Biology subjects

Kreeger, P. K.

Publications and source records attributed to Kreeger, P. K..

4 recordsLinked to original sources

bioRxiv2026

Systems serology of responses against tumor antigens in ovarian cancer reveal disrupted Fc-mediated immunity

High-grade serous ovarian cancer (HGSOC) represents 75% of ovarian cancer cases and 80% of deaths, with most patients relapsing despite initial treatment response. The limited effectiveness of immunotherapies in HGSOC indicates urgent need for novel therapeutic approaches. HGSOC patients produce tumor-binding autoantibodies (TBAs) with high tumor selectivity. Since effective antibody-mediated tumor cell killing requires Fc domain interactions with immune cells, we hypothesized that, although TBAs recognize tumor cells, they might still poorly elicit cell killing responses. Using a systems serology approach, we profiled TBA subclass and biophysical interactions with Fc receptors in HGSOC, comparing them to antiviral antibody responses. TBAs were consistently identified within ascites and serum and were heterogeneous in subclass composition. However, TBAs consistently lacked the capacity to bind Fc{gamma}RIIIa despite abundant interaction with Fc{gamma}RIIa and poorly elicited antibody-dependent cellular cytotoxicity, suggesting their Fc features prevent cell killing responses. Restoring Fc{gamma}RIIIa interaction may be a promising therapeutic approach in HGSOC. HighlightsO_LITBAs in ovarian carcinoma patients consistently lack interaction with Fc{gamma}RIIIa C_LIO_LIAscites- and serum-derived TBAs have heterogeneous subclass composition C_LIO_LISystems analysis shows complex serologic differences between TBAs and antiviral responses C_LIO_LIPatient-expressed TBAs demonstrate little antibody-dependent cellular cytotoxicity C_LI

cancer biology↗

bioRxiv2025

Comparative proteomic analysis of the ECM composition of the human omentum and mesentery, the main sites of ovarian cancer metastasis

Due to its limited symptoms, high-grade serous ovarian cancer (HGSOC) has frequently metastasized extensively throughout the peritoneal cavity prior to its diagnosis, resulting in an overall five-year survival rate of less than 50%. The greater omentum and the small bowel mesentery are two of the most common metastatic sites in advanced HGSOC. However, the mechanisms underlying HGSOC metastatic tropism remain unknown. The extracellular matrix is a complex and dynamic meshwork of proteins that provides biochemical and mechanical signals to surrounding cells and has been shown to drive the dissemination of several cancer types to preferential distant sites. Here, using histological assessment and proteomics, we examined the composition of the extracellular matrix of paired omentum and mesentery samples from disease-free adult females. We found that the fibrillar collagen content of the mesothelial layer of the omentum was significantly higher than that of the mesentery. Using ECM-focused proteomics, we further defined the ECM composition - or matrisome - of these two tissues. We found that over 90% of the proteins detected were shared between the omentum and mesentery. Our analysis also revealed small subsets of tissue-specific ECM proteins. Future work will aim to test the possible functional contributions of these ECM proteins to HGSOC metastatic tropism. To facilitate the reuse of our dataset, we have deposited the raw mass spectrometry data and accompanying metadata files to the ProteomeXchange Consortium with the dataset identifier PXD061586.

cancer biology↗

bioRxiv2025

Fibronectin Composition and Transglutaminase 2 Cross-linking Cooperatively Regulate Ovarian Cancer Cell Adhesion in ECM-Mimetic Constructs

The extracellular matrix (ECM) plays a crucial role in tumor progression. Here, we analyzed collagen I and cellular fibronectin (cFN) in normal omentum and metastatic omentum from high-grade serous ovarian cancer (HGSOC). The levels of both proteins were significantly elevated and collagen I fibers were significantly thicker in HGSOC metastases. Moreover, the ECM cross-linking enzyme transglutaminase 2 (TG2) was increased in omental metastases, where it is enzymatically active in the extracellular environment. This information was used to develop ECM constructs recapitulating these key changes, alone and in combination, to investigate their impact on HGSOC cell adhesion. To our knowledge, this is the first report using TG2 as a cross-linking agent to generate constructs from multiple ECM components. Low levels of HGSOC cell adhesion were observed on colIagen-only (coll) gels, while inclusion of cFN or plasma fibronection (pFN) increased cell adhesion. TG2-mediated cross-linking of colI/cFN hydrogels promoted HGSOC cell adhesion, while cross-linking of coll/pFN had no effect. Cell adhesion was dependent on ligand identity and fiber diameter. When fiber thickness was held constant, the inclusion of cFN led to greater HGSOC cell adhesion relative to pFN or coll, due to interactions of {beta}1 integrins with the EDA and RGD domains of cFN. Meanwhile, when gel composition was held constant, HGSOC cell adhesion increased as fiber thickness was increased through modifications to gelation temperature. Combined, our results demonstrate how ECM changes associated with omental metastasis can support tumor progression and provide insights into methods to tailor biomaterials to support cell adhesion.

bioengineering↗

bioRxiv2021

Multi-modal profiling of the extracellular matrix of human fallopian tubes and serous tubal Intraepithelial carcinomas

Recent evidence supports the fimbriae of the fallopian tube as a potential origin site for high-grade serous ovarian cancer (HGSOC). The progression of many solid tumors is accompanied by changes in the microenvironment, including alterations of the extracellular matrix (ECM). The ECM of fallopian tube and HGSOC has not been well characterized. Therefore, we sought to determine the ECM composition of the benign fallopian tube and how it changes with the onset of serous intraepithelial carcinomas (STICs), precursor of HGSOC. The ECM composition of benign human fallopian tube was first defined from a meta-analysis of published proteomic datasets and identified 190 ECM proteins. We then conducted de novo proteomics using ECM enrichment and identified 88 proteins, 7 of which were not identified in prior studies. We further investigated the levels and localization of seven of these ECM proteins (type I, III, and IV collagens, fibronectin, laminin, versican, perlecan) and hyaluronic acid using multi-spectral immunohistochemical staining of fimbriae from patients with benign conditions or STICs. Quantification revealed an increase in stromal fibronectin and a decrease in epithelial versican in STICs. Our results provide an in-depth picture of the ECM in the benign fallopian tube and identified ECM changes that accompany STIC formation.

cancer biology↗