- by Yevlashevskaya, O. S., Davies, J. Z., Choi, J., Yuan, S., Latif, A., Poologasundarampillai, G., Gendoo, D. M. A., Wiench, M.Three-dimensional (3D) organotypic cultures recapitulate key structural features of oral tumours and provide controlled, ethical, and reproducible research platforms. However, their ability to faithfully recapitulate in vivo tissue composition and their translational relevance require rigorous validation. Here, we characterised a head and neck squamous cell carcinoma (HNSCC) model using single-cell RNA sequencing to assess maturation, cellular heterogeneity, functionality, and inter- and intra-tissue interactions within epithelial and stromal compartments. The epithelial layer of the model differentiated into populations closely resembling the […]
- by Ramade, C., Thebault, N., Scarlata, C.-M., Oreper, D., Lauzeral-Vizcaino, F., Jhunjhunwala, S., Cabarrou, B., Hornburg, M., Fournier, C., Salvioni, A., Michelas, M., Sarradin, V., Leonardi, G. C., Feliu, V., Maixent, M., Scandella, L., He, M. X., Darwish, M., Heidersbach, A., Ross, C., Xu, H., Bouquet, F., Fonseca, C., Tom Lesluyes, T., Congy-Jolivet, N., Gomez-Roca, C., Martinez, A., Devaud, C., Filleron, T., Delord, J.-P., Mazieres, J., Delamarre, L., Ayyoub, M.The contribution of neoantigen-specific T cells to PD-(L)1 efficacy has largely been inferred from tumor mutational burden. We functionally profiled circulating T cell responses against 7,038 predicted HLA-I-restricted and 21,453 HLA-II-restricted neopeptides in 27 patients with advanced non-small cell lung cancer treated with anti-PD-(L)1. CD4 responses were frequent and correlated with neoantigen availability but not clinical benefit. In contrast, the magnitude and breadth of neoantigen-specific CD8 T cell responses were associated with clinical benefit, progression-free and overall survival, independently of […]
- by Gupta, S., Mahajan, N., Kumar, M., Kumar, A.The PI3K-AKT-MTOR signalling axis is pivotal in regulating cell survival, proliferation, and growth. TSC2 (tuberous sclerosis complex subunit 2) is a well-established negative regulator of this pathway, which primarily acts by suppressing the MTORC1 activity. While the cytoplasmic role of TSC2 is well characterized, emerging evidence suggests its additional nuclear functions. Previous work from our laboratory identified TSC2 as a transcriptional repressor of the EREG (Epiregulin) gene. Building on this foundation, the present study investigates the transcriptional role of TSC2 […]
- by Liu, Y., Zhang, Z., Tao, Y., Rahgav, L., Gray-Gaillard, S., Hussaini, Y., Pan, M., Shamber, J., Kwak, J., Park, S. L., Cramer, J., Stoltz, R., Patria, J., Swanger, J., Liu, K., Sannigrahi, M. K., Houghton, M., Rodriguez, C., Carey, R. M., Brody, R., Rajasekaran, K., Weinstein, G., Linette, G. P., Carreno, B. M., Painter, M. M., Wherry, E. J., Clurman, B., Basu, D., Diab, A.Human papillomavirus-associated oropharyngeal carcinoma (HPV+ OPC) is primarily driven by viral E6 and E7 oncoproteins, which disrupt G1 checkpoint control and impose a selective dependency on WEE1-mediated G2/M regulation. While this vulnerability confers sensitivity to WEE1 inhibition, its immunologic consequences remain poorly defined. Here, we show that WEE1 inhibition elicits durable antitumor immunity in immunocompetent models of HPV+ OPC. Using murine and human preclinical systems, we demonstrate that the WEE1 inhibitor ZN-c3 (azenosertib) mediates tumor control through cell-autonomous cytotoxicity and […]
- by Quinones-Aviles, Y., Salovska, B., Markham, C. S., Di, Y., Turk, B. E., Liu, Y., Muzumdar, M. D.KRAS is mutated in over 90% of pancreatic ductal adenocarcinomas (PDAC), where hotspot alterations in codons 12, 13, and 61 drive tumor initiation and progression. Although distinct biochemical properties have been described for individual KRAS mutants, whether they generate unique allele-specific signaling programs in PDAC cells remains unresolved. Here, we systematically interrogated the molecular consequences of seven common KRAS mutant variants in reconstituted isogenic, KRAS-deficient PDAC cell lines by integrated transcriptomic, proteomic, and phosphoproteomic profiling. We found that baseline cellular […]
- by Chan Wah Hak, C., Patrikeev, A., Rullan, A., Patin, E. C., Roulstone, V., Hubbard, L. C., Guelbert, M., Appleton, E. S., Foo, S., Dean, I., Burley, A., Kyula-Currie, J. N., Baldock, H., Lee, J. Y., Nenclares, P., Nanapragasam, H., Murano, C., Pedersen, M., Bhide, S., Ono, M., Harrington, K. J., Melcher, A. A.Concomitant chemoradiotherapy (CRT) is a standard-of-care for unresectable locally-advanced head and neck squamous cell carcinoma (LA-SCCHN), but its immune effects, particularly compared to radiotherapy (RT) alone, remain unclear. Using syngeneic murine models, we integrated Nr4a3-Tocky reporter analysis with single-cell transcriptomics and T-cell receptor clonotyping comprehensively to profile intratumoural CD8 T-cells following RT/CRT. We show that CRT uniquely drives robust antigen-specific clonal expansion and biases differentiation toward progenitor (or precursor) exhausted (TPEX) phenotypes, while RT favours terminal exhaustion (TEX). Single-cell analyses […]
- by Kumarasamy, V., Wang, J., Yau, E., Abel, E. V., Witkiewicz, A., Knudsen, E.Activating mutations in KRAS drive pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC). Although mutant-selective KRAS inhibitors and pan-RAS inhibitors provide clinical benefits, the development of resistance limits durable response. Transcriptomic and proteomic analyses reveal that, despite effective suppression of mutant KRAS signaling, resistant cells sustain cell cycle progression. Distinct orthogonal mitogenic pathways are engaged in a context-dependent manner to bypass KRAS inhibition. While these pathways can be broadly inhibited using the pan-RAS-ON inhibitor RMC-6236, cells remained capable […]
- by LI, H., Sierras, A. L., Fan, R., Oeller, M., Schallmoser, K., Hultquist, A., Scheding, S.Myelofibrosis (MF) is the most severe myeloproliferative neoplasm, and current therapies rarely reverse bone marrow fibrosis, highlighting the need for improved disease models and therapeutic targets. Here, we established a humanized MF model by transplanting thrombopoietin (THPO)-overexpressing human bone marrow CD34 cells into humanized bone marrow ossicles generated in immunodeficient NSG mice. THPO overexpression induced progressive reticulin fibrosis in vivo, accompanied by myeloid skewing, increased megakaryocyte clustering, and redistribution of human hematopoietic cells to murine spleen and femur, consistent with […]
- by Friedenson, B. A.Basal breast cancers display stem cell associated basal programs, but originate from luminal progenitors. This lineage paradox may be created by Epstein-Barr virus (EBV) infection. Across more than 2,000 breast cancer genomes, coordinated methylation changes appeared in cis-regulatory elements governing stem cell differentiation. Methylation positions followed EBV-associated malignancies with striking accuracy independent of whether ER-status marked a luminal or basal cancer. EBV-driven epigenetic reprogramming was incompatible with tumor infiltrating lymphocytes and disrupted lineage specification before tumorigenesis. Breast cancers commonly showed […]
- Spatial Landscape of Pregnancy-Associated Triple Negative Breast Cancer and Mammary Gland Involutionby Veraksa, D., Mukund, K., Frankhouser, D., Yang, L., Tomsic, J., Pillai, R., Venkatasubramani, J., Schmolze, D., Wu, X.-C., LeBlanc, M.-A., Miele, L., Ochoa, A., Seewaldt, V., Subramaniam, S.Pregnancy-associated triple negative breast cancer (PA-TNBC) is one of the highest-risk breast cancers, marked by an aggressive phenotype that lacks targeted treatment options. Studies have shown that post-lactational mammary gland involution plays a role in this increased risk. To delineate the underlying mechanisms, our study characterized the transcriptional state of the epithelia and surrounding microenvironment in women with PA-TNBC, comparing those diagnosed pre-involution (PRE) and post-involution (POST,
- by Zhang, X., Wong, W., Cho, H. S., Yang, D., Dixon, G., Luo, R., Liu, D., Torre, D., Umeda, S., Gonzalez, F., Askan, G., Yavas, A., Damodaran, J. R., Rickert, R. W., Kappagantula, R., Pan, F. C., Aveson, V. G., Grimont, A., Pulecio Rojas, J. A., Kaplan, S. J., Pan, H., Leach, S. D., Iacobuzio-Donahue, C. A., Chandwani, R., Leslie, C. S., Huangfu, D.The lack of accurate, human-based models recapitulating early-stage pancreatic ductal adenocarcinoma (PDAC) has hindered therapeutic development. Using pluripotent stem cell-derived pancreatic progenitor organoids, we established a human PDAC model that faithfully reproduces the genetic, epigenetic, and transcriptomic trajectory of tumor initiation and progression in vitro, validated against clinical datasets and histopathology. We demonstrate that CDKN2A loss, nearly universal in patients but dispensable in mouse models, is essential for neoplastic transformation when combined with KRAS and TP53 mutations, while SMAD4 loss […]
- by Haase, S., Banerjee, K., Mujeeb, A. A., Halseth, T., Liu, L., Yu, M., Sriramulu, S., Sheth, M., Raghuram, S., Lowenstein, P. R., Schwendeman, A., Castro, M. G.Diffuse hemispheric gliomas (DHGs) are highly aggressive and infiltrative CNS tumors that are refringent to treatment, and with a 5-year overall survival of around 20%. A fraction of DHGs is driven by mutations in the histones H3.1 and H3.3. In this study, we demonstrate that the expression of histone H3.3 glycine 34 to arginine mutations (H3.3-G34R) result in the epigenetic and transcriptional activation of the NF-{kappa}B signaling pathway in DHG. To target this vulnerability, we designed high density lipoprotein (HDL) […]
- by Sipila, K., Vietri Rudan, M., Bhosale, P., Matthew Blakeley, M., Ganier, C., Kennedy, R., Rognoni, E., Watt, F. M.A critical hallmark of carcinogenesis is the ability of cancer cells to evade the loss of self-renewal normally imposed by terminal differentiation. However, therapies directly attempting to promote differentiation have shown limited efficacy in solid tumours and the cellular mechanisms behind cancer cell persistence are poorly understood. Here we established a patient-derived orthotopic head and neck squamous cell carcinoma (HNSCC) model in vivo that recapitulates the genetic, cellular and histopathological heterogeneity of HNSCC. Experimental induction of differentiation and clonal lineage […]
- by Chen, T., Lv, Y., Wang, J., Yuan, Y., Xu, K., Shi, M., Li, W., Ye, B.Dysregulated HSP90AA1 chaperone activity is a hallmark of multiple human cancers, yet its post-translational modifications in esophageal squamous cell carcinoma (ESCC) are poorly defined. Here, we identify a PRMT5-driven modification of HSP90AA1, symmetric dimethylation at arginine 182 (R182), as a pivotal switch that fuels ESCC progression. HSP90AA1 physically associates with PRMT5, and genetic or pharmacologic PRMT5 blockade diminishes HSP90AA1-R182 methylation and downstream oncogenic signaling. Functionally, HSP90AA1 loss suppresses ESCC cell proliferation, migration, and invasion; enforces cell cycle arrest and reverses […]
- by Wang, D., Fishel, M., Samiei, A., Gampala, S., Hu, C.-D., Chen, S., Zhang, G.Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive sarcomas with poor prognosis and a strong tendency for metastasis and relapse. Surgical removal remains the mainstay of treatment but is frequently ineffective or impractical. Currently, no effective targeted therapy exists for this type of malignancy. PRMT5, a type II protein arginine methyltransferase, has recently emerged as a promising therapeutic target in various human cancers with MTAP loss, which results in cancer cell dependency on PRMT5 activity. The frequent loss of […]
- by Striepen, J., Culibrk, L., Dananberg, A., Rozowsky, J. S., Petljak, M., Maciejowski, J.APOBEC3 cytosine deaminases are major sources of cancer mutations. In lung adenocarcinoma (LUAD), APOBEC3 activity drives tumor evolution and therapy resistance, nominating these enzymes as therapeutic targets. Although APOBEC3A drives the major portion of APOBEC3-associated mutational signature burdens across cancers, the relative contributions of individual APOBEC3 paralogs in LUAD remain unclear, limiting effective targeting. Here, we define the roles of endogenously misregulated APOBEC3 deaminases in LUAD using CRISPR-Cas9 knockouts and whole-genome sequencing of 197 long-term propagated single-cell clones. We show […]
- by Himonas, K., Manoharan, A., Roy, K., Rattigan, K. M., Ianniciello, A., Zarou, M., Sarnello, D., Martin, L., Shoemaker, R., Sumpton, D., Tardito, S., Halsey, C., Helgason, V.Nutrient availability is a critical environmental factor that influences the metabolism and adaptability of cancer cells, including acute lymphoblastic leukaemia (ALL) cells, prone to relapse in the central nervous system (CNS). Currently available cell culture media contain supraphysiological nutrient levels and do not represent the restricted metabolic environment of CNS-ALL which resides in the leptomeninges surrounded by cerebrospinal fluid (CSF). Therefore, we formulated a novel physiological CSF-like cell culture medium (CSFmax) that recapitulates the unique metabolite composition of the CSF. […]
- by Nuckhir, M., Cabral, S., Eckersley, G., Clarke, R. B., Ahluwalia, A., Harrison, H.Metastatic breast cancer is responsible for around 11,500 deaths a year in the UK. The primary tumour likely plays a major role in priming the distant site for metastasis and crosstalk between primary and metastatic sites may be essential for secondary tumour growth. We have developed and novel in vitro model in which we can further study these interactions, allowing evaluation of niche priming and cancer cell conditioning as well as assessing their influence on cell homing and colonisation. In […]
- by Anderson, H. G., Bazargan, S., Nusbaum, D. J., Poch, M. A., Pilon-Thomas, S., Rejniak, K. A.Even under the same treatment, responses can vary. Virtual cohorts build on an available, often limited, dataset can capture these differences and enable the discovery of treatment protocols that work well for a wide variety of individuals. In this paper, we refined current virtual cohort pipelines by improving data handling, ensuring the virtual cohort can be used to stratify individuals into treatment subgroups based on their data, and validating that the virtual cohort matches the observed data variability. To illustrate, […]
- by Tan, M., Schow, S., Liu, Y., Lum, R., Massoudi, D., Dhanasekaran, R., So, S., Chua, M.-S.BackgroundHepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, highlighting the urgent need for effective therapies. Niclosamide, an FDA-approved anthelmintic, reverses HCC gene expression profile to that of normal hepatocytes, and exhibits promising anti-tumor activity in HCC in vitro; however, its clinical translation is limited by poor aqueous solubility, low bioavailability, and short systemic exposure, resulting in lack of in vivo activity. We previously used an established phosphate prodrug approach to provide proof-of-concept that increasing oral bioavailability was […]
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