- by Billingham, L. K., Delay, S. L., Tripathi, S., Olson, I. E., Zilinger, K., Subbiah, J., Wang, Z., Sadagopan, N. S., Chia, T.-Y., Najem, H., Cognet, G., Katz, J. L., Vazquez-Cervantes, G. I., Wang, S., Wan, H., Murphy, A. R., Lipshutz, A. B., Duffy, J. T., Valyasnikova, I. V., Zhang, P., Heiland, D. H., Ahmed, A. U., Lee-Chang, C., Heimberger, A. B., Perry, J. S., Muir, A., Chandel, N. S., Miska, J.Glioblastoma (GBM) is most common and aggressive primary brain tumor in adults, for which standard of care has not changed in twenty years. GBM tumor associated macrophages (TAMCs), consisting of infiltrating myeloid cells from the periphery and resident microglia cells, are pro-tumorigenic, promoting tumor growth. Fructose is one of the most abundant metabolites in the GBM tumor microenvironment (TME), as well as in the healthy central nervous system (CNS). In the CNS and GBM, microglia are the predominant expressors of […]
- by Liyanage, A., Burger, R., Shi, A., Sopp, B., Zhu, B., Mumey, B.Single-cell sequencing (SCS) enables investigating tumor evolution at a single cell resolution. A common type of analysis to investigate evolutionary structure from an SCS experiment is to determine a phylogenetic tree structure from the data. This problem has been well-studied under the assumption that mutations only accumulate in the evolution of cancer and there is a simple characterization of when the data is compatible with a perfect phylogeny based on the absence of a special "conflict'" submatrix. SCS data can […]
- by Baliyan, A., Mohapatra, I., Paul, S., Safiriyu, A. A., Mondal, S. K., Mishra, D., Mandal, A. K.Cervical cancer, which is the fourth most common gynaecological cancer across the globe, has a poorly understood molecular pathogenesis and etiology. Current methods of diagnosis are based on cytology, histology and presence of Human Papillomavirus (HPV). Shortcomings of these methods lie with poor quality of smears which is very common in Papanicolaou (pap) smears, limited sensitivity in terms of early detection, dependence on presence of HPV, etc. Due to its high sensitivity and non-targeted approach, Matrix Assisted Laser Desorption Ionization […]
- by Li, Y., Tang, S., Wang, H., Zhu, H., Guo, S., Zhang, Y., Lu, Y., Sun, M., He, J., Li, Y., Zhang, Y., Shi, X., Miao, Y., Zhong, C., Zhu, Y., Ju, Y., Liu, Y., Wang, Y., Chen, L., Zhou, H., Jin, G., Gao, D.Chemotherapy remains the cornerstone of pancreatic ductal adenocarcinoma (PDAC) treatment. However, most cases of PDAC finally progress to advanced chemoresistant disease. This highlights an urgent need to develop new pharmacological strategies to overcome chemotherapy resistance using clinical grade inhibitors. Here, we established a biobank comprising 260 organoid lines derived from 322 pancreatic cancer patients. These organoids underwent extensive multi-omics profiling and drug sensitivity testing for both chemotherapy and targeted therapy. Increased protein glycosylation and cholesterol metabolism signaling pathways were especially […]
- by Ghaemi, B., Lopez-Bertoni, H., Kuddannaya, S., Sall, S., Laterra, J., Liu, G., Bulte, J.Glioblastoma (GBM) contain mesenchymal cancer stem cells that drive tumor aggressiveness and recurrence and exhibit aberrant glycosylation during proneural-to-mesenchymal transition. A comprehensive analysis of human GBM transcriptomic datasets revealed an upregulation of 13 genes involved in mannosylation. Histopathological staining of a tissue array representing 35 GBM cases revealed elevated mannose, correlating with increased expression of the mesenchymal marker CD44. Mannose-weighted chemical exchange saturation transfer magnetic resonance imaging (MANw CEST MRI) detected elevated mannose levels in aggressive mesenchymal GBM neurospheres in […]
- by Kuo, H.-H., Bhinder, B., Gokozan, H. N., Gorski, K., Chandra, P., Manohar, J., Guevara, D., Otilano, J., Moyer, J., Tranquille, M., Ackermann, S., Capuano, J., Cheung, C., Caiazza, T. A., Reuben, P. L., Irizarry, A., Tsomides, A. M., Sigouros, M., Wilkes, D., King, A., Kane, T., Al Assaad, M., Al Zoughbi, W., Ohara, K., Auh, J., Waltman, P., Madorsky Rowdo, F. P., Podaza, E., Gallegos, V., Nguyen, J., Shah, R., Shah, M., Ocean, A., Scherr, D., Altorki, N., Frey, M., Molina, A. M., Newman, L., Bea, V., Chapman-Davis, E., Goncalves, M. D., Saxena, A., Shukla, P. J., Holcomb, K., Simmons, R., TagWe developed a tumor-matched, pan-cancer patient-derived organoid (PDO) platform comprising 220 PDOs from 190 patients across 15 cancer types to advance functional precision oncology. Our comprehensively characterized PDOs showed 93% histopathology concordance, 80% median genomic concordance for driver mutations, and a 0.85 median gene expression correlation with parent tumors. Gene expression in PDOs remained stable across [≥] 10 passages, supporting reproducibility for long-term drug screening. Even PDOs with low genomic concordance retained oncogenic drivers, supporting their use as disease models. […]
- NSUN2 drives intestinal stem cell expansion and colorectal tumour initiation via MAPK/ERK signallingby Bastem Akan, A., Billard, C. V., Chen, S.-Y., Huang, P.-H., Cammareri, P., Hall, A. E., Preyzner, P., Din, F. V. N., Myant, K. B.Colorectal cancer is initiated by loss of the APC gene, which drives expansion of LGR5+ intestinal stem cell (ISC) populations. Whilst LGR5+ ISC expansion is a critical step for tumour initiation and progression, its regulation is poorly understood. Emerging evidence suggests post-transcriptional RNA modifications play a key role in cancer biology, but their role in CRC initiation has not been explored. Here, we identify the m5C methyltransferase NSUN2 as a key regulator of ISC expansion and intestinal tumourigenesis. NSUN2 is […]
- by Zhou, Z., La Ferlita, A., Palavalli, M., Chen, X. F., Tyler, L., Ejaz, A., Beane, J., Polanco, P., Huang, H., Kim, A. C.Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer-related mortality in the United States. Peritoneal metastasis (PM), a malignant dissemination within the peritoneal cavity, affects approximately 20% of CRC patients and accounts for 25-35% of stage IV cases. CRC PM is associated with dismal outcomes, with a median overall survival of only 16 months on systemic chemotherapy and an almost 0% five-year survival rate, largely due to frequent treatment resistance and limited […]
- by Young, D., Aguilan, J., Cutler, R., Stransky, S., DeAngelo, J., Roth, J., Malachowska, B., Vercellino, J., Bell, B., Shechter, D., Tofilon, P., Phillips, R., Guha, C., Sidoli, S.A key driver of Glioblastoma (GBM) heterogeneity and therapy resistance is the capacity of glioma stem-like cells (GSCs) to hijack developmental signaling programs. However, it remains unclear how GSCs regulate these adapted developmental signaling pathways and how these pathways might be therapeutically exploited. The arginine methyltransferase, CARM1, has been shown to play critical roles in maintaining stem cell pluripotency, preventing differentiation, and recently was discovered to be upregulated in Glioblastoma. To date, there is little to no understanding of the […]
- by Latham, S. L., O'Donnell, Y. E., Girgis-Cook, O., Clearwater, M. S., Bryce, N. S., Mok, E., Lynn, S. A., Ni, J., Alfred, S., Leong, K. H., Quek, L.-e., Murphy, K., Pantarelli, C., Dragutinovic, I., Naeini, M., Thiel, C., Cadell, A., Phimmachanh, M., Sharma, R., Millar, E., Han, J. Z., Hastings, J. F., Koehler, M., Brummer, T., Young, A., O'Toole, S., Oakes, S., Hardeman, E., Lock, J., Kolch, W., Taft, M. H., Nobis, M., Goldstein, L., Timpson, P., Parker, B. L., Holst, J., Gunning, P. W., Cox, T. R., Morris, J. C., Croucher, D. R.Although c-Jun N-terminal Kinase (JNK) represents an attractive anti-cancer target, its pleiotropic functionality limits the use of direct JNK inhibitors. Here, we identify a distinct subcellular pattern of JNK activity as a therapeutic vulnerability in breast cancer, where cytoplasmic JNK activity predicts poor survival outcomes, is elevated in triple-negative breast cancers (TNBC) and is essential for metastatic outgrowth. Mechanistic analyses reveal cytoplasmic JNK acts through multiple mechanisms, with downstream targets involved in cellular metabolism and cytoskeletal regulation. On this basis, […]
- by Lee, J. H., Chen, M., Wen, T., Anderson, R. A., Cryns, V. L.The tumor suppressor p53 maintains genome stability in the setting of cellular stress and is frequently mutated in cancer. The stability of p53 is regulated by its interaction with the oncoprotein MDM2, a ubiquitin E3 ligase. Recently, nuclear phosphoinositides were reported to bind and stabilize p53. Here, we report that genotoxic stress induces the type I phosphatidylinositol phosphate kinase (PIPKI) and its product phosphatidylinositol 4,5-bisphosphate (PIP2) to bind and regulate the stability and function of MDM2. Following genotoxic stress, nuclear […]
- by Garrelick, V. J., Gul, N., Horrieh, P., Mustafa, D., Patel, A. A. H., Dankis, M., Alvarez, S. W., Berndtson, J., Schwarz, M., Persson, A., Zahirovic, F., Wiel, C., Sayin, V. I., Lindahl, P.Lung cancer cells are vulnerable to iron-dependent oxidation of phospholipids leading to ferroptosis, a process countered by glutathione peroxidase-4 that converts lipid hydroperoxides to lipid alcohols using glutathione as reducing agent. Since ferroptosis-inducing agents are in clinical development, identifying modifiers of ferroptosis susceptibility is warranted. Here, we investigate the impact of amino acids on susceptibility to buthionine sulfoximine (BSO), a glutamate-cysteine ligase inhibitor that blocks biosynthesis of glutathione. We found that reduced amounts of amino acids other than cysteine increased […]
- by Geretovszky, A., Röst, G.We construct a mathematical model of cancer dynamics with chemotherapeutic treatment, in the presence of bacteria that are capable of metabolizing the chemotherapeutic drug, hence sabotaging the treatment. We investigate the possibility of complementing the cancer treatment with antibiotic drugs, thus eradicating the bacteria or at least mitigating their negative impact on the prospects of therapy. Our model is a nonlinear system of four differential equations, for which we perform a complete analysis, explicitly characterizing the four possible outcomes, depending […]
- A Dual-Action Liposome-Peptide Formulation Synergistically Counteracts A Gain-of-Function p53 Mutantby Ghosh Chaudhary, S., Bhowmick, S., Bhattacharya, S., Roy, S., Ali, N.ObjectiveInactivation of p53 tumor suppressor functions, often through missense mutations, is essential for carcinogenesis. A sub-class of such p53 missense mutations gains new functions, including drug resistance and enhanced proliferation, in addition to its loss of function. Among the most frequent gain-of-function p53 mutants, R273H occurs in tumors of many tissue origins and imparts aggressive character and resistance to drugs to the tumor. Tumors bearing p53R273H are generally resistant to all available therapies, and need for novel interventions are urgently […]
- by Kral, A. J., Jia, L., Sim, G., Wan, L., Krainer, A. R.Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy, driven by oncogenic KRAS mutations and dysregulated oncogenes, such as SRSF1, MYC, and AURKA. Although KRAS-targeted therapies are in development, resistance mechanisms underscore the need to identify alternative vulnerabilities. Here, we uncover an SRSF1-AURKA-MYC oncogenic circuit, wherein SRSF1 regulates AURKA 5UTR alternative splicing, enhancing AURKA protein expression; AURKA positively regulates SRSF1 and MYC post-translationally, independently of its kinase activity; and MYC in turn transcriptionally upregulates both SRSF1 and AURKA. Elevated SRSF1 […]
- by Guerrero Quiles, C., Fahy, S., Bartak, M., Gonzalez A., J., Powell, E., Reed, R., Reeves, K., Baker, A., Hoskin, P., James, N. D., Hall, E., Huddart, R. A., Porta, N., West, C., Biolatti, V., Choudhury, A.Muscle-invasive bladder cancer (MIBC) is a prevalent disease that can be treated with radiotherapy, but has a poor prognosis. Radiation-induced extracellular matrix (ECM) remodelling and fibrosis can induce tumour resistance and recurrence, but has not been studied in MIBC. Here we aimed to characterise the impact of radiation on the ECM composition of MIBC. Materials and MethodsThree MIBC cell lines (T24, UMUC3, J82) were treated with fractionated radiation. We used proteomics to analyse the ECM composition produced by surviving cancer […]
- by Jungk, P., Kschischo, M.Replication stress (RS) is a major driver of genomic instability and cancer development, caused by impaired DNA replication that can lead to chromosomal instability (CIN). Although RS is mechanistically linked to CIN, its relationship with cellular proliferation is complex. Depending on the context, RS can either promote or suppress cell growth. Existing RS gene expression signatures overlook this complexity, relying on the overexpression of oncogenes such as MYC, which introduces a proliferation bias. To disentangle genuine RS from confounding cell […]
- by VanderVere-Carozza, P. S., Jordan, M. R., Garrett, J. E., Pollok, K. E., Hinshaw, H. D., Sulaiman, X., Liu, S., Wan, J., Pawelczak, K. S., Turchi, J. J.Poly (ADP-ribose) polymerase inhibitors (PARPi) are standard of care for many BRCA1 deficient cancers, though few cures are achieved. We sought to determine if targeting the protection of the single-strand DNA gaps induced by PARPi in BRCA-deficient cancers could increase efficacy. Replication protein A (RPA) participates in critical protein-protein and protein-DNA interactions to protect single-stranded DNA (ssDNA) and support DNA metabolism. We have reported the optimization of small molecule RPA inhibitors (RPAi) that target protein-ssDNA interactions to chemically exhaust RPA […]
- by Sauer, T., Gruner, C., Kern, K., Rackisch, A., Tischner, L., Schulz, K., Ostermann, J., Cohrs, L., Kohl, M., Verschoor, A., Gemoll, T.BackgroundColorectal cancer (CRC) is frequently associated with metastasis, resulting in high mortality rates. Platelets are known to play a crucial role in the metastatic cascade influencing tumor microenvironment remodeling, promoting cell transformation, facilitating metastatic niche formation, and shielding circulating tumor cells from immune surveillance. However, platelet proteomic alterations during tumor cell-induced platelet aggregation (TCIPA) remain largely unexplored. This study aims to characterize the proteomic profile of TCIPA in CRC using an in vitro model that recapitulates key aspects of CRC […]
- by Pope, A. N., Moose, D. L., Hudson, G. O., Weresh, H. R., Taylor, E. B., Henry, M. D.Circulating tumor cells (CTCs) face challenges to their survival including mechanical and oxidative stresses that are different from cancer cells in solid primary and metastatic tumors. The impact of adaptations to the fluid microenvironment of the circulation on the outcome of the metastatic cascade are not well understood. Here we find that cancer cells (PC-3, MDA-MB-231, Myc-CaP) exposed to brief pulses of high-level FSS exhibit enhanced invasiveness and anchorage-independent proliferation in vitro and enhanced metastatic colonization/tumor formation in vivo. Cancer […]
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