on their "circular in vitro reporting of cleavage sites by sequencing" (CIRCLE-seq) and targeted deep sequencing experiments on samples from three Anopheles mosquito gene drive populations, the investigators estimated that off-target mutations occur up to 1.42 percent of the time, though those off-target changes do not appear to be subject to the gene drive in the mosquitos. "The findings of this study represent an important milestone for the understanding and managing of CRISPR-Cas9 specificity in mosquitos," they write, "and demonstrates that CRISPR off-target editing in the context of a mosquito gene drive can be reduced to minimal levels."

Investigators at the University of Texas MD Anderson Cancer Center and elsewhere report on findings from an analysis of human papillomavirus (HPV)-negative head and neck squamous cell carcinomas, particularly a so-called "immune paradox" that involves immune suppression in somatic copy number alteration-rich tumors that prompt cytotoxic immune responses in precancerous forms of the disease. From genomic data generated for the Cancer Genome Atlas project, along with molecular profiles on 188 HPV-negative oral precancer cases and dozens of cell lines, the team found that specific deletions involving chromosome 9p and related JAK-STAT pathway deletions not only drive the transition from oral precancers to cancer, but also dial down cytotoxic T cell activity against tumors as well as response to anti-PD-1 immune checkpoint blockade immunotherapy.

A Boston University-led team digs into precancerous lesions that turn up in bronchial tissue prior to lung squamous cell carcinoma development. Using RNA sequencing, immunohistochemistry, and other experiments in mouse models and cell cultures, the researchers saw signs that polarity within bronchial epithelial cells helps to maintain homeostasis, while conditional deletion of a gene called CRB3 led enhanced activity of the transcriptional regulators YAP and TAZ. That, in turn, prompted them to explore the consequences of deleting YAP or TAZ or inhibiting ERBB receptors targeted by YAP/TAZ-regulated genes, which appeared to repair pre-cancerous growth. "Genetic deletion of YAP/TAZ or pharmacological inhibition of ERBB receptors prevents and treats pre-cancer airway lesion development following lung epithelial damage," they write, "offering important knowledge that may guide therapeutic strategies for intercepting the development of squamous lung cancers."

The Scan

More Boosters for US

Following US Food and Drug Administration authorization, the Centers for Disease Control and Prevention has endorsed booster doses of the Moderna and Johnson & Johnson SARS-CoV-2 vaccines, the Washington Post writes.

From a Pig

A genetically modified pig kidney was transplanted into a human without triggering an immune response, Reuters reports.

For Privacy's Sake

Wired reports that more US states are passing genetic privacy laws.

Science Paper on How Poaching Drove Evolution in African Elephants

In Science this week: poaching has led to the rapid evolution of tuskless African elephants.