Biology subjects

Decker-Farrell, A. R.

Publications and source records attributed to Decker-Farrell, A. R..

4 recordsLinked to original sources

bioRxiv2026

16S ribosomal RNA modification drives transcript-specific translation efficiency

Bacterial ribosomal RNAs (rRNAs) are decorated with conserved nucleotide modifications, but the functionality of these modifications is often underexplored. MraW (RsmH) is a 16S rRNA methyltransferase that fine-tunes ribosomal function. We identified a loss-of-function allele in mraW that corrected a late-stage sporulation defect in Bacillus subtilis by bypassing a key sporulation checkpoint via altered translational regulation. Purified ribosomes isolated from {Delta}mraW cells displayed a [~]2-fold decrease in translation efficiency; in vivo, {Delta}mraW cells produced decreased levels of the sporulation checkpoint protein CmpA. This regulation was mediated by sequences from the 5 untranslated region and the coding sequence of cmpA, which form a step-loop structure that occlude early codons of the mRNA. Proteomic analysis revealed that MraW directly or indirectly regulates the production of multiple proteins, some of which form similar structural elements as the cmpA transcript. We propose that MraW modification of 16S rRNA enhances translation efficiency in general, and that specific transcripts, whose gene products are likely required in limiting quantities, have evolved structural features that act as a regulatory mechanism to govern protein levels. This type of regulation may be most apparent in bacteria which exhibit uncoupled transcription and translation. HIGHLIGHTSO_LIA conserved 16S rRNA modification enhances translation of structured mRNAs C_LIO_LIEarly mRNA stem-loops impose translational control dependent on ribosome modification C_LIO_LImRNA structure and rRNA modifications likely co-evolved to fine-tune protein dosage C_LI

microbiology↗

bioRxiv2024

Tumor-selective treatment of metastatic pancreatic cancer with an engineered, probiotic living drug

Pancreatic ductal adenocarcinoma (PDAC) poses significant challenges for effective treatment, with systemic chemotherapy often proving inadequate due to poor drug delivery and the tumors immunosuppressive microenvironment. Engineered bacteria present a novel approach to target PDAC, leveraging their ability to colonize tumors and deliver therapeutic payloads. Here, we engineered probiotic Escherichia coli Nissle 1917 (EcN) to produce the pore-forming Theta toxin (Nis-Theta) and evaluated its efficacy in a preclinical model of PDAC. Probiotic administration resulted in selective colonization of tumor tissue, leading to improved overall survival compared to standard chemotherapy. Moreover, this strain exhibited cytotoxic effects on both primary and distant tumor lesions while sparing normal tissues. Importantly, treatment also modulated the tumor microenvironment by increasing anti-tumor immune cell populations and reducing immunosuppressive markers. These findings demonstrate the potential of engineered probiotic bacteria as a safe and effective therapeutic approach for PDAC, offering promise for improved patient outcomes.

cancer biology↗

bioRxiv2023

Tumor-selective effects of active RAS inhibition in pancreatic ductal adenocarcinoma

Broad-spectrum RAS inhibition holds the potential to benefit roughly a quarter of human cancer patients whose tumors are driven by RAS mutations. However, the impact of inhibiting RAS functions in normal tissues is not known. RMC-7977 is a highly selective inhibitor of the active (GTP-bound) forms of KRAS, HRAS, and NRAS, with affinity for both mutant and wild type (WT) variants. As >90% of human pancreatic ductal adenocarcinoma (PDAC) cases are driven by activating mutations in KRAS, we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models, including human and murine cell lines, human patient-derived organoids, human PDAC explants, subcutaneous and orthotopic cell-line or patient derived xenografts, syngeneic allografts, and genetically engineered mouse models. We observed broad and pronounced anti-tumor activity across these models following direct RAS inhibition at doses and concentrations that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumor versus normal tissues. Treated tumors exhibited waves of apoptosis along with sustained proliferative arrest whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS inhibition in the setting of PDAC.

cancer biology↗

bioRxiv2023

Tumor Explants Elucidate a Cascade of Paracrine SHH, WNT, and VEGF Signals Driving Pancreatic Cancer Angiosuppression

The sparse vascularity of Pancreatic Ductal Adenocarcinoma (PDAC) presents a mystery: what prevents this aggressive malignancy from undergoing neoangiogenesis to counteract hypoxia and better support growth? An incidental finding from prior work on paracrine communication between malignant PDAC cells and fibroblasts revealed that inhibition of the Hedgehog (HH) pathway partially relieved angiosuppression, increasing tumor vascularity through unknown mechanisms. Initial efforts to study this phenotype were hindered by difficulties replicating the complex interactions of multiple cell types in vitro. Here we identify a cascade of paracrine signals between multiple cell types that act sequentially to suppress angiogenesis in PDAC. Malignant epithelial cells promote HH signaling in fibroblasts, leading to inhibition of WNT signaling in fibroblasts and epithelial cells, thereby limiting VEGFR2-dependent activation of endothelial hypersprouting. This cascade was elucidated using human and murine PDAC explant models, which effectively retain the complex cellular interactions of native tumor tissues.

cancer biology↗