- by Nersesian, S., Abou-Hamad, J., Durocher, E., Akiki, G., Domecq, C., Southworth, A., Deng, H., Meunier, L., de Ladurantaye, M., Mes Masson, A.-M., Tessier Cloutier, B., Cook, D. P.Epithelial heterogeneity defines high-grade serous ovarian carcinoma (HGSC), yet principles that generate this diversity within and across tumours remain unclear. Integrating single-cell RNA sequencing (scRNA-seq) data from 13 studies (1,980,703 cells, 371 samples), we resolve a dominant axis of secretory cell polarization spanning proliferative, progenitor-like SecA cells and quiescent SecB cells expressing a mucosal injury response program. Targeted spatial transcriptomics across 8 whole HGSC tissues and a 97-patient tissue microarray shows this axis is spatially deterministic: tumour architecture shapes a […]
- by Malone, M. K., Brownlee, C. W.Importin is a nuclear transport factor which canonically has a role in binding and shuttling NLS-containing proteins from the cytoplasm into the nucleus. Recently, it has been shown that when palmitoylated by specific palmitoyl acyl transferases, importin can partition to the plasma membrane where its roles remain widely unknown. Patients with breast cancer displaying increased importin expression have advanced tumor size, poor tumor differentiation, and reduced overall and recurrence-free survival. In this study, we use palmitoylation altering pharmacological agents to […]
- by Wells, J., Maser, R. S., Doty, R., Tucker, A., Memishian, W., McGee, T., Mitchell-Hutchinson, N., Ramkissoon, P. J., Lesbirel, S., Charette, J. R., Munger, H., Beckett, T., Bult, C. J.MicroRNAs (miRNAs) have been widely implicated in cancer initiation and progression, yet examination of the effects of global miRNA disruption on these processes has been limited. We developed novel genetically engineered mouse models of Kras-driven pulmonary adenocarcinoma (LUAD) with cell-type-specific disruption of miRNA biosynthesis via Dicer1 allele deletion, which exhibit significant differences in tumor progression rates and expected survival. Dicer1 is an RNase III enzyme that is required for the biogenesis of mature, functional miRNAs. Lung tumor progression was accelerated, […]
- by Nnam, C. F., Li, Y., Zhang, M., Mboya, E. A., Kolling, F., Perreard, L., Palys, T. J., Pflugradt, E., Pioli, P. A., Ernstoff, M. S., Seigne, J. D., Pettus, J. R., Ren, B., Song, L., Brugarolas, J., Christensen, B. C., Salas, L. A.Clear cell renal cell carcinoma (ccRCC) is characterized by transcriptional reprogram-ming driven by hypoxia signaling, metabolic rewiring, and immune modulation. While gene-level analyses have defined key features of ccRCC biology, they do not capture isoform-level variation arising from alternative splicing. Differential transcript usage (DTU) represents an additional regulatory layer that may influence protein function, pathway activity, and clinical outcomes, yet its role in ccRCC biology and prognosis re-mains incompletely understood. We assessed differential expression in 127 ccRCC tu-mors and 33 […]
- by Fisher, J., Stepanchick, E., Wilson, A., Kida, J., Adam, M., Perez Otero, M. V., Badar, T., Ferrer, A., Kusne, Y., Patnaik, M. M., Chlon, T. M.Germline variants in DDX41 are the most frequent genetic predisposition to adult hematologic malignancies. The most common variants are truncating, implicating loss of function in the pathogenesis. However, non-truncating variants account for 30-40% of cases, and their impact on essential DDX41 functions remains unknown. We utilized a genetic complementation assay to assess the functionality of 10 recurrent germline non-truncating variants of DDX41. All variants restored viability to Ddx41-deficient hematopoietic progenitor cells at exogenous expression levels. In contrast, the hotspot mutant […]
- by Lake, R. J., Tshibangu, C., Candia, N. J., Abfalterer, Q. U., Lagutina, I. V., Pauken, C., Leslie, K. K., Steinkamp, M. P., Fan, H.-Y.Therapeutic resistance remains a major challenge in advanced and recurrent endometrial cancer (EC). Aberrant NOTCH signaling has been associated with aggressive tumor behavior and therapeutic resistance across multiple malignancies, yet its therapeutic significance in EC remains incompletely defined. We investigated whether auranofin (AuR), a noncanonical modulator of NOTCH signaling through the transcriptional effector RBPJ, alters platinum responsiveness in EC models. Elevated NOTCH3 copy-number was associated with poorer overall survival in the TCGA-UCEC cohort. AuR treatment reduced RBPJ occupancy at canonical […]
- by Mandloi, A., Larson, C. R., Baines, J., Tran, T. M., Roy, S., Fang, Y.-H. D., Laube, R., Patel, M., Risley, C., Welner, R. S., Masood, A., Acharyya, S., Carstens, J. L.Pancreatic ductal adenocarcinoma (PDAC) is a deadly, highly metastatic disease, driven by an interplay between cancer cells and the metastatic site-specific microenvironment. However, pre-clinical models that robustly capture these interactions within the context of matched primary and metastatic tumors are limited. Here, we present a novel transplant model system for matched pancreas and liver tumors to study PDAC metastatic progression. Using this model, we identified murine PDAC cell lines with distinct liver tropism potentials and defined a transcriptional program associated […]
- by Podszywalow-Bartnicka, P., Kozlowska, E., Serwa, R., Idaszek, J., Walejewska, E., Kepczynska, A., Mietelska-Porowska, A., Pilanc-Kudlek, P., Wolczyk, M., Schärfen, L., Le, B. V., Swieszkowski, W., Piwocka, K., Skorski, T., Neugebauer, K. M.Tyrosine kinase inhibitors (TKIs) are the first-line therapy for chronic myeloid leukemia (CML), yet fail to eliminate quiescent CML cells residing in the bone marrow (BM). While transcriptome adaptation and metabolic rewiring have been recognized as mechanisms enabling CML survival, the contribution of RNA processing, known to expand the repertoire of isoforms and directly mediate therapy resistance in leukemia, is poorly characterized. We previously found that a subset of alternative splicing (AS) changes detected in CML cells surviving months of […]
- by Ishikawa, T.TP53-mutant cancers often accumulate p53 protein, creating a potential abundance-amplified therapeutic target, but wild-type p53 can also rise in stressed normal cells. This study defines the quantitative design requirements for an intracellular strategy targeting RHSVV/PAb240-like conformational exposure of p53 in TP53-mutant/high-p53 cancer. We integrated DepMap cell-line annotations, p53 abundance data, NCI TP53 mutation resources, and Human Protein Atlas normal-tissue immunohistochemistry, and modeled RHSVV/PAb240-like exposure as a latent design variable. Abundance-only models were compared with latent RHSVV exposure-discriminated models across target-engagement […]
- by Maedomari, M., Kawada, S., Harashima, N.Kalanchoe pinnata is a perennial plant that grows wild in tropical regions and is traditionally used as a medicinal plant. Plants of the Kalanchoe genus have been shown to possess several effects, including antibacterial and antihypertensive properties. However, effects such as the induction of apoptosis in cancer cells have not been reported for any substance other than leaf extracts of this plant and remain unexplained. Therefore, in this study, we investigated the effects of extracts from various parts of K. […]
- by Tan, J., Xiong, Y., Cheng, A., Zhang, C.-S., Zhong, M., Ma, J., Zhao, J., Zhuang, Y., Wang, W., Pan, G., Lin, Z., Zhou, S., Zhou, H., Su, G., Hong, X.Gastric cancer (GC) is strongly associated with changes in the gastric microbiome. However, the direct contribution of individual pathogenic species to tumor initiation and progression remains poorly defined. Here, we identified Candida albicans (C. albicans), a fungus that ranks as the most significantly enriched taxon in GC tissues, can directly promote gastric carcinogenesis. We found that when C. albicans alone was colonized into the gastric mucosa of mice, it induced the complete sequence of GC-associated preneoplastic lesions, including chronic gastritis, […]
- A functional genomics screen identifies novel drivers of FR900359 resistance in uveal melanoma cellsby Dupuy, A., Murray, S. D., Riordan, J. D., Anderson, E. R., Onken, M. D., Blumer, K. J., Stipp, C. S.Uveal melanoma (UM) is the most common form of intraocular cancer in adults and has a median survival rate of ~1 year after metastasis occurs. Metastatic UM is largely refractory to treatment and there are no effective pharmacological therapies, resulting in poor overall survival. Activating mutations in GNAQ and GNA11 proteins (GNAQ/11) are the oncogenic initiators in >90% UM cases. While there are no targeted therapies yet identified for the GNAQ/11 oncoproteins, a natural compound called FR900359 (FR) is a […]
- by Mokhashi, O. M., Xin, R., Gao, L., Chhabra, R., Hale, S., Ongkeko, W. M.Although immune checkpoint inhibitors targeting the programmed death-ligand 1 (PD-L1) axis have transformed the treatment of recurrent and metastatic head and neck squamous cell carcinoma (HNSCC), durable clinical responses remain limited to a minority of patients, and the determinants of treatment resistance remain incompletely understood. Human papillomavirus (HPV) infection, alcohol consumption, tobacco use, and are the three most prominent etiological risk factors for HNSCC; however, despite their well-established individual roles in disease development, the influence of their combined exposure on […]
- by Flowers, B., Lialios, P., DiLollo, I., Smith, N., Whalley, J., Lee, J.-S.Across gastrointestinal (GI) cancers, shared malignant programs are layered onto strong anatomical, lineage, and microenvironmental variation, making it difficult to distinguish disease-relevant long noncoding RNAs (lncRNAs) from context-dependent transcriptional signals. We developed a pan-GI integrative framework to classify lncRNAs across colorectal adenocarcinoma, gastric adenocarcinoma, and esophageal cancer using bulk and single-cell transcriptomic resources. This framework evaluates lncRNAs across four complementary dimensions: recurrent tumor-associated expression, clinical association with disease progression and overall survival, co-expression network context, and malignant epithelial expression at […]
- by Valbuena-Goiricelaya, E., Elurbide, J., Latasa, M. U., Lopez-Pascual, A., Uriarte, I., Colyn, L., Inacio, P., Arnes-Benito, R., Adan-Villaescusa, E., Castello-Uribe, B., Franceschini, B., Milana, F., Strnad, P., Frankova, S., Sticova, E., Fabian, O., Amat, I., Urman, J., Lleo, A., Huch, M., Arechederra, M., Berasain, C., Fernandez-Barrena, M. G., Avila, M. A.Cholangiocarcinoma (CCA) is a highly aggressive malignancy characterized by poor prognosis, limited therapeutic options, and a predominantly immunosuppressive tumor microenvironment. Protein arginine methyltransferase 1 (PRMT1), the major mediator of asymmetric arginine dimethylation, has been implicated in multiple oncogenic processes, although its role in CCA remains unknown. Here, we demonstrate that PRMT1 is frequently overexpressed in human CCA and is associated with aggressive molecular subtypes and immune-desert tumors. Genetic dependency analyses and pharmacological inhibition using type I PRMT inhibitors markedly impaired […]
- by Soave, C., Polin, L., Ducker, C., Ong, V., Kim, S., Pardy, L., Li, J., Bao, X., Huang, Y., Shaw, P. E., Khupse, R., Ratnam, M.Androgen receptor (AR)-dependent prostate cancer (PCa) cells require co-activation of ELK1 by AR to activate a critical set of cell cycle and mitosis genes, regardless of hormone – sensitivity. A small molecule antagonist (KCI807) that inhibits AR-dependent growth by selectively binding to AR and blocking its association with ELK1 is limited as a drug by auto-induced metabolism. Using structure-activity data, consistent with modeling a physically mapped KCI807 binding pocket, we developed a new class of compounds with a different core […]
- by Tran, D., Vaska, A., El Rayes, T., Lovinger, N., Elbanna, Y. A., Lee, E., Burd, C. E., Zippin, J. H., Huse, M.How the cutaneous microenvironment influences early melanomagenesis is poorly understood. Here, we assessed the effects of three immune perturbations on premalignant melanocyte expansion in an autochthonous mouse model of disease. Depletion of regulatory T (Treg) cells markedly accelerated melanoproliferation, an unexpected phenotype that was associated with monocyte and macrophage infiltration, the production of inflammatory and angiogenic factors, and vascular leakage. In line with these observations, single cell transcriptomic analysis of Treg cell deficient skin revealed robust accumulation of monocyte-derived macrophages […]
- by Bansal, S., Aparicio, L., Krishnan, A., Liu, C., Caprio, L., Chiarella, A., Sarti, S., Piersant, J., Rahiman, C., An, J., Mccann, P., Sen, N., Ragaishis, B., Derakhshan, F., Taback, B., Rustgi, A., Izar, B., Spina, C.BackgroundRadiotherapy efficacy is constrained by an immunosuppressive tumor microenvironment (TME) enriched in extracellular adenosine and suppressive myeloid populations that attenuate cytotoxic T-cell responses. The CD73-adenosine-A2a/A2b receptor axis represents a key metabolic immune checkpoint; however, the relative contributions of tumor cell-intrinsic versus host-derived adenosine signaling to radiotherapy response remain incompletely defined. MethodsUsing orthotopic murine breast carcinoma models, we interrogated radiation-induced adenosine dynamics and downstream immune remodeling through quantitative adenosine measurements, bulk RNA sequencing, and multiparameter flow cytometry. Genetically engineered models were […]
- by Lohano, S. V., Sad, K., Kyle, A. J., Hill, E. J., Sloan, S. A., Corbett, A. H., Spangle, J. H.Histone mutations, characterized as oncohistones, have emerged as important oncogenic driver events by altering chromatin structure and/or chromatin modifications, thereby dysregulating gene expression. While H3 tail domain oncohistone mutations such as H3K27M and H3K36M are well characterized, it is currently unknown whether mutations within the H3 globular domain represent oncogenic driver events. Using publicly available cancer patient tumor data, here we identify H3R131C as a recurrent histone H3 globular domain mutation. H3R131C mutation is present in diverse human tumors including […]
- by Liang, C., Liu, Z., Xu, X., Xu, Z., Zhang, Q., Zhang, T., Mangan, R. J., Xiu, B., Wu, G., Akhshi, T., Sandusky, Z. M., Gray, G. K., Zhang, N., Kuziel, G., Traphagen, N. A., Fass, S. B., Grayson, A., Ho, L.-L., Gu, S. S., Wang, S., Sheng, Z. Z., Zhang, Y., Adib, E., Chen, T., Jeselsohn, R., Kellis, M., Brown, M.Circadian regulation shapes tissue physiology, yet how it organizes cellular and molecular dynamics within the tumor microenvironment (TME) and influences tumor immunity remains unclear. Using temporal single-nucleus multiomic profiling of mouse breast tumors, we uncovered extensive circadian programs that are both cell-type-specific and shared across the TME, governing proliferation and immune responses. Notably, cancer epithelial cells exhibited global acrophase misalignment relative to immune populations. This intercellular desynchrony manifests as temporal decoupling between tumor proliferation and immune activation, discordant antigen presentation […]
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