- by Patterson, N., Badoi, A., Vadla, G. P., Hasani, M., Moyer, J., Ramirez, C. D. L. N., Chabu, C.Aberrant activation of the androgen receptor (AR) pathway drives prostate cancer (PCa). Androgen deprivation therapy (ADT) and next-generation AR blockade (e.g., enzalutamide) are initially effective, but virtually all patients develop castration-resistant prostate cancer (CRPC), which frequently transitions to treatment-emergent neuroendocrine PCa (tNEPC) following AR suppression. The molecular logic that links AR blockade to lineage plasticity remains incompletely understood. Here, we identify PSMA2 (Proteasome Subunit Alpha 2) as a treatment-induced effector that mechanistically connects AR blockade to tNEPC evolution. Enzalutamide induces […]
- by Okuda, R., Harmel, C., Xu, Q., Mary, H., Schulz, P., Steinacher, L., D'Arcangelo, E., Gjeta, B., Signer, M., Cubela, I., Bickle, M., Lutolf, M. P., Cabon, L., Lukonin, I., Camp, G.Complex multilineage organoid systems lack quantitative phenotyping methods preserving spatial architecture at high throughput. Current approaches compromise biological complexity, spatial resolution, or robust homogeneous multilineage assembly. We establish an integrated experimental-computational platform for high-throughput spatial phenotyping of multilineage organoids through developing a modular tumoroid culture system incorporating pancreatic ductal adenocarcinoma (PDAC) cells and cancer-associated fibroblasts (CAFs) in 384-well format with multiplexed whole-mount imaging. We developed Phenocoder, a machine learning framework combining conditional variational autoencoders with spatial graph analysis to extract […]
- by Ramezani, S., Zacharias, N. M., Norton, W., Davis, J. S., Dominic, A., Armijo, R., Wang, M., Wendt, R. E., Carson, D. D., Harrington, D. A., Farach-Carson, M. C., Bhattacharya, P. K.Visualization of colorectal cancer (CRC) lesions is complicated by their location in the colon and tumor morphology. Reliance on a single surface biomarker for direct identification risks false negatives due to temporal changes and/or tumor heterogeneity. We developed a multiplexed system of complementary biomarker targets in an effort to capture a broader range of lesions with diverse temporal and/or phenotypic expression. We identified Mucin-1 (MUC1) and epithelial cell adhesion molecule (EPCAM) as useful targeting pairs by examining multiple colon tumor […]
- by Schulte, A. J., Andrechek, E.Metastasis is a leading cause of mortality in breast cancer patients, yet the signaling promoting metastatic dissemination is not completely understood. Prior literature implicates neuronal innervation in tumor progression, including recent studies in breast cancer progression with the 4T1 and PyMT cell line orthotopic injection models. Our experiments address the immune limitations of these studies with an alternative model to elucidate neuronal control of metastatic breast cancer by using a MMTV-PyMT transplant model and resiniferatoxin (RTX) for denervation. To this […]
- by Shastry, R. K. R., Kale, A., Tee, S. S.Hepatocellular carcinoma (HCC) most often arises in cirrhotic livers, yet the biological impact of cirrhosis severity on the tumor proteome remains poorly understood. Here, we performed a comprehensive quantitative proteomic analysis of 141 HCC tumors stratified by the degree of cirrhosis to delineate fibrosis-related molecular heterogeneity. Principal component analysis revealed substantial overlap between groups, indicating that increasing cirrhosis severity produces incremental rather than global proteomic shifts. Nevertheless, 295 proteins showed significant differential abundance (Hedge's g > 0.3, p < 0.05), […]
- by Wang, X., Liu, X., Wang, Z.Background: Breast cancer (BC) incidence continues to rise globally, with diverse clinical presentations that remain challenging to predict. Purpose: To compare the predictive performance of conventional 2D DCE-MRI-based radiomics models with advanced 3D DCE-MRI-based radiomics models for determining estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2), and Ki-67 expression in breast cancer patients. Material and Methods: This study included 385 patients with histologically confirmed breast cancer. Semi-automatic segmentation was applied to delineate regions of interest […]
- by Dong, Y. C., Villasenor, K. E., Yoon, S., Islam, A., Vasquez, L., Gurevich, A., McLaughlin, S., Gade, T. P., Cormode, D. P.Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. For patients with unresectable disease, locoregional therapies, such as transarterial chemoembolization (TACE), are the standard of care. However, even with this treatment, the average survival rate is only 27% at 5 years. Recent studies have demonstrated the potential of novel approaches to improve responses through more complete embolization and targeting ischemia-induced molecular dependencies. To build on these findings, we developed an injectable chitosan-based hydrogel system (AuNP-Lys05-gel) that we hypothesized […]
- by Xirenayi, S., Camp, S. Y., Garza, A. E., Rustagi, Y., Pimenta, E., Shannon, E., Nag, A., Betherman, A., Anselmo, A., Trowbridge, R., Thorner, A. R., Park, J., Bi, K., Van Allen, E. M.The application of single-cell transcriptomic approaches has deepened our understanding of tumor heterogeneity, immune dynamics, and molecular programs underlying therapy response. The recent development of fixation-compatible single-cell platforms, such as 10x Genomics Flex, offers the opportunity to profile archived formalin-fixed, paraffin-embedded (FFPE) specimens, expanding access to clinically valuable samples. However, most benchmarking studies of recent single-cell RNA sequencing (scRNA-seq) technologies have relied on peripheral blood mononuclear cells, limiting their relevance to human tissues. Here, we compared three 10x single-cell RNA […]
- by Sanchez, G. B., Patel, P., Gomez-Crase, P., Kim, C., Rose, K. L., Rafat, M.Ionizing radiation (IR) is an integral component of cancer therapy. Cellular exposure to IR typically leads to major biological consequences including cell death and senescence. Furthermore, tissue injury in known to involve the release of damage-associated molecular patterns (DAMPs) into the extracellular space, which trigger inflammation and wound healing. However, DAMP release in the context of radiation injury remains to be fully characterized. Evidence suggests that extracellular vesicle (EV) secretion and associated cargo components are part of the cellular response […]
- by Mohebbi, S., Dostmohammadi, A., Amjadian, S., Abdi, Z., Torkian, H., Ghavidel, M., Rahbar, M., Movahed, A. Y., Rastidoust, N., Mahdizad, F., Akbari, A., Farsi, S. M., Azadedel, F., Abdollahi, L., Farhadnejad, R., Salmanzadeh, N., Sadeghi, H., Moradi, S.MicroRNAs (miRNAs) have the potential to serve as oncogenes or tumor suppressors, playing important roles in the pathogenesis of human cancers. Despite the growing recognition of miRNA significance, the contributed information remains scattered in the publications. This fragmentation underscores the need for a centralized and comprehensive database that consolidates miRNA expression patterns, functional roles, and regulatory interactions across diverse cancer types. So far, several miRNA databases have been developed, but neither of them enables in-depth functional analysis or comparative visualization […]
- by Alonso-Manresa, S., Serra, C., Munoz, L., Bataller, M., Garcia-Mayea, Y., Pajarin, M. E. L., Prats, B. G., Zamora, S. M., Riascos, Z. V. D., Llebaria, A., Josa-Cullere, L.Chloroquine (CQ) and hydroxychloroquine (HCQ) inhibit autophagy and have shown promise as adjuvant anticancer agents, particularly for targeting therapy-resistant cancer stem cells (CSCs). However, their clinical utility is limited by systemic toxicity and poor tumour selectivity. Here we report the design, synthesis, and photochemical evaluation of [7-(diethylamino)coumarin-4-yl]methyl (DEACM)-caged CQ and HCQ derivatives as visible-light-activated autophagy inhibitors. Selective caging of the aliphatic amine fully suppressed biological activity in the dark and enabled rapid, efficient release of the parent drugs upon illumination. […]
- by Majumder, R., Datta, P., Moolayadukkam, S., Nakamura, B., Izquierdo, U., Joshi, R., Sedighi, S., Chen, T. C., Neman, J.Primary and metastatic brain tumors are among the deadliest and treatment-resistant cancers, mainly because of their inherent resistance to chemoradiation and limited drug delivery across the blood-brain barrier (BBB). Identifying molecules that can cross the BBB and serve as sonosensitizers is crucial for developing noninvasive, targeted therapies such as sonodynamic therapy (SDT). To overcome the limitations of traditional low-throughput screening, a New Approach Methodology (NAM) was developed, starting with AI-driven molecular discovery. A positive-unlabeled neural network, trained on over 200 […]
- by Ashkani, E. G., Dickinson, A. M., Olson, W. C., Taylor, J. J., Slingluff, C. L.BackgroundVaccines targeting melanoma antigens can elicit CD8+ T cell responses, but a growing body of work suggests CD4+ T cells also play a role in tumor control. Induction of CD4+ cells may also support B cells in producing tumor antigen-specific antibodies (Abs). We investigated Abs induced by vaccination with a cocktail of six class II MHC-restricted melanoma peptides (6MHP) and the effect of adjuvant type on Ab isotypes. We hypothesized that the vaccines would induce Abs that respond to different […]
- by de Carne Trecesson, S., East, P., Pillsbury, C., Silva dos Santos, M., Cha, H., Colliver, E., Gilmore, T., Rana, S., Moore, C., Lighterness, S., Caswell, D. R., Boumelha, J., Tomaschko, M., Baer, R., Eyles, J., Teixeira, B., Saeed, M., Litchfield, K., Molina-Arcas, M., Lee, S.-H., MacRae, J., Hobson, P., Swanton, C., Downward, J.Lung adenocarcinoma (LUAD) is a leading cause of cancer death worldwide, with RAS signalling as a key oncogenic driver. Although KRAS mutations have been linked to immune evasion in preclinical models, the relationship between RAS activity and tumour immunity or response to immunotherapy in patients remains unclear. Here, we applied our previously validated RAS84 transcriptional signature to stratify LUAD patient cohorts and dissect the immune landscape associated with RAS signalling. We report that tumours with elevated RAS activity exhibited features […]
- by Vazquez, E. N., Lozano, C., Honan, A. M., Zaika, E., Houghton, J., El-Rifai, W., Zaika, A., Chen, Z.Background and AimsGastric cancer (GC) demographics have shifted, with a growing impact on younger populations, particularly women. Chronic Helicobacter pylori (HP) infection is the leading risk factor for GC; however, decreasing HP prevalence means it is unlikely the cause of rising incidence of early-onset GC. Autoimmunity, which is more prevalent in women, has been proposed as a contributing factor. As autoimmunity prevalence increases, HP and gastric autoimmunity are likely to converge within one individual. This study aimed to examine how […]
- by Jiang, Y., Cheng, S., Zhang, C. Y., Jin, X., Li, L., Fraidenburg, M., Wang, C., Kim, I. Y., Mu, P.Resistance to androgen receptor (AR)-targeted therapies such as enzalutamide in castration-resistant prostate cancer (CRPC) often arises through lineage plasticity, yet the molecular mechanisms that define this process remain incompletely understood. While previous studies reported that Notch1 and Notch2 exert distinct and sometimes opposing effects in prostate cancer differentiation, the integrated role of Notch pathway activity has not been systematically explored. Here, we identify Notch signaling as a graded Rheostat that governs prostate cancer cell fate transitions. Integrative transcriptomic and functional […]
- by Denu, R. A., Singh, A. K., Jiang, Y., Zheng, Z., Ingram, D. R., Wani, K. M., Lazcano, R., Ginn, M. P., Anand, K., Singh, B. K., Ballard, J. C., Kochat, V., Chatterjee, B., Padron, W., Landers, S. M., Bhalla, A., Multani, A., Dharmaiah, S., Malgulwar, P. B., Cai, Y., Lin, H., Huse, J. T., Ying, H. T., Keung, E. Z., Wang, W.-L., Conley, A. P., Patel, S., Somaiah, N., Farooqi, A., Lazar, A. J., Nassif Haddad, E. F., Torres, K. E., Rai, K.ATRX is one of the most frequently altered genes in sarcoma and encodes an ATP-dependent chromatin remodeler implicated in maintaining heterochromatin. However, ATRX alterations have not been leveraged for sarcoma treatment. We observed loss of ATRX protein in 14% of soft tissue leiomyosarcoma (STLMS, n =127), 53% of uterine leiomyosarcoma (ULMS, n = 95), 37% of undifferentiated pleomorphic sarcoma (UPS, n = 82), and 8% of dedifferentiated liposarcoma (DDLPS, n = 84). ATRX loss was associated with significantly worse outcomes […]
- by Khadilkar, R. J., Chowdhury, U., Panzade, G., Karnik, P. N., Birwadkar, P., Tashu, T.Cancer cachexia involves systemic metabolic deregulation along with classical features of muscle wasting, lipolysis, and chronic inflammation. While tumor non-autonomous effects on peripheral organs are recognized, how the tumor rewires the circulating immune cells and hematopoiesis remains unclear. We utilized a Drosophila larval cancer cachexia model by expressing yki3SA in the adult midgut precursors (AMP), which gives rise to a tumor in the larval midgut and recapitulates key cachectic phenotypes, including insulin resistance. Tumor-induced cachexia results in perturbed blood cell […]
- by Arribas, A. J., Civanelli, E., Scalise, C., Cascione, L., Rinaldi, A., Rossi, D., Zucca, E., Carosella, L., Raniolo, S., Limongelli, V., Bertoni, F.BackgroundBTK and BCL2 represent key therapeutic targets in B-cell lymphomas, including marginal zone lymphoma (MZL). Here, we evaluated the novel BTK degrader BGB-16673, and the second-generation BCL2 inhibitor sonrotoclax in a panel of MZL cell lines, including models with acquired resistance to BTK, BCL2 and PI3K inhibitors, as single agents and in combination. MethodsCytotoxicity, transcriptomic changes, apoptosis, and protein expression were assessed for BGB-16673 alone and in combination with venetoclax, sonrotoclax, bendamustine, selinexor, lenalidomide, and tazemetostat. ResultsBGB-16673 demonstrated single-agent activity […]
- by Tanooka, H.Compared with transplanted tumors, autochthonous tumors are difficult to cure by experimental radiation therapy in mice. Here we analyzed differences in immune gene expression profiles between mouse fibrosarcomas subcutaneously induced by 3-methylcholanthrene (3MC) and their transplants. The immune genes examined were pd1, pdl1, pdl2, cd3d, cd8a, cd8b, ifn{gamma}, dx5, grzmb, and foxp3. Among 12 tumors, one was non-transplantable and showed a benign character with an abundance of DX5+ natural killer cells and CD8+ T cells together with increased IFN{gamma} expression. […]
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