Biology subjects

Loveless, I.

Publications and source records attributed to Loveless, I..

6 recordsLinked to original sources

bioRxiv2025

Comparative Analysis of Primary and Liver Fibroblasts Reveals MET as a Potent Target in Pancreatic Cancer Metastasis

The tumor microenvironment drives many malignant features of pancreatic ductal adenocarcinoma (PDAC). The fibroblasts within pancreatic tumors promote tissue remodeling, immune suppression, and resistance to therapy. However, the interactions between stromal populations and pancreatic cancer cells are less understood in the liver, the most frequent site of PDAC metastasis. To address this, we employ single cell transcriptomics to compare primary pancreatic vs. liver PDAC lesions. Here, we identify the expression of hepatocyte growth factor (HGF) in fibroblasts and its receptor MET in cancer cells are both markedly increased in the PDAC liver niche. Using functional assays, we validate that mitogenic MET signaling is activated in PDAC cells by liver-derived fibroblasts. Importantly, the inhibition of MET signaling leads to reduced tumor growth in immune competent mouse models. Collectively, our data demonstrates that liver stromal-epithelial crosstalk networks engage in signaling pathways distinct from primary pancreatic tumors, highlighting opportunities to develop new treatments for metastatic disease.

cancer biology↗

bioRxiv2024

Circulating miR-126-3p is a mechanistic biomarker for knee osteoarthritis

As a chronic joint disease, osteoarthritis (OA) is a major contributor to pain and disability worldwide, and yet there are currently no validated soluble biomarkers or disease-modifying treatments. Since microRNAs are promising mechanistic biomarkers that can be therapeutically targeted, we aimed to prioritize reproducible circulating microRNAs in knee OA. We performed secondary analysis on two microRNA-sequencing datasets and found circulating miR-126-3p to be elevated in radiographic knee OA compared to non-OA individuals. This finding was validated in an independent cohort (N=145), where miR-126-3p showed an area under the receiver operating characteristic curve of 0.91 for distinguishing knee OA. Measuring miR-126-3p in six primary human knee OA tissues, subchondral bone, fat pad and synovium exhibited the highest levels, and cartilage the lowest. Following systemic miR-126-3p mimic treatment in a surgical mouse model of knee OA, we found reduced disease severity. Following miR-126-3p mimic treatment in human knee OA tissue explants, we found direct inhibition of genes associated with angiogenesis and indirect inhibition of genes associated with osteogenesis, adipogenesis, and synovitis. These findings suggest miR-126-3p becomes elevated during knee OA and mitigates disease processes to attenuate severity.

molecular biology↗

bioRxiv2023

ROR2 regulates cellular plasticity in pancreatic neoplasia and adenocarcinoma

Cellular plasticity is a hallmark of pancreatic ductal adenocarcinoma (PDAC) starting from the conversion of normal cells into precancerous lesions to the progression of carcinoma subtypes associated with aggressiveness and therapeutic response. We discovered that normal acinar cell differentiation, maintained by the transcription factor Pdx1, suppresses a broad gastric cell identity that is maintained in metaplasia, neoplasia, and the classical subtype of PDAC in mouse and human. We have identified the receptor tyrosine kinase Ror2 as marker of a gastric metaplasia (SPEM)-like identity in the pancreas. Ablation of Ror2 in a mouse model of pancreatic tumorigenesis promoted a switch to a gastric pit cell identity that largely persisted through progression to the classical subtype of PDAC. In both human and mouse pancreatic cancer, ROR2 activity continued to antagonize the gastric pit cell identity, strongly promoting an epithelial to mesenchymal transition, conferring resistance to KRAS inhibition, and vulnerability to AKT inhibition. SignificanceWe discovered the receptor tyrosine kinase ROR2 as an important regulator of cellular identity in pancreatic precancerous lesions and pancreatic cancer. ROR2 drives an aggressive PDAC phenotype and confers resistance to Kras inhibitors, suggesting that targeting ROR2 will enhance sensitivity to this new generation of targeted therapies.

cancer biology↗

bioRxiv2023

Mass cytometry identifies dysregulation of circulating and cutaneous immune cells in patients with hidradenitis suppurativa

2.BackgroundHidradenitis suppurativa (HS) is a multifactorial, inflammatory skin disease. Increased systemic inflammatory comorbidities and serum cytokines highlight systemic inflammation as a feature of HS. However, the specific immune cell subsets contributing to systemic and cutaneous inflammation have not been resolved. ObjectiveIdentify features of peripheral and cutaneous immune dysregulation. MethodsHere, we generated whole-blood immunomes by mass cytometry. We performed a meta-analysis of RNA-seq data, immunohistochemistry, and imaging mass cytometry to characterize the immunological landscape of skin lesions and perilesions from patients with HS. ResultsBlood from patients with HS exhibited lower frequencies of natural killer cells, dendritic cells, and classical (CD14+CD16-) and nonclassical (CD14-CD16+) monocytes, as well as higher frequencies of Th17 cells and intermediate (CD14+CD16+) monocytes than blood from healthy controls. Classical and intermediate monocytes from patients with HS had increased expression of skin-homing chemokine receptors. Furthermore, we identified a CD38+ intermediate monocyte subpopulation that was more abundant in the immunome of blood from patients with HS. Meta-analysis of RNA-seq data found higher CD38 expression in lesional HS skin than in perilesional skin, and markers of classical monocyte infiltration. Imaging mass cytometry showed that CD38+ classical monocytes and CD38+ monocyte-derived macrophages were more abundant in lesional HS skin. ConclusionOverall, we report targeting CD38 may be worth pursuing in clinical trials. 3. Key MessagesO_LIMonocyte subsets express markers of activation in circulation and HS lesions C_LIO_LITargeting CD38 may be a viable strategy for treating systemic and cutaneous inflammation in patients with HS C_LI 4. Capsule SummaryDysregulated immune cells in patients with HS express CD38 and may be targeting by anti-CD38 immunotherapy.

immunology↗

bioRxiv2023

The Hidradenitis Suppurativa 'Omics Database (HS-OmicsDB)

Large scale meta-analyses of genomics and genetics have spurred research in a number of fields, such as cancer, genetics and immunology. Publicly available omics databases provide valuable hypothesis generating and validation tools. To date, no such initiative has been undertaken for Hidradenitis Suppurativa (HS), an inflammatory skin disease of unknown etiology. We present here, a longitudinal initiative seeking to aggregate publicly available omics data to enhance research efforts in HS. In its first iteration, we include bulk and single-cell RNA sequencing data from untreated HS patients. Our data, aggregated from publicly available GEO datasets provides a tool to profile gene expression in specific tissue types (i.e. lesional, perilesional, nonlesional and healthy skin) as well as map cell-specific gene expression on single-cell data from HS lesions.

bioinformatics↗

bioRxiv2019

Clonal evaluation of prostate cancer molecular heterogeneity in biopsy samples by dual immunohistochemistry and dual RNA in situ hybridization

Prostate cancer is frequently multifocal. Although there may be morphological variation, the genetic underpinnings of each tumor are not clearly understood. To assess the inter and intra tumor molecular heterogeneity in prostate biopsy samples, we developed a combined immunohistochemistry and RNA in situ hybridization method for the simultaneous evaluation of ERG, SPINK1, ETV1, and ETV4. Screening of 601 biopsy cores from 120 consecutive patients revealed multiple alterations in a mutually exclusive manner in 37% of patients, suggesting multifocal tumors with considerable genetic differences. Furthermore, the incidence of molecular heterogeneity was higher in African Americans patients compared to Caucasian American patients. About 47% of the biopsy cores with discontinuous tumor foci showed clonal differences with distinct molecular aberrations. ERG positivity occurred predominantly in low Gleason grade cancer, whereas ETV4 expression was observed mostly in high Gleason grade cancer. Further studies revealed correlation between the incidence of molecular markers and clinical and pathologic findings, suggesting potential implications for diagnostic pathology practice, such as defining dominant tumor nodules and discriminating juxtaposed but molecularly different tumors of different grade patterns.

cancer biology↗