Biology subjects

Molina, E.

Publications and source records attributed to Molina, E..

6 recordsLinked to original sources

bioRxiv2026

Provisional extracellular matrix signaling network regulates tumor lymphoneogenesis and response to immunotherapy

Tertiary lymphoid structures (TLS) predict response to checkpoint inhibition, and conventional dendritic cells (cDC) are required to build and maintain them. What renders a niche permissive for their assembly is unknown: chemokines recruit the cellular constituents but do not specify how they organize. Here we show that the organizing signal is a matrix fragment. Proteolysis of the proteoglycan versican (VCAN) releases the matrikine versikine, constitutively in germinal center light zones and inducibly in tumor stroma. Versikine activates CD11b+ cDC and expands cDC1 to assemble TLS-archetypal triads, apposed DC: CD4+ T: CD8+ T units. Versikine-conditioned DC engage progenitor-exhausted CD8+ T cells (Tpex) and Th1-polarized follicular helper CD4+ T cells. Excess unproteolyzed VCAN inverts this toward DC-Treg crosstalk and Tpex loss. Versikine supplied as mRNA or recombinant protein sensitizes refractory tumors to PD-L1 blockade. VCAN proteolysis prospectively predicted outcomes after PD-1 blockade in metastatic colorectal cancer. Matrikines organize chemokine-recruited cells into functional immune niches.

immunology↗

bioRxiv2026

The lysosomal channel RECS1 regulates extracellular vesicle biogenesis

Lysosomal ion channels play key roles in regulating membrane trafficking, autophagy, and cell death. RECS1 is a pH-sensitive lysosomal calcium channel previously implicated in lysosome-mediated apoptosis. Here, we identify a novel role for RECS1 in exosome biology. Using immunoprecipitation followed by mass spectrometry, we mapped RECS1 interactors under apoptotic and lysosomal stress conditions. Notably, Syntenin-1, a key scaffolding protein in ESCRT-independent exosome biogenesis, emerged as the top hit. We validated the physical interaction between RECS1-Syntenin-1 using various approaches. RECS1 localized to secreted exosomes, and its overexpression increased exosome production, as measured by nanoparticle tracking analysis. Intriguingly, a channel-dead RECS1 retained both Syntenin-1 interaction and the ability to promote exosome release, suggesting a channel-independent mechanism. Our findings identify RECS1 as a structural component of the exosomal trafficking machinery and a modulator of extracellular vesicle biogenesis. This work connects lysosomal signalling with intercellular communication and suggests a broader role for RECS1 in stress-responsive secretion.

cell biology↗

bioRxiv2026

Rational engineering of sdAb-based CAR T cells targeting BCMA enhances antitumor efficacy and persistence in Multiple Myeloma

BCMA-directed CAR T therapies have transformed the treatment of relapsed/refractory multiple myeloma (MM), yet durable responses remain limited by insufficient persistence and functional exhaustion. The contribution of antigen-binding domain properties to CAR T cell performance is not fully defined. Here, we report the rational discovery and engineering of BCMA-targeting single-domain antibodies (sdAbs) and their incorporation into second-generation CAR T cells. We generated sdAbs recognizing distinct BCMA epitopes with diverse binding kinetics. Comprehensive biophysical and functional characterization identified sdAb5 as a lead candidate with balanced binding kinetics and a non-overlapping epitope relative to clinically approved constructs. sdAb-based CAR T cells exhibited potent antigen-specific cytotoxicity, minimal tonic signaling, and preserved IL-2 production without excessive inflammatory activation. In xenograft models, sdAb5-based CAR T cells induced durable tumor control, enhanced persistence, and improved responses to tumor rechallenge compared with ide-cel and cilta-cel constructs. Notably, this superior functionality correlated with balanced binding kinetics rather than maximal affinity. Single-cell transcriptomic analyses corroborated these findings, revealing a restrained inflammatory activation in sdAb5-based CAR T cells with preservation of transcriptional plasticity. Collectively, these findings support antigen-binding optimization as a key determinant of CAR T-cell durability and identify sdAb5 as a candidate for next-generation BCMA-directed therapies in MM.

bioengineering↗

bioRxiv2022

MYC directly transactivates CR2/CD21, the receptor of the Epstein-Barr virus, and enhances the viral infection of Burkitt lymphoma cells

The molecular hallmark of Burkitt lymphoma (BL) is a chromosomal translocation that results in deregulated expression of MYC oncogene. This translocation is present in virtually all BL. MYC is an oncogenic transcription factor deregulated in about half of total human tumors, by translocation or other mechanisms. Transcriptomic studies reveal more than 1000 genes regulated by MYC but a much smaller fraction of these genes is directly activated by MYC. All the endemic BL and many sporadic BL cells are associated to the Epstein-Barr virus (EBV) infection. The currently accepted mechanism for the MYC and BL association is that EBV is the causing agent inducing MYC translocation. Complement receptor 2 or CR2 (also called CD21) is a membrane protein that serves as EBV receptor in lymphoid cells. Here we show that CR2 is a direct MYC target gene. This conclusion is based on several evidences. First, MYC downregulation is linked to CR2 downregulation both in proliferating and in arrested cells. Second, MYC binds human CR2 promoter and this binding depends on E-box elements. Third, MYC activates CR2 promoter in an E-box dependent manner. Four, MYC activates CR2 transcription in the absence of protein synthesis. Importantly, MYC also induces CR2 expression in mouse primary B cells. Thus, CR2 is a bona fide MYC direct target gene. Moreover, higher MYC expression levels in Burkitt lymphoma-derived cells result in a more efficient EBV infection. We propose an alternative mechanism compatible with the correlation between EBV infection and MYC translocation observed in endemic BL, i.e., that deregulated MYC in BL cells occurs first and favors the EBV infection.

cancer biology↗

bioRxiv2021

Bovine neutrophils release extracellular traps and cooperate with macrophages in Mycobacterium avium subsp. paratuberculosis clearance

Mycobacterium avium subsp. paratuberculosis (Map) is the underlying pathogen causing bovine paratuberculosis (PTB), an enteric granulomatous disease that mainly affects ruminants and for which an effective treatment is needed. Macrophages are the primary target cells for Map, which survives and replicates intracellularly by inhibiting phagosome maturation. Neutrophils are present at disease sites during the early stages of the infection, but seem to be absent in the late stage, in contrast to healthy tissue. Although neutrophil activity has been reported to be impaired following Map infection, their role in PTB pathogenesis has not been fully defined. Neutrophils are capable of releasing extracellular traps consisting of extruded DNA and proteins that immobilize and kill microorganisms, but this mechanism has not been evaluated against Map. Our main objective was to study the interaction of neutrophils with macrophages during an in vitro mycobacterial infection. For this purpose, neutrophils and macrophages from the same animal were cultured alone or together in the presence of Map or Mycobacterium bovis Bacillus-Calmette-Guerin (BCG). Extracellular trap release, mycobacteria killing as well as IL-1{beta} and IL-8 release were assessed. Neutrophils released extracellular traps against mycobacteria when cultured alone and in the presence of macrophages without direct cell contact, but resulted inhibited in direct contact. Macrophages were extremely efficient at killing BCG, but ineffective at killing Map. In contrast, neutrophils showed similar killing rates for both mycobacteria. Co-cultures infected with Map showed the expected killing effect of combining both cell types, whereas co-cultures infected with BCG showed a potentiated killing effect beyond the expected one, indicating a potential synergistic cooperation. In both cases, IL-1{beta} and IL-8 levels were lower in co-cultures, suggestive of a reduced inflammatory reaction. These data indicate that cooperation of both cell types can be beneficial in terms of decreasing the inflammatory reaction while the effective elimination of Map can be compromised. These results suggest that neutrophils are effective at Map killing and can exert protective mechanisms against Map that seem to fail during PTB disease after the arrival of macrophages at the infection site.

immunology↗

bioRxiv2018

Myc stimulates cell cycle progression through the activation of Cdk1 and phosphorylation of p27

Cell cycle stimulation is a major transforming mechanism of Myc oncoprotein. This is achieved through at least three concomitant mechanisms: upregulation of cyclins and Cdks, downregulation of Cdk inhibitors p15 and p21 and the degradation of p27. The Myc-p27 antagonism has been shown to be relevant in human cancer. To be degraded, p27 must be phosphorylated at Thr-187 to be recognized by Skp2, a component of the ubiquitination complex. We previously described that Myc induces Skp2 expression. Here we show that not only Cdk2 but Cdk1 phosphorylates p27 at the Thr187, which was previously unreported. Moreover, Myc induced p27 degradation in murine fibroblasts through Cdk1 activation, which was achieved by Myc-dependent cyclin A and B induction. In the absence of Cdk2, p27 phosphorylation at Thr-187 was mainly carried out by cyclin A2-Cdk1 and cyclin B1-Cdk1. We also show that Cdk1 inhibition was sufficient for the synthetic lethal interaction with Myc. This result is relevant because Cdk1 is the only Cdk strictly required for cell cycle and the reported synthetic lethal interaction between Cdk1 and Myc.\n\nSummary blurbMyc antagonizes p27 activity in cancer. Myc activates Cdk1 to phosphorylate p27, marking p27 for degradation. This depends on Myc-mediated cyclin A and B induction. Cdk1 inhibition is sufficient for a synthetic lethal interaction with Myc

cancer biology↗