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Interactions between cells and the extracellular matrix, mediated by integrin adhesion complexes, play key roles in fundamental cellular processes, including the sensing and transduction of mechanical cues. Here, we investigate systems-level changes in the integrin adhesome in patient-derived cutaneous squamous cell carcinoma cells and identify the actin regulatory protein Mena as a key node in the adhesion complex network. Mena is connected within a subnetwork of actin-binding proteins to the LINC complex component nesprin-2, with which it interacts and co-localises at the nuclear envelope. Moreover, Mena potentiates the interactions of nesprin-2 with the actin cytoskeleton and the nuclear lamina. CRISPR-mediated Mena depletion causes altered nuclear morphology, reduces tyrosine phosphorylation of the nuclear membrane protein emerin and downregulates expression of the immunomodulatory gene PTX3 via the recruitment of its enhancer to the nuclear periphery. We uncover an unexpected role for Mena at the nuclear membrane, where it controls nuclear architecture, chromatin repositioning and gene expression. Our findings identify an adhesion protein that regulates gene transcription via direct signalling across the nuclear envelope. Cells transmit mechanical force to the nucleus via the cytoskeleton. Here, the authors reveal a role for the actin regulator Mena in force transmission at the nuclear envelope, where it regulates nuclear architecture, chromatin organization and gene expression.

Improving responses to cancer immunotherapies requires deeper insight into the cellular mechanisms governing T cell-mediated anti-tumor immunity. TMEM33 is an endoplasmic reticulum-resident transmembrane protein enriched across multiple tumor types, with reported functions in anti-viral immunity as well as calcium and lipid homeostasis, yet its role in tumor immunosurveillance remains unknown. Using murine genetic models, we demonstrate that host TMEM33 constrains anti-tumor CD8 T cell responses. Constitutive mice exhibited delayed melanoma tumor growth and increased CD8 T cell infiltration. Antigen-specific CD8 compartments in tumors of mice showed TCF-1 PD-1 progenitor-exhausted cell (Tpex) enrichment, elevated effector function and reduced exhaustion, alongside improved effector memory expansion and T-bet expression in draining lymph nodes. We highlight that TMEM33 functions intrinsically within the T cell compartment, as TMEM33 deletion (1) enhanced polyclonal activation of naive CD8 T cells , (2) promoted preferential Tpex accumulation among adoptively transferred naive OT-I cells in B16F10-OVA tumors and draining lymph nodes, and (3) improved the potency of -expanded OT-I cells in controlling tumor growth during adoptive cell therapy. Finally, in a large, prospectively recruited metastatic melanoma cohort, lower expression in patient CD8 T cells significantly correlated with improved survival and elevated (encoding TCF-1). Collectively, our findings define TMEM33 as a formerly unrecognized intrinsic determinant of tumor-directed CD8 T cell fate that limits Tpex maintenance, and restrains cell therapy responses, suggesting that its modulation may strengthen immunotherapeutic efficacy.

Chromosomal instability (CIN), a characteristic feature of esophageal adenocarcinoma (EAC), drives tumor aggressiveness and therapy resistance, presenting an intractable problem in cancer treatment. CIN leads to constitutive stimulation of the innate immune cGAS-STING pathway, which has been typically linked to anti-tumor immunity. However, despite the high CIN burden in EAC, the cGAS-STING pathway remains largely intact. To address this paradox, we developed novel esophageal cancer models, including a CIN-isogenic model, discovering myeloid-attracting chemokines - with the chemokine (IL-8) as a prominent hit - as conserved CIN-driven targets in EAC. Using high-resolution multiplexed immunofluorescence microscopy, we quantified the extent of ongoing cGAS-activating CIN in human EAC tumors by measuring cGAS-positive micronuclei in tumor cells, validated by orthogonal whole-genome sequencing-based CIN metrics. By coupling CIN assessment with single-nucleus RNA sequencing and multiplex immunophenotypic profiling, we found tumor cell-intrinsic innate immune activation and intratumoral myeloid cell inflammation as phenotypic consequences of CIN in EAC. Additionally, we identified increased tumor cell-intrinsic expression in CIN EAC, accounting for the inflammatory tumor microenvironment. Using a novel signature of CIN, termed CIN , which captures ongoing CIN-associated gene expression, we confirm poor patient outcomes in CIN tumors with signs of aberrantly rewired cGAS-STING pathway signaling. Together, our findings help explain the counterintuitive maintenance and expression of cGAS-STING pathway components in aggressive, CIN tumors and emphasize the need to understand the contribution of CIN to the shaping of a pro-tumor immune landscape. Therapeutic strategies aimed at disrupting the cGAS-driven inflammation axis may be instrumental in improving patient outcomes in this aggressive cancer.

Interactions between cells and the extracellular matrix, mediated by integrin adhesion complexes (IACs), play key roles in cancer progression and metastasis. We investigated systems-level changes in the integrin adhesome during metastatic progression of a patient-derived cutaneous squamous cell carcinoma (cSCC), and found that the actin regulatory protein Mena is enriched in IACs in metastatic cSCC cells. Mena is connected within a subnetwork of actin-binding proteins to the LINC complex component nesprin-2, with which it interacts and co-localises at the nuclear envelope of metastatic cells. Moreover, Mena potentiates the interactions of nesprin-2 with the actin cytoskeleton and the nuclear lamina. CRISPR-mediated Mena depletion causes altered nuclear morphology, reduces tyrosine phosphorylation of the nuclear membrane protein emerin and downregulates expression of the immunomodulatory gene PTX3 via the recruitment of its enhancer to the nuclear periphery. We have uncovered an unexpected novel role for Mena at the nuclear membrane, where it controls the LINC complex, nuclear architecture, chromatin repositioning and cancer gene expression. This is the first description of an adhesion protein regulating gene transcription via direct signalling across the nuclear envelope.

The mass of the top quark is measured using a sample of [Formula: see text] candidate events with at least six jets in the final state. The sample is selected from data collected with the CMS detector in pp collisions at [Formula: see text] TeV in 2011 and corresponds to an integrated luminosity of 3.54 [Formula: see text]. The mass is reconstructed for each event employing a kinematic fit of the jets to a [Formula: see text] hypothesis. The top-quark mass is measured to be [Formula: see text] GeV. A combination with previously published measurements in other decay modes by CMS yields a mass of [Formula: see text] GeV.