Biology subjects

Marin, I.

Publications and source records attributed to Marin, I..

8 recordsLinked to original sources

bioRxiv2026

Tissue retention of dendritic cells drives age-associated protective tolerogenic lymphoid structures

Ectopic lymphoid structures are typically associated with chronic tissue inflammation in autoimmunity and cancer, where they can amplify local immune responses. Similar structures arise spontaneously with age, yet their origin and function remain unclear. Here we identify tissue retention of mature migratory conventional dendritic cells (cDCs) as a driver of age-associated lymphoid organization. Mature cDCs accumulated within lymphoid structures in aged human and mouse tissues. We demonstrate that impaired cDC egress or pharmacological cDC expansion induced de novo structures in mice across multiple otherwise homeostatic organs without associated pathology. Strikingly, senescence-associated tissue cues, which promoted a distinct cDC maturation state, were required for lymphoid niche initiation. Unlike inflammatory structures described in disease, these cDC-driven structures preferentially accumulated tissue-adapted regulatory T cells and protected against inflammatory injury, revealing a previously unrecognized regulatory dimension of age-associated lymphoid organization.

immunology↗

bioRxiv2026

Passive Physiological Responses Fail to Predict Context-Dependent Action Selection in Bats

How social animals encode vocalizations, assign them value, and formulate behavioral responses remains largely unknown. We asked whether physiological signatures of social-call perception predict behavioral responses across contexts, using the Egyptian Fruit Bat (Rousettus aegyptiacus), an auditory specialist with a rich repertoire of social calls. Using heart rate monitoring during playback of conspecific vocalizations, we found that females showed larger heart rate responses than males to social calls (aggression and distress), whereas non-social echolocation calls evoked no sex difference. In vivo recordings from primary auditory cortex (A1) revealed call-selective units whose selectivity was independent of frequency tuning, with the largest selective fraction for distress calls. In a behavioral assay, female bats approached a distress-call playback only when a live conspecific was coupled with it. However, in isolation, the same calls elicited interest (grooming, pointing) but no approach. Together, the neural and autonomic signatures of social-call perception are present across contexts, whereas the behavioral response is not. Social context, therefore, does not modulate the behavioral readout of social calls; rather, it gates it. Significance StatementHow a social animal converts the perception of a vocalization into behavior remains poorly understood. Using the Egyptian Fruit Bat (Rousettus aegyptiacus), we show that physiological and neural responses to social calls are present in isolation, whereas approach behavior is not. We conclude that social context acts as a necessary gate between sensory representation and action, not a modulator that adjusts an existing response.

neuroscience↗

bioRxiv2025

Bcl-xL interaction with VDAC1 reduces mitochondrial Ca2+ uptake, allowing the establishment of Therapy-Induced Senescence.

Cellular senescence, a state of irreversible growth arrest, is characterized by various phenotypic changes, including altered mitochondrial function. While the role of mitochondria in senescence is well-established, the mechanisms underlying their involvement remain unclear. Here, we investigate the early stages of therapy-induced senescence (TIS) and identify a novel anti-apoptotic mechanism mediated by Bcl-xL and VDAC1, two key regulators of mitochondrial calcium (Ca{superscript 2}) homeostasis. We find that Bcl-xL expression increases in early TIS cells and localizes to the mitochondria, where it interacts with the voltage-dependent anion channel 1 (VDAC1). This interaction dampens mitochondrial Ca{superscript 2} uptake, thereby preventing Ca{superscript 2} overload and apoptosis. Disrupting this interaction using the BH3 mimetic ABT-263 or Bcl-xL-targeting siRNA increases mitochondrial Ca{superscript 2} uptake, leading to apoptosis and blocking the formation of senescent cells. These findings uncover a previously unrecognized role of the Bcl-xL-VDAC1 axis in regulating mitochondrial Ca{superscript 2} dynamics during the onset of senescence. Our work provides mechanistic insight into how senescent cells evade apoptosis,highlighting potential therapeutic targets for selectively eliminating them in cancer and age-related diseases.

cell biology↗

bioRxiv2025

Intratumoral cDC1-T Cell Clusters Serve as Sites of Local Costimulation to Enhance CTL-Mediated Tumor Rejection

T cells are essential for anti-tumor immunity, but their ability to eliminate tumors depends on coordinated interactions with type 1 conventional dendritic cells (cDC1s). While cDC1s are known for cross-presenting tumor-derived antigens in lymph nodes to prime CD8+ T cells, their role within the tumor itself remains less well understood. Here, we use the Skin Tumor Array by Micro-Poration (STAMP) model to investigate how cDC1-T cell interactions shape immune responses and influence tumor fate. Our data reveal that it is the spatial distribution of both cDC1s and T cells that determines whether a tumor can be rejected. We defined three primary immunotypes based on the spatial distribution of T cells and cDC1s: T cell-inflamed/dendritic cell-inflamed (TC-In/DC-In) tumors, where T cells and cDC1s co-infiltrate the tumor; T cell-inflamed/dendritic cell-excluded (TC-In/DC-Ex) tumors, where T cells infiltrate but cDC1s remain at the periphery; and T cell-excluded/dendritic cell-excluded (TC-Ex/DC-Ex) tumors, which lack both cDC1 and T cell infiltration. Notably, TC-In/DC-In tumors are more likely to undergo rejection, whereas TC-In/DC-Ex tumors persist despite T cell infiltration. Within TC-In/DC-In tumors, cDC1s engage in direct interactions with T cells, upregulate co-stimulatory molecules, and sustain effector T cell responses, while cDC1s in TC-In/DC-Ex tumors express higher migration-associated genes, suggesting a propensity to exit the tumor. We further show that chemokine modulation, particularly through CXCL9, CCL5, and XCL1, can reshape immune infiltration patterns to promote intra-tumoral cDC1-T cell clustering and improve tumor rejection. These findings underscore the unexpectedly important role of cDC1 positioning and function in sustaining effective anti-tumor immunity and highlight spatially organized cDC1-T cell clusters as critical hubs for local T cell activation.

immunology↗

bioRxiv2022

The efficacy of chemotherapy is limited by intratumoural senescent cells that persist through the upregulation of PD-L2

Anti-cancer therapies often result in a subset of surviving cancer cells that undergo therapy-induced senescence (TIS). Senescent cancer cells strongly modify the intratumoural microenvironment favoring immunosuppression and, thereby, tumour growth. An emerging strategy to optimise current therapies is to combine them with treatments that eliminate senescent cells. To this end, we undertook an unbiased proteomics approach to identify surface markers contributing to senescent cells immune evasion. Through this approach, we discovered that the immune checkpoint inhibitor PD-L2, but not PD-L1, is upregulated across multiple senescent human and murine cells. Importantly, blockade of PD-L2 strongly synergises with genotoxic chemotherapy, causing remission of solid tumours in mice. We show that PD-L2 inhibition prevents the persistence of chemotherapy-induced senescent cells, which exert cell-extrinsic immunomodulatory actions. In particular, upon chemotherapy, tumours deficient in PD-L2 fail to produce cytokines of the CXCL family, do not recruit myeloid-derived suppressor cells (MDSCs) and are eliminated in a CD8 T cell-dependent manner. We conclude that blockade of PD-L2 improves chemotherapy efficacy by reducing the intratumoural burden of senescent cells and their associated recruitment of immunosuppressive cells. These findings provide a novel strategy to exploit vulnerabilities arising in tumour cells as a result of therapy-induced damage and cellular senescence.

cancer biology↗

bioRxiv2022

Induction of senescence renders cancer cells highly immunogenic

Cellular senescence is a stress response that activates innate immunity. However, the interplay between senescent cells and the adaptive immune system remains largely unexplored. Here, we show that senescent cells display enhanced MHC class I (MHC-I) antigen processing and presentation. Immunization of mice with senescent syngeneic fibroblasts generates CD8 T cells reactive against both normal and senescent fibroblasts, some of them targeting senescence-associated MHC-I-peptides. In the context of cancer, we demonstrate that senescent cancer cells trigger strong anti-tumor protection mediated by antigen-presenting cells and CD8 T cells. This response is superior to the protection elicited by cells undergoing immunogenic cell death. Finally, induction of senescence in patient-derived cancer cells exacerbates the activation of autologous tumor-reactive CD8 tumor-infiltrating lymphocytes (TILs) with no effect on non-reactive TILs. Our study indicates that immunization with senescent cancer cells strongly activates anti-tumor immunity, and this can be exploited for cancer therapy. STATEMENT OF SIGNIFICANCEOur study shows that senescent cells are endowed with a high immunogenic potential, superior to the gold standard of immunogenic cell death. The induction of senescence in cancer cells can be exploited to develop efficient and protective CD8-dependent anti-tumor immune responses.

cancer biology↗

bioRxiv2022

Identification of transcriptional network disruptions in drug-resistant prostate cancer with TraRe

Metastatic castration-resistant prostate cancer (mCRPC) presents very low survival rates due to lack of response or acquired resistance to the available therapies. To date no molecular mechanisms of resistance have been identified, pointing out their complex dynamics. To identify key genes and processes associated with phenotypically-driven regulatory differences, we developed TraRe, a computational method that provides a three-tier analysis: i) at the network level, inferring differentially regulated modules; ii) at the regulon level, identifying regulatory relationships linked to phenotypic differences; and iii) at the single gene level, identifying TFs consistently linked to rewired modules. We applied TraRe (available in Bioconductor with full documentation) to transcriptomic data from 46 mCRPC patients with Abiraterone-response clinical data and uncovered abrogated immune response regulatory modules that showed strong differential regulation in Abi-resistant patients. These modules were replicated in an independent mCRPC study. Further, we experimentally validated key rewiring predictions and their associated transcription factors. Among them, ELK3, MXD1, and MYB were found to have a differential role in cell survival for Abi-response-specific settings. Moreover, we identified the role of ELK3 in cell migration capacity, which could have direct impact on mCRPC. Collectively, these findings shed light on the underlying regulatory mechanisms driving abiraterone response.

bioinformatics↗

bioRxiv2021

Proteomic landscape of multi-layered breast cancer internal tumor heterogeneity

Despite extensive research, internal tumor heterogeneity presents enormous challenges to achieve complete therapeutic responses. Changes in protein expression are central determinants of cancer phenotypes that reflect potential therapeutic targets. However, previous proteomic studies did not address internal heterogeneity, therefore, masked the necessary spatial resolution to achieve a comprehensive understanding of cancer complexity. Here we present the first large-scale multi-focal breast cancer proteomic study of 330 tumor regions which associated cancer cell function, pathological parameters, and spatial localization of each tumor region. We found marked internal proteomic heterogeneity even within tumors presenting homogeneous receptor expression. Additionally, analysis of the internal heterogeneity, based on coexisting receptor expression or histological patterns in single tumors, showed significant functional differences between homogeneous and heterogeneous tumors related to cancer metabolism, immunogenicity, and proliferation. We anticipate that this study will serve as a starting point towards the development of improved cancer therapy and diagnostics.

cancer biology↗