- by Zhou, B. P., Chu, T. L. H., Gallant, A. K., Wang, S., Bhat, T. A., Ghorayeb, R., Gough, C., Garcia, R. E., Pujana, M. A., Lim, C. J., Maxwell, C. A.The metastatic process initiates with collective cell invasion into surrounding tissues and axillary nodes, and subsequent colonization at a distant site. Previously, we found collective invasion is augmented during the G2 cell cycle phase, facilitated through Aurora kinase A (AURKA)-mediated centrosome polarization in the leader cell. Here, we identify cell cycle-associated gene signatures as overrepresented in axilla and liver metastatic sites, with AURKA expression strongly correlated with breast cancer metastasis signatures, and pan-cancer patient survival. Then, we show GFP-AURKA expression […]
- by Chen, W., Maio, G., Chen, X., Lu, X., Zhao, J., Arora, N., Liu, Y., Ziolkowski, L. M., Macleod, K. F., Zhou, Y., Lin, H.KRAS mutations underlie many human cancers. While inhibitors such as Sotorasib and Adagrasib targeting KRAS mutants have shown promise, additional strategies are required to address the broader spectrum of KRAS-driven cancers, particularly those displaying drug resistance. Thus, there is a need to better understand KRAS signaling and develop new therapeutic strategies. Here we show that KRAS4A is palmitoylated on Cys180 by a palmitoyl transferase, DHHC7 (gene name ZDHHC7). Palmitoylation promotes KRAS4A plasma membrane localization, and more importantly, nanoclustering. This in […]
- by Segal, D., Kainacher, L., Muffel, T., Geiger, T. M., Lechner, S., Mavridi, D., Balourdas, D.-I., Nelles, M. L., Schaetz, C., Knapp, S., Joerger, A. C., Nowak, R. P., Steinebach, C., Winter, G. E.Chromatin accessibility is essential for maintaining the fidelity of gene regulation and is dynamically regulated by epigenetic enzymes that are often dysregulated in cancer. The most commonly mutated regulator is the modular, multi-subunit Brahma-associated factor (BAF) chromatin remodeling complex. Previous attempts to exploit BAF complex mutations as potential tumor vulnerabilities using loss-of-function approaches have shown limited clinical success. Here, we instead propose a gain-of-function (GOF) strategy and establish Transcriptional/Remodeling chemical Inducers of Proximity (TRIPs), a class of neomorphic molecules that […]
- by Skupa, S. A., Hernandez, J. B., Smith, A. L., Drengler, E. M., Seth, A. K., Rai, S. N., Clayton, J. B., D'Angelo, C. R., El-Gamal, D.Background: The composition and function of the gut microbiome have been shown to contribute to both health and disease. One of the most powerful modulators of microbial composition and function is diet. Materials & Methods: Using the E-TCL1 murine model of B-cell chronic lymphocytic leukemia (CLL), we assigned male and female mice to a high-fat, high-carbohydrate Western diet (HF) or standard chow (CH) diet. Results: Mice consuming a HF diet had significantly shorter survival than those consuming a CH diet, […]
- by Bui, Q. T., Basavaraja, R., Dhamdhere, M. R., Holczbauer, A., Paruzzo, L., Guruprasad, P., Scaglione, M., Tang, Y., Sun, Y., Beiting, D. P., Nash, E. K., Fazelinia, H., Spruce, L., Wang, A., Tan, K., Guo, W., Conn, C. S., Fan, Y., Koumenis, C., Spiegelman, V. S., Rui, H., Diehl, J. A., Atherton, M. J., Stanger, B., Bailis, W., Ruella, M., Fuchs, S.Immunosuppressive tumor microenvironment (TME) inactivates CD8+ cytotoxic lymphocytes (CTLs). Here, we identify SPTBN2 spectrin as a key immunosuppressive regulator induced in CTLs in response to nutritional deficit. In human pancreatic and colorectal cancers, SPTBN2 expression negatively correlated with CTL infiltration and patients survival. In TME of mouse pancreatic and colorectal adenocarcinomas, SPTBN2 inactivated intratumoral CTLs, stimulated tumor growth and conferred cross-resistance to anti-cancer therapies. SPTBN2 knockout protected CAR T-cells from trogocytosis and increased their memory state. SPTBN2 maintained levels of […]
- by Saad, E., Hammad, M.Oncolytic adenovirus (ADV) therapy faces heterogeneous responses, implying tumor-intrinsic resistance. We identify interleukin-17 (IL-17) signaling as a novel potential barrier associated with multi-modal cellular reprogramming. Transcriptomic analysis of ADV-treated 4T1 murine mammary carcinoma cells revealed specific upregulation of Il17rb, Il17rd, and Il17f, indicating viral induction of this inflammatory axis. The IL-17 signature correlates strongly with a cancer stemness phenotype. Metabolically, it associates with increased lipid metabolism and suppressed glycolysis, suggesting a state resistant to viral replication. Furthermore, it broadly negatively […]
- by Ibanez-Rios, M.-I., Aalam, S. M. M., Ritting, M. L., Jore, A., Chaludiya, K., Emperumal, C. P., Jakub, J. W., McLaughlin, S. A., Degnim, A. C., Couch, F., Boughey, J. C., Yadav, S., Sadanandam, A., Sherman, M. E., Radisky, D., Knapp, D. J. H. F., Kannan, N.The normal adult male breast has not been characterized at single-cell resolution, leaving the cellular basis of male breast cancer biology undefined. Here we present an integrated single-cell RNA sequencing atlas of the adult human breast comprising 174,471 cells from 17 donors (3 male, 14 female), including 18,117 male-derived cells. This revealed that the male breast retains all three epithelial populations, basal (BC), luminal progenitor (LP), and luminal committed cells (LC), but with an increase in LC at the expense […]
- by Han, S. H., Cheon, Y. J., Lee, H. M., Seo, H., Lee, J. Y., Kim, M. J., Yoon, S. R., Choi, D., Ryu, C. J.B7-H3 (CD276) is an immune checkpoint molecule frequently overexpressed in hepatocellular carcinoma (HCC) and represents a promising therapeutic target. However, its roles in tumor cell adhesion, metastatic behavior and immune evasion–particularly in interactions with natural killer (NK) cells–remain incompletely understood. In the present study, B7-H3 was depleted using small interfering RNA and CRISPR/Cas9 in epithelial (Huh7 and HepG2) and mesenchymal (SNU449) HCC cell lines. Tumor cell survival, apoptosis, adhesion, migration and invasion were evaluated using functional assays. Expression of adhesion […]
- by Tang, Q., Lian, C., Han, X., Zhang, X., Wang, Z., Wang, B., Zhu, T., Lin, X., Wang, X., Xu, Y., Xiao, M., Wang, Z., Li, J., Chen, S., Wang, Y., Liu, Y., Li, S., Shen, Z., Lu, X., Han, X., Zhou, Y., Xiao, M., Ran, J., Cao, X., Xu, X., Samano-Sanchez, H., Rodriguez, A., Wang, L., Chen, S., Xu, Z., Zhang, S., Yang, N., Tang, Y., Liu, J.Lung squamous cell carcinoma (LUSC) lacks clearly defined key drivers and effective targeted therapies, reflecting an incomplete understanding of its molecular pathogenesis. Here, we identify SMAD4 as a critical regulator of three-dimensional (3D) genome organization in LUSC and uncover a mechanistic link between tumor suppressor loss and oncogenic transcriptional activation. By integrating clinical datasets, genetically engineered mouse models, human and murine LUSC cell lines, and multi-omics analyses, we demonstrate that SMAD4 deficiency promotes LUSC progression by unleashing EP300-mediated enhancer-promoter looping […]
- by Ravid, A., Ladany, H., Gusev, A., Maruvka, Y. E.Cancer development is shaped by somatic mutational processes that leave characteristic patterns known as mutational signatures. The inherited determinants of variability in signature activity remain largely unknown. Common germline variants that regulate this activity, which we term Signature Quantitative Trait Loci (SigQTLs), are expected to have modest individual effects, requiring cohorts of tens of thousands of samples for reliable detection. Clinical targeted-panel sequencing datasets achieve this scale, but present a fundamental challenge: individual tumors typically harbor too few mutations for […]
- by Kaniowski, D., Boguszewska-Czubara, A., Ebenryter-Olbinska, K., Kulik, K., Suwara, J., Wnorowski, A., Wojcik, J., Budzynska, B., Michalak, A., Ziogas, A., Nawrot, B., Swiech, O.The clinical translation of RNA interference (RNAi) therapeutics remains limited by inefficient delivery and cancer-target accumulation. Here, we report the development of a new cationic liposome (CLP) nanocarrier engineered for delivery and controlled-release of small interfering RNA (siRNA) targeting the epidermal growth factor receptor (EGFR) in human colorectal cancer. CLPs were synthesized from ethylphosphocholine-based lipids and PEGylated components, with folic acid (FA) tissue-specific ligand and fluorophore labelling. These nanocarriers exhibited robust physicochemical stability across a broad pH and temperature range, […]
- Cell state-specific metabolic networks govern ferroptosis versus apoptosis in small cell lung cancerby Kim, J. W., Bebber, C. M., Dai, Y., Bopp, S., Edenhofer, A., Li, A. M., Rosner, T., Berning, L., Yang, M., Leak, L. B., Stroh, J., Shrestha, B., Abdallah, A., Prymidis, D., Olivos, H., Baron, M., Nguyen, T., Shue, Y. T., Nishiga, Y., Drainas, A., Chaikovsky, A., Szylo, K., Li, Y., Kang, Y. P., Manoj, P., Quintanal Villalonga, A., Rudin, C. M., DeNicola, G. M., Dixon, S. J., Frezza, C., Ye, J., von Karstedt, S., Sage, J.Cellular heterogeneity and plasticity are hallmarks of cancer that contribute to tumor growth and therapy resistance. Here we investigated metabolic heterogeneity in small cell lung cancer (SCLC), an aggressive neuroendocrine (NE) cancer type. Through integrated transcriptomic and metabolomic analyses, we identified a universal dependency on exogenous cysteine/cystine (Cys) across all NE/non-NE SCLC cell states. Notably, NE and non-NE cells with low levels of the ASCL1 transcription factor die from ferroptosis upon Cys depletion. In contrast, ASCL1-high cells die from apoptosis […]
- by Xu, Y., Zhang, X., Chen, W., Li, Y., Lu, L., Huang, R., Liao, J., Li, H., Zheng, W.PurposeDifferentially expressed genes (DEGs) between colorectal cancer liver metastasis (CRLM) epithelium and primary colorectal cancer (CRC) epithelium (LMR DEGs) identified based on single-cell RNA sequencing (scRNA-seq) data may become new biomarkers for CRC prognosis. MethodsAn scRNA-seq dataset was used to describe the cellular landscape of primary CRC and CRLM and identify LMR DEGs. Prognostic LMR DEGs were identified in the bulk RNA-seq dataset. Based on the prognostic LMR DEGs, multiple machine learning algorithm combinations were compared in terms of their […]
- by Ralston, C. Q., Flesken-Nikitin, A., Fu, D.-J., Ashe, C. S., Harlan, B. A., Hossain, M. M., Wang, D. K., Yemelyanova, A., Schmoeckel, E., Godwin, A. K., Mayr, D., Cosgrove, B. D., Nikitin, A. Y.High-grade serous carcinoma (HGSC), the most lethal form of ovarian cancer, preferentially originates in the tubal epithelium (TE) of the distal uterine tube (also known as Fallopian tube or oviduct). Mouse models are widely used to study how HGSC initiates in humans; however, the extent to which mouse and human uterine tubes are comparable remains unclear. Here, we conduct cross-species single-cell transcriptomic comparative analyses and organoid assay validations to reveal conserved differentiation trajectories from bipotent progenitors to secretory or ciliated […]
- by Goel, H. L., Wang, T., Dimitrov, B. S., Kumar, A., Silva, C. A., Fitzgerald, T. J., Mercurio, A. M.Ionizing radiation can be an effective therapy for prostate cancer. Unfortunately, however, more aggressive prostate cancers such as neuroendocrine prostate cancer (NEPC) are often radiation resistant, which contributes to their high degree of morbidity and mortality. In this study, we used an unbiased approach to identify novel mechanisms that contribute to resistance to radiation and that are associated with neuroendocrine differentiation. Specifically, we compared the expression of cell surface proteins by mass spectrometry in prostate cancer cell lines that had […]
- by Boelens, M., Tulkens, D., Christiaens, A., Houbart, W., Demuynck, S., Creytens, D., Vleminckx, K.Well- and dedifferentiated liposarcomas (WDLPS and DDLPS) are characterized by extensive copy- number alterations rather than recurrent gene-inactivating mutations, obscuring the molecular mechanisms that drive disease progression and, critically, the transition from well-differentiated to the more aggressive dedifferentiated tumor states. Despite marked differences in clinical behavior and prognosis, the regulatory events underlying adipocytic lineage destabilization in DDLPS remain poorly understood. Here, we establish an in vivo model of retroperitoneal liposarcoma in Xenopus tropicalis through early embryonic mosaic perturbation of p53 […]
- by Oladokun, F. A., Oladokun, F. A., Ajayi, A. A., Ibrahim, A., Aladeloye, R. S., Akinfe, O. A., Oludaiye, F. R., Moens, T., Badmos, H., Abolaji, A. O., Cagan, R. L.Colorectal cancer across sub-Saharan Africa presents a growing global health burden, with increasing cases and mortality linked to late diagnosis, limited healthcare access and lack of effective treatments. African patients typically present with aggressive disease marked by distinct genomic signatures, indicating the need for targeted treatment approaches. We integrated genetic modelling, phenotypic scoring, imaging and biochemical analysis to explore how mutations found in individual Nigerian colorectal cancer patients influence drug responsiveness. We used the data from Cancer Genome Atlas to […]
- by Cramer, E. M., Heiland, R., Lima da Rocha, H., Bergman, D. R., Gray, J. W., Mills, G. B., Fertig, E. J., Macklin, P., Heiser, L. M., Chang, Y. H.Multiplexed tissue imaging (MTI) has revealed recurrent tumor microenvironment (TME) architectures with prognostic value, yet these measurements are inherently static, obscuring dynamic changes in the TME that govern therapeutic response. Here, we introduce a trajectory-centric framework that reconstructs continuous TME dynamics by integrating agent-based mathematical modeling and simulation with state space analysis. This approach yields a mechanistically constrained reference landscape built entirely from in silico simulation, and onto which static patient biospecimens can be projected and mapped onto simulated TME […]
- by Heo, S.-H., Kim, K.-H., Song, H.-Y., Lee, S.-w., Baek, I.-J., Ryu, J.-W., Ryu, S.-H., Seo, S.-M., Jo, S.-J.Humanized mice (hu-mice), which recapitulate the human immune system, have become increasingly important for preclinical immunotherapy studies. Among these models, the human peripheral blood mononuclear cells (PBMC)-engrafted hu-mice model is the simplest and fastest. However, its utility is hindered by the development of lethal graft-versus-host disease (GvHD) and the insufficient reconstitution of human leukocytes. To address these limitations, we developed PBMC hu-mice models using a novel strain, NOD-CD47nullRag2nullIL-2r{gamma}null (RTKO) focusing on the immunological defects of the NOD strain and the […]
- by Vantsev, N. A., Zhao, L., Morioka, S., Kajiho, H., Sasaki, J., Sasaki, T., Abrams, C. S., Tong, W.JAK2 is a key regulator of cytokine-mediated proliferative signaling in hematopoietic stem and progenitor cells. Activating mutations, most commonly JAK2 V617F, trigger aberrant cytokine signaling driving the pathogenesis of myeloproliferative neoplasms (MPNs). Phosphatidylinositol transfer proteins (PITPs) facilitate phosphoinositide synthesis by delivering phosphatidylinositol to lipid kinases, though their roles in oncogenic signaling have remained poorly defined. Here we show that PITP{beta} is critical for the development of JAK2V617F-driven MPN in mice. Deleting Pitp{beta} across the hematopoietic system, but not Pitp, prolonged […]
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