Biology subjects

Widmer, J.

Publications and source records attributed to Widmer, J..

2 recordsLinked to original sources

bioRxiv2023

Neoadjuvant Therapy Differentially Remodels Carcinoma and Tumor Microenvironment in Pancreatic Ductal Adenocarcinoma: Insights from Spatially Resolved Transcriptomics

PurposeNeoadjuvant therapy (NAT) is increasingly being used for pancreatic ductal adenocarcinoma (PDAC) treatment. However, its distinct effects on carcinoma cells and the tumor microenvironment (TME) are not fully understood. This study employs spatial transcriptomics and single-cell RNA sequencing to investigate how NAT differentially remodels PDACs carcinoma cells and TME. Experimental DesignWe used spatial transcriptomics to compare gene expression profiles in carcinoma cells and the TME between NAT-treated and NAT-naive PDAC patients and correlated with their clinicopathologic features. Complementary single-nucleus RNA sequencing (snRNA-seq) analysis was conducted to validate our findings and identify cell types driving NAT-induced gene expression alterations. ResultsWe found NAT not only induces apoptosis and inhibits proliferation in carcinoma cells but also significantly remodels the TME. Notably, NAT induces a coordinated upregulation of multiple key complement genes (C3, C1S, C1R, C4B and C7) in the TME, making the complement pathway one of the most significantly affected pathways by NAT. Patients with higher TME complement expression following NAT exhibit improved overall survival; more immunomodulatory and neurotrophic cancer-associated fibroblasts (CAFs); more CD4+ T cells, monocytes and mast cells; and lower immune exhaustion gene expression. snRNA-seq analysis demonstrates C3 complement upregulation specifically in CAFs but not in other stroma cell types. ConclusionsOur findings indicate that NAT may reduce immunosuppression in PDAC by enhancing complement production and signaling within the TME. These findings suggest that local complement dynamics could serve as a novel biomarker for prognosis, evaluating treatment response and resistance, and guiding therapeutic strategies in NAT-treated PDAC patients. Translational RelevanceAs neoadjuvant therapy (NAT) increasingly becomes the preferred approach in treating resectable and borderline resectable pancreatic ductal adenocarcinoma (PDAC), there is a growing demand for novel biomarkers specifically tailored for post-NAT PDAC patients. Our study focused on how NAT differentially remodels the tumor cells and the tumor microenvironment (TME). We demonstrate that NAT can enhance local complement production and signaling in PDACs TME, which is associated with reduced immune exhaustion and improved overall survival. Our results highlight the importance of local complement dynamics in influencing treatment response, resistance, and overall clinical outcomes in PDAC. This new mechanism provides new opportunities in biomarker development which could facilitate more accurate prognostication and precise treatment stratification, particularly for patients undergoing NAT in PDAC.

genomics↗

bioRxiv2020

Bioremediation Potential of Select Bacterial Species for the Neonicotinoid Insecticides, Thiamethoxam and Imidacloprid

The neonicotinoid insecticides, including thiamethoxam (THM) and imidacloprid (IMI), have become increasingly favored in the past decade due to their specificity as insect neurotoxicants. However, neonicotinoids have been implicated as a potential contributing factor in Colony Collapse Disorder (CCD), the widespread disappearance of honey bees, which affects produce production on a global scale. The environmental persistence of neonicotinoids underscores the importance of developing a sustainable, ecologically-friendly remediation technique to remove residual insecticides from the environment. The present study characterizes the neonicotinoid bioremediation potential of six bacterial species: Pseudomonas fluorescens, Pseudomonas putida, Pseudomonas aeruginosa, Alcaligenes faecalis, Escherichia coli, and Streptococcus lactis. In Phase I, we evaluated the utilization of IMI or THM as the sole carbon or nitrogen source by P. fluorescens, P. putida, and P. aeruginosa. All three species were better able to utilize THM over IMI as their sole carbon or nitrogen source, and better growth was noted when THM was used as the sole nitrogen source compared to the sole carbon source. Thus, further studies proceeded with THM only. In Phase II, we assessed the kinetics of THM removal from aqueous media by the six species. Significant (p<0.0001) reductions in 70 mg/L THM concentration were observed for P. fluorescens (67%), P. putida (65%), P. aeruginosa (52%), and A. faecalis (39%) over the 24-day study period, and for E. coli (60%) and S. lactis (12%) over the 14-day study period. The amount of time required to remove 50% of the THM in the media (T50) was: 12 days (d) (E. coli), 18 d (P. fluorescens), 19 d (P. putida), and 23 d (P. aeruginosa). Neither A. faecalis nor S. lactis achieved 50% removal during the study periods. The THM removal by all species followed a first-order kinetic reaction and half-lives were calculated accordingly. HPLC chromatograms of P. fluorescens, P. putida, and E. coli cultures revealed that as the area of the THM peak decreased over time, the area of an unidentified metabolite peak increased. In Phase II, we sought to characterize this metabolite and the overall metabolic efficiency of these three species. Maximal THM removal occurred at 30{degrees}C for all bacterial species assessed. Identification of the metabolite is currently underway, which will allow determination of whether the metabolite is less toxic than the parent compound, a prerequisite for this remediation technique to be viable. If the metabolite is found to be less hazardous than THM, further testing will follow to evaluate the use of this bioremediation technique in the field.

ecology↗