Biology subjects

Sanz-Flores, M.

Publications and source records attributed to Sanz-Flores, M..

3 recordsLinked to original sources

bioRxiv2025

Reconfiguration of tumor cells with LCOR transcription factor mRNA nanotherapy to enhance immunotherapy efficacy

Transcription factors (TFs) are generally deemed undruggable due to their structural complexity. mRNA technologies have paved the way to overcome this therapeutic limitation by enabling the development of mRNA protein replacement therapies. Here we explore the newly described TF activity of LCOR (Ligand-dependent corepressor), which suppresses tumor growth by inducing the antigen presentation machinery (APM) of the tumor cells and constrains cellular plasticity. These LCOR effects facilitate recognition of the tumor by the immune system and immune-mediated tumor cell death. To deliver Lcor mRNA into tumor cells, we have used poly {beta}-(amino esters) (pBAE) nanoparticles (NPs) for local delivery of Lcor mRNA in breast cancer primary tumor models. We have engineered pBAE-NPs with high potential for efficiently encapsulate mRNA and facilitate cellular uptake. Our results show optimal endosomal escape, which results in high transfection efficiency in vitro and in vivo, restoring LCOR function in tumor cells and engaging their APM. In preclinical triple-negative breast cancer (TNBC) models, the intratumoral delivery of Lcor mRNA led to a reduction in tumor growth. Importantly, the combination of Lcor mRNA-loaded NPs with anti-PDL1 or anti-CTLA4 immunotherapies eradicated most of the tumors in our preclinical TNBC model. Overall, our nanotherapeutic strategy emerges as an innovative TF-replacement therapy, leveraging the immunogenic effects of LCOR to eradicate breast cancer tumors when combined with immunotherapy. Gaphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=105 SRC="FIGDIR/small/646434v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@1814de3org.highwire.dtl.DTLVardef@207a08org.highwire.dtl.DTLVardef@2bddc1org.highwire.dtl.DTLVardef@1ebc3a2_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

The G-Protein Couple Receptor Kinase 2 (GRK2) Orchestrates Hair Follicle Homeostasis

Tightly regulated cell-cell and cell-niche intercommunications via intertwined signaling networks are involved in maintaining normal hair follicle (HF) homeostasis, cycling and cell fate determination. However, knowledge of specific mechanisms by which hair loss takes place under pathological situations is needed. Using a keratinocyte-specific knockout mouse model, we uncover that the G-protein-coupled receptor kinase 2 (GRK2) signaling node plays a key role in HF homeostasis. Epidermal GRK2 ablation causes alterations during anagen induction, giving rise to abnormal cyst-like structures. HF-linked cysts display aberrant growth and differentiation patterns as well as lineage infidelity, displaying features of abortive HFs unable to fully acquire canonical hallmarks. Cysts triggered by GRK2 deletion displace the dermal papilla away from the bulge and promote irreversible changes in HF stem cell architecture, leading to bulge destruction and hair loss. Our data provide unforeseen roles of GRK2 in epidermal physiology and uncover mechanisms linking dystrophic follicular cysts formation with hair loss, with potential connections to pathogenic processes operating in immune-mediated alopecias.

cell biology↗

bioRxiv2023

PP2A-B55alpha,delta phosphatase counteracts Ki67-dependent chromosome individualization during mitosis

Cell cycle progression is regulated by the orderly balance between kinase and phosphatase activities. PP2A phosphatase holoenzymes containing the B55 family of regulatory B subunits (PP2A-B55) function as major CDK1-counteracting phosphatases during mitotic exit in mammals. However, the identification of the specific mitotic roles of these PP2A-B55 complexes has been hindered by the existence of multiple B55 isoforms. Here, through the generation of loss-of-function genetic mouse models for the two ubiquitous B55 isoforms (B55 and B55{delta}), we report that PP2A-B55 /{delta} complexes display overlapping roles in controlling the dynamics of proper chromosome individualization and clustering during mitosis. In the absence of PP2A-B55/{delta} activity, mitotic cells display increased chromosome individualization in the presence of enhanced phosphorylation and perichromosomal loading of Ki-67. These data provide experimental evidence for a new regulatory mechanism by which the balance between kinase and PP2A-B55 phosphatase activity controls the Ki-67-mediated spatial organization of the mass of chromosomes during mitosis.

cell biology↗