Year: 2023
Type: article
Abstract: A major pharmacological assumption is that lowering disease-promoting protein levels is generally beneficial. For example, inhibiting metastasis activator BACH1 is proposed to decrease cancer metastases. Testing such assumptions requires approaches to measure disease phenotypes while precisely adjusting disease-promoting protein levels. Here we developed a two-step strategy to integrate protein-level tuning, noise-aware synthetic gene circuits into a well-defined human genomic safe harbor locus. Unexpectedly, engineered MDA-MB-231 metastatic human breast cancer cells become more, then less and then more invasive as we tune BACH1 levels up, irrespective of the native BACH1. BACH1 expression shifts in invading cells, and expression of BACH1's transcriptional targets confirm BACH1's nonmonotone phenotypic and regulatory effects. Thus, chemical inhibition of BACH1 could have unwanted effects on invasion. Additionally, BACH1's expression variability aids invasion at high BACH1 expression. Overall, precisely engineered, noise-aware protein-level control is necessary and important to unravel disease effects of genes to improve clinical drug efficacy.
Source: Nature Chemical Biology
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $11,690
Funders: U.S. Department of Health and Human Services, Roswell Park Alliance Foundation, Roswell Park Cancer Institute, Irma T. Hirschl Trust, Bergmark Foundation, National Institutes of Health, National Cancer Institute, National Institute of General Medical Sciences, Laufer Center for Physical and Quantitative Biology, Stony Brook University
Awards: Regulation of RKIP Function, G2023241003, G234907677, G3015188539, Recording the natural history of cancer progression using a Crainbow model of HER2+ cancer, G3383766017, G3396040047, G3753100843, G3901559682, G4693961085, G4801435656, Defining the role of type III collagen and the collagen-binding receptor DDR1 in metastatic dormancy, G5520316217, Regulation of non-proteolytic ubiquitination in cancer chemoresistance and progression, G7825900601, G9000025035, Dynamics and evolution of synthetic and natural gene regulatory networks, The Tisch Cancer Institute - Cancer Center Support Grant
OpenAlex ID: W4378212594