Biology subjects

Boniface, C.

Publications and source records attributed to Boniface, C..

7 recordsLinked to original sources

bioRxiv2025

Expression of Lysyl Oxidase Family Enzymes During Human Endometrial Decidualization

Lysyl oxidases (LOXs), comprising lysyl oxidase (LOX) and lysyl oxidase like 1-4 (LOXL1-4), constitute a highly conserved enzyme family. Their primary function is the crosslinking of collagen and elastic fibers, thereby modulating the structure and function of the extracellular matrix. Our primary objective was to elucidate the localization of LOXs within human endometrial tissues and to investigate the expression profile of LOXs during in vitro human endometrial stromal cell decidualization. Immunohistochemical localization revealed that all LOXs were expressed in human endometrium during both the proliferative and secretory phases of menstrual cycle. All five LOXs were expressed in human endometrial stromal cells cultured in vitro. Gene expression levels of LOX, LOXL1, and LOXL2 significantly decreased during endometrial stromal cell decidualization in vitro. In contrast, LOXL3 and LOXL4 gene expression remained unaffected. Protein levels of LOX, LOXL1, and LOXL3 also showed a significant reduction. Additionally, conditioned media analysis revealed abundant secretion and release of LOX and LOXL1-3 into the extracellular space at all time points examined, with their levels remaining constant. The primary targets of LOXs, collagen and elastic fibers, undergo significant synthesis and processing during endometrial stromal cell decidualization in vitro. This observation was supported by the differential gene expression levels of factors involved in their processing and assembly. Collectively, this study demonstrates the expression of LOXs in the human endometrium and their potential role in extracellular matrix reorganization during decidualization.

cell biology↗

bioRxiv2023

Multiplex imaging of localized prostate tumors reveals changes in mast cell type composition and spatial organization of AR-positive cells in the tumor microenvironment

Mapping spatial interactions of cancer, immune and stromal cells present novel opportunities for patient stratification and for advancing immunotherapy. While single-cell studies revealed significant molecular heterogeneity in prostate tumors, there is currently no understanding of how immune cell heterogeneity impacts spatial coordination between tumor and stromal cells in localized tumors. Here, we used cyclic immunofluorescent imaging on whole-tissue sections to uncover novel spatial associations between cancer and stromal cells in low- and high-grade prostate tumors and tumor-adjacent normal tissues. Our results provide a spatial map of 699,461 single-cells that show epigenetic and molecular differences in distinct clinical grades. We report unique populations of mast cells that differentially express CD44, CD90 and Granzyme B (GZMB) and demonstrate GZMB+ mast cells are spatially associated with M2 macrophages in prostate tumors. Finally, we uncover recurrent neighborhoods that are primarily driven by androgen receptor positive (AR+) stromal cells and identify transcriptional networks active in AR+ prostate stroma.

cancer biology↗

bioRxiv2022

Epigenetic Control of Hundreds of Chromosome-Associated lncRNA Genes Essential for Replication and Stability

ASARs are long noncoding RNA genes that control replication timing of entire human chromosomes in cis. The three known ASAR genes are located on human chromosomes 6 and 15, and are essential for chromosome integrity. To identify ASARs on all human chromosomes we utilized a set of distinctive ASAR characteristics that allowed for the identification of hundreds of autosomal loci with epigenetically controlled, allele-restricted behavior in expression and replication timing of coding and noncoding genes, and is distinct from genomic imprinting. Disruption of noncoding RNA genes at five of five tested loci resulted in chromosome-wide delayed replication and chromosomal instability, validating their ASAR activity. In addition to the three known essential cis-acting chromosomal loci, origins, centromeres, and telomeres, we propose that all mammalian chromosomes also contain "Inactivation/Stability Centers" that display allele-restricted epigenetic regulation of protein coding and noncoding ASAR genes that are essential for replication and stability of each chromosome.

genetics↗

bioRxiv2020

An Integrated Clinical, Omic, and Image Atlas of an Evolving Metastatic Breast Cancer

Mechanisms of therapeutic resistance manifest in metastatic cancers as tumor cell intrinsic alterations and extrinsic microenvironmental influences that can change during treatment. To support the development of methods for the identification of these mechanisms in individual patients, we present here an Omic and Multidimensional Spatial (OMS) Atlas generated from four serial biopsies of a metastatic breast cancer patient during 3.5 years of therapy. This resource links detailed, longitudinal clinical metadata including treatment times and doses, anatomic imaging, and blood-based response measurements to exploratory analytics including comprehensive DNA, RNA, and protein profiles, images of multiplexed immunostaining, and 2- and 3-dimensional scanning electron micrographs. These data reveal aspects of therapy-associated heterogeneity and evolution of the cancers genome, signaling pathways, immune microenvironment, cellular composition and organization, and ultrastructure. We present illustrative examples showing how integrative analyses of these data provide insights into potential mechanisms of response and resistance, and suggest novel therapeutic vulnerabilities.

cancer biology↗

bioRxiv2020

Large-scale Characterization of Drug Responses of Clinically Relevant Proteins in Cancer Cell Lines

Perturbation biology is a powerful approach to developing quantitative models of cellular behaviors and gaining mechanistic insights into disease development. In recent years, large-scale resources for phenotypic and mRNA responses of cancer cell lines to perturbations have been generated. However, similar large-scale protein response resources are not available, resulting in a critical knowledge gap for elucidating oncogenic mechanisms and developing effective cancer therapies. Here we generated and compiled perturbed expression profiles of ~210 clinically relevant proteins in >12,000 cancer cell-line samples in response to >150 drug compounds using reverse-phase protein arrays. We show that integrating protein response signals substantially increases the predictive power for drug sensitivity and aids in gaining insights into mechanisms of drug resistance. We build a systematic map of protein-drug connectivity and develop an open-access, user-friendly data portal for community use. Our study provides a valuable information resource for a broad range of quantitative modeling and biomedical applications. HighlightsO_LIA large collection of cancer cell line protein responses to drug perturbations C_LIO_LIPerturbed protein responses greatly increase predictive power for drug sensitivity C_LIO_LIBuild a systematic map of protein-drug connectivity based on response profiles C_LIO_LIDevelop a user-friendly, interactive data portal for community use C_LI

systems biology↗

bioRxiv2019

Multi-region exome sequencing of ovarian teratomas reveals 2N near-diploid genomes, paucity of somatic mutations, and extensive allelic imbalances shared across mature, immature, and disseminated components

Immature teratoma is a subtype of malignant germ cell tumor of the ovary that occurs most commonly in the first three decades of life, frequently with bilateral ovarian disease. Despite being the second most common malignant germ cell tumor of the ovary, little is known about its genetic underpinnings. Here we performed multi-region whole exome sequencing to interrogate the genetic zygosity, clonal relationship, DNA copy number, and mutational status of 52 pathologically distinct tumor components from 10 females with ovarian immature teratomas, with bilateral tumors present in 5 cases and peritoneal dissemination in 7 cases. We found that ovarian immature teratomas are genetically characterized by 2N near-diploid genomes with extensive loss of heterozygosity and an absence of genes harboring recurrent somatic mutations or known oncogenic variants. All components within a single ovarian tumor (immature teratoma, mature teratoma with different histologic patterns of differentiation, and yolk sac tumor) were found to harbor an identical pattern of loss of heterozygosity across the genome, indicating a shared clonal origin. In contrast, the 4 analyzed bilateral teratomas showed distinct patterns of zygosity changes in the right versus left sided tumors, indicating independent clonal origins. All disseminated teratoma components within the peritoneum (including gliomatosis peritonei) shared a clonal pattern of loss of heterozygosity with either the right or left primary ovarian tumor. The observed genomic loss of heterozygosity patterns indicate that diverse meiotic errors contribute to the formation of ovarian immature teratomas, with 11 out of the 15 genetically distinct clones determined to result from the failure of meiosis I or II. Overall, these findings suggest that copy-neutral loss of heterozygosity resulting from meiotic abnormalities may be sufficient to generate ovarian immature teratomas from germ cells.

cancer biology↗

bioRxiv2018

Targeting mitochondria in cancer therapy could provide a basis for the selective anti-cancer activity

To determine the target of the recently identified lead compound NSC130362 that is responsible for its selective anti-cancer efficacy and safety in normal cells, structure-activity relationship (SAR) studies were conducted. First, NSC13062 was validated as a starting compound for the described SAR studies in a variety of cell-based viability assays. Then, a small library of 1,4-naphthoquinines (1,4-NQs) and quinoline-5,8-diones was tested in cell viability assays using pancreatic cancer MIA PaCa-2 cells and normal human hepatocytes. The obtained data allowed us to select a set of both non-toxic compounds that preferentially induced apoptosis in cancer cells and toxic compounds that induced apoptosis in both cancer and normal cells. Anti-cancer activity of the selected non-toxic compounds was confirmed in viability assays using breast cancer HCC1187 cells. Consequently, the two sets of compounds were tested in multiple cell-based and in vitro activity assays to identify key factors responsible for the observed activity. Inhibition of the mitochondrial electron transfer chain (ETC) is a key distinguishing activity between the non-toxic and toxic compounds. Finally, we developed a mathematical model that was able to distinguish these two sets of compounds. The development of this model supports our conclusion that appropriate quantitative SAR (QSAR) models have the potential to be employed to develop anticancer compounds with improved potency while maintaining non-toxicity to normal cells.

cancer biology↗