Biology subjects

Martinez-Reyes, I.

Publications and source records attributed to Martinez-Reyes, I..

3 recordsLinked to original sources

bioRxiv2026

Spatiotemporal Mapping of Tertiary Lymphoid Structure Heterogeneity Shapes Immune Niches and Clinical Outcomes in Intrahepatic Cholangiocarcinoma

Intrahepatic cholangiocarcinoma (iCCA) is a highly lethal malignancy with limited therapeutic options. The spatial architecture and functional diversity of tertiary lymphoid structures (TLSs) in iCCA remain unclear. Here, we present a multimodal spatial atlas of TLSs and identified Intra-tumoral TLSs (iTLSs) as independent prognostic markers. Bulk proteomic profiling of 214 discovery and 155 validation cases identified a four-tier TLS-based TME classification system and supported development of a TLS-predictive random forest classifier. Imaging mass cytometry revealed that iTLS tumors harbor structured immune architectures, where M1-like tissue-resident macrophages (RTMs), dendritic cells, and CXCL13 CD4 T cells co-localize to form antigen-presenting neighborhoods (apc-CNs) spatially coupled to TLS core regions (TLScore-CNs). Single-cell spatial transcriptomics further resolved 61 TLSs into 14 spatial niches and defined a pseudo-temporal maturation continuum: aggregated, activated, and post-activated. Intra-niche communication, primarily mediated by ifnCAFs, iCAFs, and CXCL12 macrophages, evolved dynamically with maturation. Single-nucleus RNA-sequencing combined with Tangram-based spatial mapping revealed CXCL12 macrophages and iCAFs forming a peripheral band in aggregated TLSs, while ifnCAFs infiltrated TLS interiors during activation. These findings define TLS heterogeneity and provide insights for stroma-directed immunotherapy. TeaserAn atlas of tertiary lymphoid structures reveals immune-stroma interactions in Intrahepatic cholangiocarcinoma.

immunology↗

bioRxiv2024

Oncogene inactivation-induced senescence facilitates tumor relapse

Oncogene-directed therapies can induce profound tumor regression in oncogene-addicted cancers such as BRAF-mutant melanoma and KRAS-driven pancreatic cancer, but their long-term benefit is often limited by resistance and early relapse. The mechanisms that allow residual cells to adapt, persist in a dormant state, and eventually fuel recurrence remain poorly understood. Here, we show that oncogene inactivation rapidly induces hallmark features of senescence together with a pro-inflammatory senescence-associated secretory phenotype (SASP). In vivo, oncogene inactivation-induced senescence (OIIS) predisposed tumors to relapse, characterized by polyploidy, chromosomal instability, and acquisition of alternative oncogenic pathways such as Mdm2 upregulation. Tumor microenvironment profiling by spectral flow cytometry revealed that relapse was associated with neovascularization and a shift from an immune-activated to an immunosuppressive milieu, indicating that senescent cells remodel their niche to promote regrowth. Importantly, OIIS features were also observed in human BRAFV600E melanoma cells treated with vemurafenib, confirming the clinical relevance of our findings. Together, our findings establish OIIS as a double-edged process: it initially restrains tumor growth but simultaneously creates conditions that favor recurrence. By defining the genetic, metabolic, cytogenetic, and microenvironmental hallmarks of OIIS, our study highlights adaptations to oncogene deprivation that limit the durability of targeted therapies.

cancer biology↗

bioRxiv2020

SGK1 Signaling Promotes Glucose Metabolism and Survival in Extracellular Matrix Detached Cells

Loss of integrin-mediated attachment to extracellular matrix (ECM) proteins can trigger a variety of cellular changes that impact cell viability. Foremost among these is the activation of anoikis, caspase-mediated cell death induced by ECM-detachment. In addition to anoikis, loss of ECM-attachment causes profound alterations in cellular metabolism that can lead to anoikis-independent cell death. Here, we describe a surprising role for serum and glucocorticoid kinase-1 (SGK1) in the promotion of energy production when cells are detached. Our data demonstrate that SGK1 activation is necessary and sufficient for ATP generation during ECM-detachment and anchorage-independent growth. More specifically, SGK1 promotes a substantial elevation in glucose uptake due to elevated GLUT1 transcription. In addition, carbon flux into the pentose phosphate pathway (PPP) is necessary to accommodate elevated glucose uptake and PPP-mediated glyceraldehyde-3-phosphate (G3P) is necessary for ATP production. Thus, our data unmask SGK1 as master regulator of glucose metabolism and cell survival during ECM-detached conditions.

cell biology↗