Biology subjects

Garcia-Garcia, A.

Publications and source records attributed to Garcia-Garcia, A..

3 recordsLinked to original sources

bioRxiv2025

Bioengineered human bone-mimetic niche compositions regulatebreast cancer cell quiescence and therapy response

Disseminated tumor cells (DTCs) in the bone are widely regarded as the cellular seeds of late metastatic relapse in estrogen receptor-positive (ER+) breast cancer (BC). However, how distinct bone compartments influence BC cell quiescence and endocrine therapy response remains unclear. Mechanistic insight has been hindered by limited access to human bone samples and by the lack of relevant human models that permit controlled manipulation of stromal compartments. Here, we developed a fully human, 3D bone-mimetic system for modular, controllable assembly of engineered osteoblastic (eON), vascularized (eVN), and vascularized osteoblastic (eVON) niche compositions. These niches were generated by perfusion culture of human bone marrow-derived mesenchymal stromal cells (hBM-MSCs) and/or human adipose tissue-derived stromal vascular fraction (hAT-SVF) cells within porous ceramic scaffolds. The resulting tissue microenvironments were then used as a substrate for the culture of an ER+ BC cell line, expressing a mutant reporter of p27 to monitor the quiescent status. We found that the eON enhanced BC cell proliferation, whereas the eVN was enriched in quiescent BC cells positive for NR2F1, a dormancy-associated transcription factor, and located near perivascular elements. Treatment with the selective ER degrader fulvestrant reduced BC cell numbers in vascularized niches (eVN and eVON) but not in eON, despite comparable receptor degradation. In summary, we developed a modular human platform for dissecting niche-specific regulation of BC quiescence, proliferation, and endocrine therapy response. The system can be further used to investigate perivascular niche-dependent mechanisms of BC cell dormancy and to guide the development of therapeutic strategies preventing recurrence in ER+ BC patients.

bioengineering↗

bioRxiv2023

Atypical memory B cells form a pre-plasmacellular reservoir for steady-state IgD responses to common nasopharyngeal antigens

The human nasopharyngeal mucosa includes organized lymphoepithelial structures continually engaged in frontline immune responses to aerodigestive antigens. Advancing our understanding of these responses might lead to the development of new strategies for the prevention and treatment of common immune disorders such as allergies. Here we identified a hitherto elusive tonsillar subset of atypical IgD class-switched IgD+IgM- memory (IgD-ME) B cells that were clonally related to IgD+IgM- germinal center (IgD-GC) B cells and IgD-secreting IgD+IgM- plasma cells (IgD-PCs) but not anergic IgD+IgM- B cells. Consistent with their pre-plasmacellular properties, IgD-ME B cells served as preferential precursors of IgD-PCs over IgD-GC B cells. IgD antibodies from IgD+IgM- cells acquired reactivity to multiple oral, airborne and commensal antigens through a mutation-dependent pathway involving both innate and adaptive signals. Thus, IgD-ME B cells may form a ready-to-use pre-plasmacellular reservoir for steady-state IgD responses likely aimed at enhancing nasopharyngeal homeostasis. One Sentence SummaryTonsillar atypical memory B cells form a ready-to-use pre-plasmacellular repertoire for IgD responses to common aerodigestive antigens.

immunology↗

bioRxiv2021

Evolutionary Perspective And Expression Analysis Of Intronless Genes Highlight The Conservation On Their Regulatory Role

Eukaryotic gene structure is a combination of exons generally interrupted by intragenic non-coding DNA regions termed introns removed by RNA splicing to generate the mature mRNA. Thus, eukaryotic genes can be either single exon genes (SEGs) or multiple exon genes (MEGs). Among SEGs, intronless genes (IGs) are a subgroup that additionally lacks introns at their UTRs, and code for proteins essentially involved in development, growth, and cell proliferation. Gene expression of IGs has been proposed to be highly specialized for neuro-specific functions and linked to cancer, neuropathies, and developmental disorders. The abundant presence of introns in eukaryotic genomes is pivotal for the precise control of gene expression. Notwithstanding, IGs exempting splicing events entail a higher transcriptional fidelity, making them even more valuable for regulatory roles. This work aimed to infer the functional role and evolutionary history of IGs using the mouse genome. Intronless protein-coding genes consist of a subgroup of ~6 % of a total of 21,527 genes with one exon. To understand the prevalence, biological relevance, and evolution, we identified and studied their 1,116 functional proteins. We validated differential expression in transcriptomics data of early embryo stages using mouse telencephalon tissue. Our results showed that expression levels of IGs are lower compared to MEGs. However, strongly upregulated IGs include transcription factors (TFs) such as the class 3 of POU (HMG Box), Neurog1, Olig1, and BHLHe22, BHLHe23, among other essential genes including the beta cluster of protocadherins. Most striking was the finding that IG-encoded BHLH TFs qualify the criteria to be referred to as microprotein candidates. Finally, predicted protein orthologs in other six genomes confirmed a high conservancy of IGs associated with regulating neurobiological processes and with chromatin organization and epigenetic regulation in Vertebrata. Moreover, this study highlights that IGs are essential modulators of regulatory processes, as Wnt signaling pathway and biological processes as pivotal as sensory organs developing at a transcriptional and post-translational level. Overall, our results suggest that IG proteins have specialized, prevalent, and unique biological roles and that functional divergence between IGs and MEGs is likely to be the result of specific evolutionary constraints.

evolutionary biology↗