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Acute pancreatitis is a frequent cause of hospital admission, managed with intravenous (IV) fluids, analgesia, and oral feeding when tolerated. In patients with hypertriglyceridemia-induced pancreatitis, insulin and other therapies may be necessary for disease resolution. We present a case of a patient with severe acute pancreatitis and euglycemic diabetic ketoacidosis (DKA) with known lipase maturation factor 1 (LMF1) gene mutations, which can impact insulin efficacy on triglyceride metabolism through altered lipoprotein lipase activity, successfully treated with intravenous insulin. This case highlights the effectiveness of insulin therapy even in those with LMF1 gene mutations., Competing Interests: Conflict of interest: The authors have no conflict of interest to disclose., (© 2025 Greater Baltimore Medical Center.)

Synthetic lethality is a genetic interaction that results in cell death when two genetic deficiencies co-occur but not when either deficiency occurs alone, which can be co-opted for cancer therapeutics. Pairs of paralog genes are among the most straightforward potential synthetic-lethal interactions by virtue of their redundant functions. Here, we demonstrate a paralog-based synthetic lethality by targeting vaccinia-related kinase 1 (VRK1) in glioblastoma (GBM) deficient of VRK2, which is silenced by promoter methylation in approximately two thirds of GBM. Genetic knockdown of VRK1 in VRK2-null or VRK2-methylated cells resulted in decreased activity of the downstream substrate barrier to autointegration factor (BAF), a regulator of post-mitotic nuclear envelope formation. Reduced BAF activity following VRK1 knockdown caused nuclear lobulation, blebbing, and micronucleation, which subsequently resulted in G2-M arrest and DNA damage. The VRK1-VRK2 synthetic-lethal interaction was dependent on VRK1 kinase activity and was rescued by ectopic expression of VRK2. In VRK2-methylated GBM cell line-derived xenograft and patient-derived xenograft models, knockdown of VRK1 led to robust tumor growth inhibition. These results indicate that inhibiting VRK1 kinase activity could be a viable therapeutic strategy in VRK2-methylated GBM., Significance: A paralog synthetic-lethal interaction between VRK1 and VRK2 sensitizes VRK2-methylated glioblastoma to perturbation of VRK1 kinase activity, supporting VRK1 as a drug discovery target in this disease., (©2022 The Authors; Published by the American Association for Cancer Research.)

For many solid malignancies, lymph node (LN) involvement represents a harbinger of distant metastatic disease and, therefore, an important prognostic factor. Beyond its utility as a biomarker, whether and how LN metastasis plays an active role in shaping distant metastasis remains an open question. Here, we develop a syngeneic melanoma mouse model of LN metastasis to investigate how tumors spread to LNs and whether LN colonization influences metastasis to distant tissues. We show that an epigenetically instilled tumor-intrinsic interferon response program confers enhanced LN metastatic potential by enabling the evasion of NK cells and promoting LN colonization. LN metastases resist T cell-mediated cytotoxicity, induce antigen-specific regulatory T cells, and generate tumor-specific immune tolerance that subsequently facilitates distant tumor colonization. These effects extend to human cancers and other murine cancer models, implicating a conserved systemic mechanism by which malignancies spread to distant organs., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Immune responses to cancer are highly variable, with mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors. To understand the rules governing these varied responses, we transcriptionally profiled 371,223 cells from colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd individuals. Analysis of 88 cell subsets and their 204 associated gene expression programs revealed extensive transcriptional and spatial remodeling across tumors. To discover hubs of interacting malignant and immune cells, we identified expression programs in different cell types that co-varied across tumors from affected individuals and used spatial profiling to localize coordinated programs. We discovered a myeloid cell-attracting hub at the tumor-luminal interface associated with tissue damage and an MMRd-enriched immune hub within the tumor, with activated T cells together with malignant and myeloid cells expressing T cell-attracting chemokines. By identifying interacting cellular programs, we reveal the logic underlying spatially organized immune-malignant cell networks., Competing Interests: Declaration of interests K.P., M.H., J.H.C., V.K.K., A.J.A., O.R.-R., A. Regev., and N.H. are co-inventors on US Patent Application No. 16/995,425 relating to methods for predicting outcomes and treating colorectal cancer as described in the manuscript. A.J.A. is a Consultant for Oncorus, Arrakis Therapeutics, and Merck and receives research funding from Mirati Therapeutics, Deerfield, and Novo Ventures. R.B.C. receives consulting/speaking fees from Abbvie, Amgen, Array Biopharma/Pfizer, Asana Biosciences, Astex Pharmaceuticals, AstraZeneca, Avidity Biosciences, BMS, C4 Therapeutics, Chugai, Elicio, Fog Pharma, Fount Therapeutics/Kinnate Biopharma, Genentech, Guardant Health, Ipsen, LOXO, Merrimack, Mirati Therapeutics, Natera, N-of-one/QIAGEN, Novartis, nRichDx, Revolution Medicines, Roche, Roivant, Shionogi, Shire, Spectrum Pharmaceuticals, Symphogen, Tango Therapeutics, Taiho, Warp Drive Bio, and Zikani Therapeutics; holds equity in Avidity Biosciences, C4 Therapeutics, Fount Therapeutics/Kinnate Biopharma, nRichDx, and Revolution Medicines; and has received research funding from Asana, AstraZeneca, Lilly, and Sanofi. V.K.K. consults for Pfizer, GSK, Tizona Therapeutics, Celsius Therapeutics, Bicara Therapeutics, Compass Therapeutics, Biocon, and Syngene. G.M.B. has sponsored research agreements with Palleon Pharmaceuticals, Olink Proteomics, and Takeda Oncology; served on SABs for Novartis and Nektar Therapeutics; and received honoraria from Novartis. A.C.A. is a paid consultant for iTeos Therapeutics, and is an SAB member for Tizona Therapeutics, Compass Therapeutics, Zumutor Biologics, and ImmuneOncia, which have interests in cancer immunotherapy. A.C.A.’s interests were reviewed and managed by the BWH and Partners Healthcare in accordance with their conflict of interest policies. M.G. receives research funding from BMS, Merck, and Servier. J.W.R., C.A.F., and M.L.H. are employees of and stockholders for NanoString Technologies Inc. D.R.Z. is a former employee of NanoString Technologies Inc. B.I. is a consultant for Merck and Volastra Therapeutic. R.B. is an UptoDate Author. A. Rotem is an equity holder in Celsius Therapeutics and NucleAI. K.N. has research funding from Janssen, Revolution Medicines, Evergrande Group, Pharmavite; advisory board: Seattle Genetics, BiomX; consulting: X-Biotix Therapeutics; research funding: BMS, Merck, and Servier. B.E.J. is on the SAB for Checkpoint Therapeutics. O.R.-R. is a named inventor on patents and patent applications filed by the Broad Institute in single-cell genomics. From October 2020, O.R.-R. is an employee of Genentech. A. Regev. is a founder of and equity holder in Celsius Therapeutics, an equity holder in Immunitas Therapeutics, and was an SAB member for Thermo Fisher Scientific, Syros Pharmaceuticals, and Neogene Therapeutics until August 1, 2020. From August 1, 2020, A. Regev. is an employee of Genentech. A. Regev. is a named inventor on several patents and patent applications filed by the Broad Institute in single-cell and spatial genomics. N.H. holds equity in BioNTech and is an advisor for Related Sciences/Danger Bio., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Tumor evolution from a single cell into a malignant, heterogeneous tissue remains poorly understood. Here, we profile single-cell transcriptomes of genetically engineered mouse lung tumors at seven stages, from pre-neoplastic hyperplasia to adenocarcinoma. The diversity of transcriptional states increases over time and is reproducible across tumors and mice. Cancer cells progressively adopt alternate lineage identities, computationally predicted to be mediated through a common transitional, high-plasticity cell state (HPCS). Accordingly, HPCS cells prospectively isolated from mouse tumors and human patient-derived xenografts display high capacity for differentiation and proliferation. The HPCS program is associated with poor survival across human cancers and demonstrates chemoresistance in mice. Our study reveals a central principle underpinning intra-tumoral heterogeneity and motivates therapeutic targeting of the HPCS., Competing Interests: Declaration of Interests T.J. is a member of the Board of Directors of Amgen and Thermo Fisher Scientific, and a co-Founder of Dragonfly Therapeutics and T2 Biosystems. T.J. serves on the Scientific Advisory Board of Dragonfly Therapeutics, SQZ Biotech, and Skyhawk Therapeutics. T.J. also received funding from Calico and currently receives funding from Johnson & Johnson, but this funding did not support the research described in this manuscript. A.R. is a co-founder and equity holder in Celsius Therapeutics and a SAB member for Thermo Fisher, Asimov, Neogene Therapeutics, and Syros Pharmaceuticals, and an equity holder of Immunitas Therapeutics. C.M.R. serves on the SAB of Bridge Medicines and Harpoon Therapeutics, and has consulted regarding oncology drug development with AbbVie, Amgen, Ascentage, Bicycle, Celgene, Daiichi Sankyo, Genentech, Ipsen, Loxo, Pharmamar, and Vavotek. None of the affiliations listed above represent a conflict of interest with the design or execution of this study or interpretation of data presented in this manuscript. Other authors have nothing to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Tumors comprise a complex microenvironment of interacting malignant and stromal cell types. Much of our understanding of the tumor microenvironment comes from in vitro studies isolating the interactions between malignant cells and a single stromal cell type, often along a single pathway., Result: To develop a deeper understanding of the interactions between cells within human lung tumors, we perform RNA-seq profiling of flow-sorted malignant cells, endothelial cells, immune cells, fibroblasts, and bulk cells from freshly resected human primary non-small-cell lung tumors. We map the cell-specific differential expression of prognostically associated secreted factors and cell surface genes, and computationally reconstruct cross-talk between these cell types to generate a novel resource called the Lung Tumor Microenvironment Interactome (LTMI). Using this resource, we identify and validate a prognostically unfavorable influence of Gremlin-1 production by fibroblasts on proliferation of malignant lung adenocarcinoma cells. We also find a prognostically favorable association between infiltration of mast cells and less aggressive tumor cell behavior., Conclusion: These results illustrate the utility of the LTMI as a resource for generating hypotheses concerning tumor-microenvironment interactions that may have prognostic and therapeutic relevance.

Androgen deprivation is the cornerstone of prostate cancer treatment. It results in involution of the normal gland to ~90% of its original size because of the loss of luminal cells. The prostate regenerates when androgen is restored, a process postulated to involve stem cells. Using single-cell RNA sequencing, we identified a rare luminal population in the mouse prostate that expresses stemlike genes ( Sca1 + ) and a large population of differentiated cells ( Psca + ). In organoids and in mice, both populations contribute equally to prostate regeneration, partly through androgen-driven expression of growth factors (Nrg2, Rspo3) by mesenchymal cells acting in a paracrine fashion on luminal cells. Analysis of human prostate tissue revealed similar differentiated and stemlike luminal subpopulations that likewise acquire enhanced regenerative potential after androgen ablation. We propose that prostate regeneration is driven by nearly all persisting luminal cells, not just by rare stem cells.Nkx3.1 + , Pbsn + ). In organoids and in mice, both populations contribute equally to prostate regeneration, partly through androgen-driven expression of growth factors (Nrg2, Rspo3) by mesenchymal cells acting in a paracrine fashion on luminal cells. Analysis of human prostate tissue revealed similar differentiated and stemlike luminal subpopulations that likewise acquire enhanced regenerative potential after androgen ablation. We propose that prostate regeneration is driven by nearly all persisting luminal cells, not just by rare stem cells., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)