Biology subjects

Wadhwa, H.

Publications and source records attributed to Wadhwa, H..

3 recordsLinked to original sources

bioRxiv2023

Spinal cord injury: a systematic review and meta-analysis of microRNA alterations

Spinal cord injury (SCI) often results in life-long disability, lost wages, reduced quality of life, and high economic burden. A bottle neck in the performance of clinical trials exists, in part, due to a lack of diagnostic and prognostic markers of injury severity and neurologic recovery. In addition, while many interventions show promise in preclinical animal models, there are currently no neurorestorative treatments for SCI patients. The development of objective biological markers (biomarkers) and molecular targets for novel treatments for SCI represent two urgent unmet clinical needs. MicroRNAs (miRNAs) represent promising molecules as objective and informative molecules of injury severity and recovery and as potential therapeutic targets. miRNAs are small, stable, regulatory RNA molecules that are evolutionarily conserved across species. miRNAs represent powerful predictors of pathology, particularly with respect to neurologic disorders. Here, we present a systematic review and meta-analysis investigating the conserved inter- and intra-species miRNA changes that occur post-SCI and provide a comprehensive resource for the SCI community. Our analysis identifies a robust set of miRNAs that are involved in the pathophysiologic processes activated in response to SCI.

neuroscience↗

bioRxiv2021

Identification of Cancer-Associated Fibroblasts in Glioblastoma and Defining Their Pro-tumoral Effects

Despite their identification in some cancers, pro-tumoral cancer-associated fibroblasts (CAFs) were presumed absent in glioblastoma given the lack of brain fibroblasts. Serial trypsinization of primary glioblastoma cultures yielded cells with CAF morphology, CAF transcriptomic profile, and mesenchymal lineage in single-cell RNA-seq. Glioblastoma CAFs were attracted to glioblastoma stem cells (GSCs) and CAFs enriched GSCs. We created a resource of inferred crosstalk by mapping expression of receptors to their cognate ligands, identifying PDGF-{beta} and TGF-{beta} as mediators of GSC effects on CAFs, and osteopontin and hepatocyte growth factor as mediators of CAF-induced GSC enrichment. Glioblastoma CAFs also induced M2 macrophage polarization by producing the EDA fibronectin variant. Glioblastoma CAFs were enriched in the subventricular zone which houses neural stem cells that produce GSCs. Including CAFs in GSC-derived xenografts induced in vivo growth. These findings are among the first to identify glioblastoma CAFs and their GSC interactions, making them an intriguing target.

cancer biology↗

bioRxiv2020

Role of c-Met/β1 integrin complex in the metastatic cascade

Metastases cause 90% of human cancer deaths. The metastatic cascade involves local invasion, intravasation, extravasation, metastatic site colonization, and proliferation. While individual mediators of these processes have been investigated, interactions between these mediators remain less well defined. We previously identified a structural complex between receptor tyrosine kinase c-Met and {beta}1 integrin in metastases. Using novel cell culture and in vivo assays, we found that c-Met/{beta}1 complex induction promotes breast cancer intravasation and adhesion to the vessel wall, but does not increase extravasation. These effects may be driven by the ability of the c-Met/{beta}1 complex to increase mesenchymal and stem cell characteristics. Multiplex transcriptomic analysis revealed upregulated Wnt and hedgehog pathways after c-Met/{beta}1 complex induction. A {beta}1 integrin point mutation that prevented binding to c-Met reduced intravasation. OS2966, a therapeutic antibody disrupting c-Met/{beta}1 binding, decreased invasion and mesenchymal gene expression and morphology of breast cancer cells. Bone-seeking breast cancer cells exhibited higher c-Met/{beta}1 complex levels than parental controls and preferentially adhere to tissue-specific matrix. Patient bone metastases demonstrated higher c-Met/{beta}1 levels than brain metastases. Thus, the c-Met/{beta}1 complex drives breast cancer cell intravasation and preferential affinity for bone tissue-specific matrix. Pharmacological targeting of the complex may prevent metastases, particularly osseous metastases.

cancer biology↗