Biology subjects

Mistriotis, P.

Publications and source records attributed to Mistriotis, P..

3 recordsLinked to original sources

bioRxiv2026

Dual inhibition of p38α MAPK and Casein kinase δ/ϵ as a novel treatment strategy for AR-independent and taxane-resistant advanced prostate cancer

Prostate cancer (PCa) is the most commonly diagnosed cancer and the second leading cause of cancer death among US men. Metastatic castration-resistant PCa (mCRPC) is a clinically advanced form of PCa, often associated with increased aggressiveness, metastatic potential, morbidity, and a higher risk of developing resistance to taxanes (TX), the first-line chemotherapy for mCRPC. Furthermore, cancer stemness and epithelial to mesenchymal trans-differentiation (EMT) potentially contribute to aggressiveness and the development of drug resistance in mCRPC. Here, we applied our drug development pipeline, secDrug, which utilizes a pharmacogenomics data-driven computational algorithm, to demonstrate that TAK-715 - a dual inhibitor of p38 MAPK and Casein kinase {delta}/{epsilon}, is a promising treatment for these advanced/lethal variants of PCa. Using in vitro cytotoxicity assays followed by cell-based functional assays in a panel of mCRPC cell lines representing TX-sensitive mCRPC, clonally derived TX-resistant lines, and a highly aggressive metastatic variant of mCRPC, we demonstrated the efficacy of TAK-715 treatment as a single agent and in combination with TX, including cancer stem-like cells. Further, we showed that the apoptotic effects of TAK-715 occur via a mitochondrial-mediated pathway. Bulk tumor RNA sequencing followed by pathway analysis identified genes associated with mitochondrial dysfunction and cell cycle arrest as the top molecular networks associated with TAK-715 single-treatment. HES1, a gene associated with nodal metastasis and PCa progression, was the top differentially expressed gene. Single-cell transcriptomics analysis revealed that TAK-715 treatment erodes the subclonal populations responsible for cancer stemness, metastasis, and drug resistance. The clinical significance of these findings was validated in silico using multiple patient datasets. Our results suggest that TAK-715 treatment has the potential to decrease oncogenic progression and cancer stem cell-like activity in drug-resistant, aggressive, and stem-like mCRPC cells.

cancer biology↗

bioRxiv2022

Integrating pharmacogenomics data-driven prediction with bulk and single-cell RNAseq to demonstrate the efficacy of an NAMPT inhibitor against aggressive, taxane-resistant, and stem-like cells in lethal prostate cancer

Metastatic prostate cancer is the second leading cause of cancer deaths in US men. Resistance to standard medical castration and secondary taxane-based chemotherapy is nearly universal. Further, presence of cancer stem-like cells (EMT/epithelial to mesenchymal transdifferentiation) and neuroendocrine PCa (NEPC) subtypes significantly contribute to aggressive/advanced/lethal variants of PCa (AVPC). In this study, first we used single-cell RNA sequencing (scRNAseq) analysis to demonstrate that ARlow PCa cells in metastatic prostate cancer, including castration-sensitive tumors, harbored signatures of EMT, and cancer stemness. Next, we introduced a novel pharmacogenomics data-driven computational approach and identified several potential agents that can be re-purposed as novel secondary drugs ("secDrugs") to treat advance variants of Prostate cancer. Using scRNAseq as a biomarker-based drug screen, we demonstrated that a majority of the single-cell subclones in mCRPC and mCSPC cell lines also showed significantly high expression of the NAMPT pathway genes, indicating that the secDrug FK866, which targets NAMPT, is potentially effective against drug-resistant and stem-cell-like subpopulation cluster. Next, we showed significant in vitro cytotoxicity of FK866 as single-agent and in combination with the taxanes or Enzalutamide against models of clinically-advanced PCa. We performed bulk- and single-cell RNAseq to identify several pathways underlining FK866 mechanism of action and found that in addition to NAMPT inhibition, FK866 regulates tumor metastasis, cell migration, invasion, DNA repair machinery, redox homeostasis, autophagy, as well as cancer stemness-related genes HES1 and CD44. Further, we performed a microfluidic chip-based cell migration assay that demonstrated that FK866 reduces cancer cell invasion and motility, indicating abrogation of metastasis. Finally, using multiple PCa patient datasets, we showed that FK866 is potentially capable of reversing expression of several genes associated with biochemical recurrence and inter-ethnic differences, including IFITM3 and LTB4R. Thus, using FK866 as a proof-of-concept drug, we introduced a novel, universally applicable preclinical drug development pipeline to circumvent subclonal aggressiveness, drug resistance, and stemness in lethal PCa.

molecular biology↗

bioRxiv2019

Trans-epithelial Fluid Pumping Performance of Renal Epithelial Cells and Mechanics of Cystic Expansion

Using a novel microfluidic platform to recapitulate fluid absorption activity of kidney cells, we report that renal epithelial cells can actively generate hydraulic pressure gradients across the epithelium. The fluidic flux declines with increasing hydraulic pressure until a stall pressure, at which the fluidic flux vanishes--in a manner similar to mechanical fluidic pumps. The developed pressure gradient translates to a force of 50-100 nanoNewtons per cell. For normal human kidney cells, the fluidic flux is from apical to basal, and the pressure is higher on the basal side. For human polycystic kidney disease (PKD) cells, the fluidic flux is reversed from basal to apical with a significantly higher stall pressure. Molecular studies and proteomic analysis reveal that renal epithelial cells are highly sensitive to hydraulic pressure gradients, developing different expression profiles and spatial arrangements of ion exchangers and the cytoskeleton in different pressure conditions. These results, together with data from osmotic and pharmacological perturbations of fluidic pumping, implicate mechanical force and hydraulic pressure as important variables during morphological changes in epithelial tubules, and provide further insights into pathophysiological mechanisms underlying the development of high luminal pressure within renal cysts.

biophysics↗