Biology subjects

Pietrowska, M.

Publications and source records attributed to Pietrowska, M..

4 recordsLinked to original sources

bioRxiv2025

Serpins A1/A3 within tumor-derived extracellular vesicles support pro-tumoral bias of neutrophils in cancer

Neutrophils are known to play an important regulatory role during tumor progression in several types of cancer. However, the mechanisms responsible for their tumorigenic bias and extended lifespan in cancer are not clear to date. This study uncovers a previously unknown mechanism by which tumor-derived small extracellular vesicles (sEVs), via their serpin cargo, reprogram neutrophils to adopt a tumor-supporting phenotype. We demonstrated here an elevated content of plasma sEVs during head and neck cancer progression, and their significant cargo enrichment with inhibitors of neutrophil serine proteases: serpins A1 and A3. Mechanistically, neutrophils educated with serpin-rich tumor-derived sEVs displayed typical pro-tumoral characteristics, including prolonged lifespan and activated CD62Llow CD11bhigh PDL1high phenotype. Functionally, such neutrophils demonstrated a strong ability to promote the epithelial-to-mesenchymal transition of tumor cells. Moreover, such neutrophils induced remarkable suppression of cytotoxic CD8 T cells, significantly reducing their tumor cell-killing capacity. Importantly, serpin cargo was essential for this activity, as serpin-depleted sEVs failed to reprogram neutrophils. These findings again highlight the clinical significance of sEVs and suggest their serpin content as important mediators of pro-tumoral functionality. Targeting the biogenesis or uptake of such immunosuppressive sEVs, or modifying their cargo, could potentially serve as a potent adjuvant anti-cancer therapy.

cancer biology↗

bioRxiv2024

Blood-based detection of MMP11 as a marker of prostate cancer progression regulated by the ALDH1A1-TGF-β1 signaling mechanism

BackgroundProstate cancer (PCa) is the second most common type of tumor diagnosed in men and the fifth leading cause of cancer-related death in male patients. The response of metastatic disease to standard treatment is heterogeneous. As for now, there is no curative treatment option available for metastatic PCa, and the clinical tests capable of predicting metastatic dissemination and metastatic response to the therapies are lacking. Our recent study identifies aldehyde dehydrogenases ALDH1A1 and ALDH1A3 as critical regulators of PCa metastases. Still, the exact mechanisms mediating the role of these proteins in PCa metastatic dissemination remain not fully understood, and plasma-based biomarkers of these metastatic mechanisms are also not available. MethodsGenetic silencing, gene overexpression, or treatment with different doses of the retinoic acid (RA) isomers, which are the products of ALDH catalytic activity, were used to modulate the interplay between retinoic acid receptors (RARs) and androgen receptor (AR). RNA sequencing (RNAseq), reporter assays, and chromatin immunoprecipitation (ChIP) analysis were employed to validate the role of RARs and AR in the regulation of the transforming growth factor-beta 1 (TGFB1) expression. Gene expression levels of ALDH1A1, ALDH1A3, and the matrix metalloproteinase 11 (MMP11) and their correlation with pathological parameters and clinical outcomes were analyzed by mining several publicly available patient datasets as well as our multi-center transcriptomic dataset from patients with high-risk and locally advanced PCa. The levels of MMP11 protein were analyzed by enzyme-linked immunosorbent assay (ELISA) in independent cohorts of plasma samples from patients with localized or metastatic PCa and healthy donors, while plasma proteome profiles were obtained for selected subsets of PCa patients. ResultsWe could show that ALDH1A1 and ALDH1A3 genes differently regulate TGFB1 expression in a RAR-and AR-dependent manner. We further observed that the TGF-{beta}1 pathway contributes to the regulation of the MMPs, including MMP11. We have confirmed the relevance of MMP11 as a promising clinical marker for PCa using several independent gene expression datasets. Further, we have validated plasma MMP11 levels as a prognostic biomarker in patients with metastatic PCa. Finally, we proposed a hypothetical ALDH1A1/MMP11-related plasma proteome-based prognostic signature. ConclusionsTGFB1/MMP11 signaling contributes to the ALDH1A1-driven PCa metastases. MMP11 is a promising blood-based biomarker of PCa progression.

cancer biology↗

bioRxiv2024

Urine microbiome changes during and after radiotherapy for prostate cancer

BackgroundThe urinary microbiome may play a new important role in the development of complications, but still, there is no information about their changes during and after radiotherapy (RT). This study aimed to use the matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) technique to identify the microbiome and assess its changes in urine samples of 88 patients irradiated for prostate cancer. Material and methodsBlood for biochemical analysis and urine samples for MALDI were collected at various time points before gold fiducial implantation (t1) at the beginning (t2) and end of radiotherapy (t3); during follow-up, 1 (t4), 4 (t5), 7 (t6) months after the end of treatment. ResultsWe identified 1801 different microbial isolates, in 89% (470/528) samples revealed the presence of at least one microbial species among which 79% (373/470) were polymicrobial. Species level: 136 G+, 29 G-, 2 Candida have been noted. The far most abundant group of the identified microorganisms was Staphylococcus members -51.6% of all isolates followed by Micrococcus (9.1%), Enterococcus (7.6%), Kocuria (5.6%), Corynebacterium (5.4%), and Streptococcus (2.2%). A lower variety of microorganisms incident was observed at the end of RT. The total number of species (TNS) was 50 at t1, increased up to 61 at t2, and then fell to the initial value of 52 at t3. The increase in biodiversity was noted after radiotherapy t4-68, t5-86, and t6-75 (p<0.05). Changes in the biodiversity of the urinary microbiota were also reflected in the differences in the total number of isolates (TNI) - 261, 281, and 273 for time points t1-t3 compared to the 292, 362, and 332 for time points t4-t6 as well as in the total number of detected genera (TNG) - 25, 29, 23 (t1-t3) and 28, 38, 31 (t4-t6). Actinomyces, Corynebacterium, Staphylococcus, Streptococcus, demonstrated significant correlation with the RT stages. Concerning individual species, only K. rhizophila abundance significantly increased with time (p=0.045). Bacteria incidence was strongly correlated with glucose levels in urine. The same correlation was observed for glucose levels in blood, but in a weak manner. Staphylococcus presence was related to higher tPSA. ConclusionRT for prostate cancer induces a dynamic response in the urinary microbiome, characterized by an initial reduction in diversity post-RT followed by a subsequent increase. Our findings highlight the significant influence of glucose levels in both urine and blood on the urinary microbiota. These insights contribute to the evolving understanding of the interplay between RT, the urinary microbiome, and patient health, paving the way for more targeted interventions and personalized approaches in prostate cancer treatment.

microbiology↗

bioRxiv2023

Venom diversity in Naja mossambica: Insights from proteomic and immunochemical analyses reveal intraspecific differences

BackgroundIntraspecific variations in snake venom composition have been extensively documented, contributing to the diverse clinical effects observed in envenomed patients. Understanding these variations is essential for developing effective snakebite management strategies and targeted antivenom therapies. This study was prompted by the observations made by clinicians, who have noted significant variations in clinical outcomes among patients bitten by Naja mossambica in different regions of Africa, which links to the phenomenon of intra-species venom variability. We aimed to comprehensively investigate venoms from three distinct populations of N. mossambica from Eswatini, Limpopo, and KwaZulu-Natal regions in Africa in terms of their protein composition and reactivity with three commercial antivenoms (SAIMR polyvalent, EchiTAb+ICP, and Antivipmyn Africa). Methodology/Principal FindingsIn contrast to previous reports, we discovered an unexpectedly high concentration of neurotoxic proteins in N. mossambica venoms (approximately 15%). The Eswatini population of Mozambique spitting cobra exhibited an increased abundance and diversity of neurotoxic proteins, including neurotoxic 3FTxs, kunitz-type inhibitors, vespryns, and mamba intestinal toxin 1. Immunochemical assessments of venom-antivenom reactivity unveiled differences, primarily related to low-abundance proteins. Notably, the reactivity of EchiTAb+ICP antivenom surpassed that of the widely used SAIMR polyvalent in serial dilution ELISA assays. Conclusions/SignificanceOur findings reveal a substantial presence of neurotoxic proteins in N. mossambica venoms, challenging previous understandings of their composition. Additionally, the detection of numerous peptides aligning to uncharacterized proteins or proteins with unknown functions underscores a critical issue with existing venom protein databases, emphasizing the substantial gaps in our knowledge of snake venom protein components. This underscores the need for enhanced research in this domain. Significantly, our research highlights the superior reactivity of EchiTAb+ICP antivenom compared to SAIMR polyvalent, providing another compelling argument for its potential as an alternative to the commonly used SAIMR antivenom. Author SummarySnakebite envenoming is a pervasive global health concern, posing substantial risks, particularly in less developed regions. The intricate variations in venom composition within a single species have been well-documented, contributing significantly to the varied clinical effects experienced by envenomed patients. It is imperative to unravel these variations, as they are pivotal in the formulation of effective snakebite management strategies and the development of targeted antivenom therapies. In this study, our focus rested on the venom of the Naja mossambica species, dwelling in diverse African regions. Our objective was to delve into the toxin composition of these venoms and understand how these toxins interact with commercially available antivenoms. This exploration was aimed to uncover which toxins, despite antivenom application, evade neutralization. This information becomes a cornerstone in the design of more potent and efficacious antivenoms, contributing to a nuanced approach in combating the complex landscape of snakebite envenoming.

biochemistry↗