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PNAS Papers on Breast Cancer Hypoxia, EMT Networks, Oral Cancer Immune Checkpoints

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.

Researchers from China and the US explore the mechanism behind hypoxia-related metastasis risk in breast cancer, describing a role for the ADAM12 gene in the process. When the team used a series of assays based on PCR, immunoblot, chromatin immunoprecipitation, and other methods to track the expression of ADAM12 and other candidates with potential ties to hypoxia-inducible factors and cancer in human breast cancer cell lines, it found that ADAM12 appeared to mediate an epidermal growth factor receptor signaling pathway prompted by lower-than-usual oxygen levels and hypoxia-inducible factors. While hypoxia-inducible factors appeared to boost expression of the ADAM12 gene, the authors report, their results suggest that cell migration, invasion, and metastasis may be obstructed by dialing down ADAM12 expression with inhibitors. "Taken together," they write, "our findings delineate a molecular mechanism by which ADAM12 activates a critical signal transduction pathway that triggers breast cancer cell motility, invasion, and metastasis."

A University of Texas MD Anderson Cancer Center-led team digs into the signaling pathways and networks that can prompt a process called the epithelial-to-mesenchymal transition (EMT), which occurs as part of normal development and during the progression of some cancers. Using single-cell RNA sequencing, flow cytometry-based cell sorting, mathematical modeling, and other approaches, the researchers followed EMT over time in epithelial cells prompted to go through this transition, characterizing key signaling nodes and cell type-specific EMT progression rates. "We demonstrate the involvement of several EMT-promoting signaling mechanisms in the cross-talk that integrates the tumor microenvironment with the tumor cells themselves to drive their reprogramming," they write, noting that the new work "identified signaling events and regulators at multiple intermediate stages during EMT and advances our knowledge of tumor progression by elucidating targets for developing novel treatment strategies to combat treatment-resistant and metastatic cancer."

Investigators at Boston University, Brigham and Women's Hospital, and the Broad Institute present evidence from mouse model experiments suggesting the aryl hydrocarbon receptor (AhR) may fall at the center of several immune checkpoints in oral squamous cell carcinoma, potentially influencing responses to some immune checkpoint inhibitor-based treatments. While T cell activity appeared to be high — and tumor growth constrained — in mice transplanted with OSCC cells missing the receptor, for example, the team saw enhanced expression of pathways linked to immune checkpoint activity and suppressed immune activity in samples from mice carrying OSCC tumors containing the AhR. Based on these and other findings, the authors argue that AhR not only contributes to immune suppression in the OSCC mouse model, but may also serve as a treatment target for help set the immune system loose on such tumors.

The Scan

Should've Been Spotted Sooner

Scientists tell the Guardian that SARS-CoV-2 testing issues at a UK lab should have been noticed earlier.

For Martian Fuel

Researchers have outlined a plan to produce rocket fuel on Mars that uses a combination of sunlight, carbon dioxide, frozen water, cyanobacteria, and engineered E. coli, according to Gizmodo.

To Boost Rapid Testing

The Washington Post writes that new US programs aim to boost the availability of rapid at-home SARS-CoV-2 tests.

PNAS Papers on Strawberry Evolution, Cell Cycle Regulators, False-Positive Triplex Gene Editing

In PNAS this week: strawberry pan-genome, cell cycle-related roles for MDM2 and MDMX, and more.