The rockefeller university

In mammalian cells, gene copy number is controlled to maintain gene expression and genome stability. However, a common molecular feature across cancer types is oncogene amplification, increasing the copy number and expression of tumor-promoting genes and thus promoting cancer progression. For example, in tyrosine kinase inhibitor (TKI)-resistant lung adenocarcinoma (LUAD), oncogene amplification is frequent. Despite the prevalence of oncogene amplification in TKI-resistant tumors, the underlying mechanisms are not fully understood. Here, we find that LUADs exhibit a unique chromatin signature demarcated by strong CTCF and cohesin deposition in drug-naive tumors, which correlates with the boundaries of oncogene amplicons in TKI-resistant LUAD cells. We identify a global chromatin-priming effect during the acquisition of TKI resistance, marked by a dynamic increase of H3K27Ac, cohesin loading and inter-TAD interactions, which occur before the onset of oncogene amplification. Furthermore, we show that METTL7A, reported to localize to the endoplasmic reticulum and inner nuclear membrane, has a chromatin regulatory function by binding to amplified loci and regulating cohesin recruitment and inter-TAD interactions. METTL7A appears to remodel the chromatin landscape prior to large-scale copy number gains. Although METTL7A depletion exerts little phenotypical effects on drug-naive cells, its depletion prevents the formation and maintenance of TKI resistant-clones, showcasing its role as cells become resistant. In summary, we unveil a mechanism required for the acquisition of TKI resistance regulated by an unexpected chromatin function of METTL7A.

Rationale: Pretargeted radioimmunotherapy (PRIT), which combines systemic antibody-based targeting with ionizing radiation, is promising for treating liver metastases in patients with colorectal cancer (CRC). Previously, we established a three-step DOTA-PRIT regimen to deliver DOTA radiometal payloads to CRC using an anti-tumor/anti-DOTA bispecific antibody (BsAb) targeting cell surface glycoprotein A33 (GPA33), a tumor antigen target expressed on over 95% of primary and metastatic CRC; a clearing agent; and a monovalent Lu-177 radiohapten called [Lu-177]Lu-ABD. More recently, we developed a bivalent Lu-177 radiohapten called [Lu-177]Lu-Gemini to enhance tumor uptake and radiohapten retention. Here, we aimed to compare the efficacy and safety of bivalent vs. monovalent three-step DOTA-PRIT regimens in orthotopic CRC liver metastasis models, to mimic a clinical path forward. Methods: We established two orthotopic CRC liver metastasis models by inoculating either SW1222-luc (GPA33high) or LoVo (GPA33low) human CRC cells in athymic nude mice under ultrasonographic guidance. Tumor targeting efficacy and dosimetry of the radiohaptens were compared using ex vivo biodistribution studies, SPECT/CT, and quantitative autoradiography. We also performed a DOTA-PRIT experiment to compare the efficacy and safety profiles of bivalent (single-cycle [Lu-177]Lu-Gemini, 48 h pretargeting interval) vs. monovalent (multicycle [Lu-177]Lu-ABD, 24 h pretargeting interval) three-step DOTA-PRIT regimens, each designed to deliver comparable total radiation doses to tumors (around 50 Gy). Results: Both radiohaptens demonstrated efficient SW1222-luc tumor targeting, with [Lu-177]Lu-Gemini showing superior targeting and tumor activity retention compared with [Lu-177]Lu-ABD. In LoVo tumors, [Lu-177]Lu-Gemini showed superior targeting, while [177Lu]Lu-ABD showed negligible targeting. Dosimetry estimates revealed higher SW1222-luc tumor mean absorbed doses for [Lu-177]Lu-Gemini (119.88 cGy/MBq, 48 h pretargeting interval) compared with [Lu-177]Lu-ABD (32.88 cGy/MBq, 24 h pretargeting interval), with more favorable blood and kidney therapeutic indices (50 and 9 for [Lu-177]Lu-Gemini, and 15 and 5 for [Lu-177]Lu-ABD, respectively). In the DOTA-PRIT experiment, both monovalent (injected activity: 3 x 44.4 MBq, 133.2 MBq total) and bivalent (injected activity: 44.4 MBq total) radiohapten regimens increased the median survival of treated mice compared with controls: 71 days for [Lu-177]Lu-ABD-treated mice, 81 days for [Lu-177]Lu-Gemini-treated mice, and 18 days for controls, without a statistical difference between treatment groups. Treatments were well tolerated, without significant weight loss or hematologic changes. Radiation-induced injuries were not identified histologically in the kidneys or bone marrow of mice submitted for necropsy. Conclusions: Our study demonstrates the exceptional benefit of a multivalent radiohapten strategy when treating an advanced model of CRC liver metastasis. Three-step GPA33 DOTA-PRIT with Lu-177-Gemini demonstrated that multivalency 1) improves PRIT therapeutic indices for blood and kidney and 2) has the potential to greatly reduce the administered activity without compromising the efficiency of the PRIT platform in clinically relevant models of target-rich and target-poor metastatic CRC.

IntroductionBiologic drug survival in psoriasis is variable. While clinical factors such as obesity and comorbidities contribute to early discontinuation, genetic predictors are less defined. The ZMIZ1/TGF-beta/STAT axis regulates immune-metabolic responses and represents a promising pharmacogenetic target.MethodsWe retrospectively analyzed 875 biologic treatment courses from 312 patients with moderate-to-severe psoriasis (NCT07041112). A pathway-based genetic score was derived from seven single nucleotide polymorphisms (SNPs) in the ZMIZ1/TGF-beta/STAT axis and dichotomized at the median. The primary outcome was time to biologic discontinuation, assessed with Kaplan-Meier curves and Cox proportional hazards models adjusted for demographic, clinical, and inflammatory covariates.ResultsPatients with a high genetic score had significantly longer drug survival (hazard ratio [HR] = 0.74; 95% confidence interval [CI]: 0.62-0.89; p = 0.0015), despite elevated baseline tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, IL-15, and leptin. This indicates that genetic background simultaneously conditioned immune-metabolic activation and treatment persistence. Predictive value was strongest for anti-IL12/23 agents (HR = 0.44; 95% CI: 0.26-0.75; p = 0.002) and anti-TNF therapies (HR = 0.79; 95% CI: 0.62-0.99; p = 0.045), but absent for anti-IL17/IL-23 agents after adjustment. None of the circulating biomarkers independently predicted survival.ConclusionA functional genetic score in the ZMIZ1/TGF-beta/STAT pathway independently predicted long-term biologic persistence in psoriasis, particularly with anti-TNF and anti-IL12/23 therapies. Its association with immune-metabolic activation suggests that genetic background shapes both inflammatory status and treatment durability. Incorporating such profiling into predictive algorithms may improve treatment personalization and biologic retention.Trial RegistrationTrial Registration NCT07041112.

Adult stem cells balance self-renewal and differentiation to build, maintain and repair tissues. The role of signalling pathways and transcriptional networks in controlling stem cell function has been extensively studied, but there is increasing appreciation that mechanical forces also have a crucial regulatory role. Mechanical forces, signalling pathways and transcriptional networks must be coordinated across diverse length and timescales to maintain tissue homeostasis and function. Such coordination between stem cells and neighbouring cells dictates when cells divide, migrate and differentiate. Recent advances in measuring and manipulating the mechanical forces that act upon and are produced by stem cells are providing new insights into development and disease. In this Review, we discuss the mechanical forces involved when epithelial stem cells construct their microenvironment and what happens in cancer when stem cell niche mechanics are disrupted or dysregulated. As the skin has evolved to withstand the harsh mechanical pressures from the outside environment, we often use the stem cells of mammalian skin epithelium as a paradigm for adult stem cells shaping their surrounding tissues.

Life is invasive, occupying all physically accessible scales, stretching between almost nothing (protons, electrons, and photons) and almost everything (the whole biosphere). Motivated by seventeenth-century insights into this infinity, this paper proposes a language to discuss life as an infinite double cascade of machines making machines. Using this simplified language, we first discuss the micro-cascade proposed by Leibniz, which describes how the self-reproducing machine of the cell is built of smaller submachines down to the atomic scale. In the other direction, we propose that a macro-cascade builds from cells larger, organizational machines, up to the scale of the biosphere. The two cascades meet at the critical point of 103 s in time and 1 micron in length, the scales of a microbial cell. We speculate on how this double cascade evolved once a self-replicating machine emerged in the salty water of prebiotic earth.

Eukaryotic ribosomal small subunit (SSU) assembly requires the SSU processome, a nucleolar precursor containing the RNA chaperone U3 small nucleolar RNA (snoRNA). The underlying molecular mechanisms of SSU processome maturation, remodelling, disassembly and RNA quality control, and the transitions between states remain unknown owing to a paucity of intermediates1, 2-3. Here we report 16 native SSU processome structures alongside genetic data, revealing how two helicases, the Mtr4-exosome and Dhr1, are controlled for accurate and unidirectional ribosome biogenesis. Our data show how irreversible pre-ribosomal RNA degradation by the redundantly tethered RNA exosome couples the transformation of the SSU processome into a pre-40S particle, during which Utp14 can probe evolving surfaces, ultimately positioning and activating Dhr1 to unwind the U3 snoRNA and initiate nucleolar pre-40S release. This study highlights a paradigm for large dynamic RNA-protein complexes in which irreversible RNA degradation drives compositional changes and communicates these changes to govern enzyme activity while maintaining overall quality control.

Many biological systems operate near the physical limits to their performance, suggesting that aspects of their behavior and underlying mechanisms could be derived from optimization principles. However, such principles have often been applied only in simplified models. Here, we explore a detailed mechanistic model of the gap gene network in the Drosophila embryo, optimizing its 50+ parameters to maximize the information that gene expression levels provide about nuclear positions. This optimization is conducted under realistic constraints, such as limits on the number of available molecules. Remarkably, the optimal networks we derive closely match the architecture and spatial gene expression profiles observed in the real organism. Our framework quantifies the tradeoffs involved in maximizing functional performance and allows for the exploration of alternative network configurations, addressing the question of which features are necessary and which are contingent. Our results suggest that multiple solutions to the optimization problem might exist across closely related organisms, offering insights into the evolution of gene regulatory networks.

The larvae of ants are essential for colony organization and growth, yet knowledge of their internal anatomy is sparse, and the homologies of many larval structures remain uncertain. We therefore used synchrotron-radiation micro-computed tomography (SR-mu -CT) and scanning electron microscopy (SEM) to investigate, respectively, the internal and external morphology of the larva of the clonal raider ant, Ooceraea biroi (FOREL, 1907), a model species for experimental biology. The documented characters are compared with conditions found in other Formicidae and Hymenoptera, and more broadly with features of larvae of other orders of Holometabola. As in other groups of Aculeata (and Orussidae), the body of Ooceraea is grub-like and depigmented, with distinctly reduced cephalic structures, and a weakly sclerotized, strongly simplified, sausage-like postcephalic body. This larval pattern reflects a distinct simplification compared with immature stages in the symphytan grade, with completely reduced eyes, antennae, and extrinsic labral muscles, vestigial palps, and missing thoracic legs and abdominal prolegs. Despite a simplified and largely uniform body configuration in apocritan larvae, including ants, there is considerable variation. Larvae of Formicidae vary distinctly in external features, especially in the general body shape, setation, and mandibular teeth. We therefore summarize eight morphological characters from previous studies to contextualize our findings, highlighting the often-underestimated diversity of larval morphology, which provides fertile ground for future study. Our study extends the knowledge of the external and internal morphology of ant larvae by taking a multi-modal approach to phenotype sampling, particularly via mu -CT. These methods have the potential of rapidly increasing the knowledge of previously neglected larval morphology, facilitating deeper investigations of evolutionary transformations in immature stages and providing a more complete picture of the evolution of an ecologically paramount group of insects.

Purpose: Curative therapies remain a significant unmet need for advanced human colorectal cancer (CRC). The aim of this study was to establish a 3-step 225Ac-DOTA pretargeted radioimmunotherapy (PRIT) system for human CRC, targeting two individual antigens: glycoprotein A33 (GPA33) and human epidermal growth factor receptor 2 (HER2). Methods: In vitro cellular uptake and internalization assays, as well as survival assays (colony forming) were performed in GPA33-and HER2-positive SW1222 human CRC cells. In vivo biodistribution and therapy studies were performed with two human CRC xenograft mouse models. Results: For both antigens, treatment with up to 74 kBq 225Ac-DOTA-PRIT in SW1222-tumored mice significantly enhanced overall survival in comparison to controls, including histologic cures. The uptake of 225Ac at the tumor correlated with antigen expression (antigen expression for GPA33:HER2 is 5:1). Cellular assays showed no significant differences in internalized fraction or nucleus-associated radioactivity between the two targets. GPA33 had a higher absorbed dose to the nucleus (1.3 Gy vs. 0.65 Gy for HER2), resulting in reduced clonogenic survival. A single cycle of either GPA33 or HER2 DOTA-PRIT (37 kBq; 193.31 Gy and 113.91 Gy (relative biological effectiveness [RBE] = 5), respectively) was equally effective. No chronic nephrotoxicity was seen at <= 20 Gy (RBE = 5). The efficacy of GPA33-directed 225Ac-DOTA-PRIT was also confirmed in a patient-derived xenograft model. Conclusion: In summary, 225Ac-DOTA-PRIT to GPA33 or HER2 was highly effective and safe in preclinical models of human CRC. Tumor response to treatment could not be predicted by nuclear absorbed dose alone, highlighting the importance of comprehensive micro-and macro-dosimetry.