- by Godfrey, T. M., Shanneik, Y., Zhang, W., Tran, T., Verbeeck, N., Patterson, N. H., Jackobs, F. E., Nagi, C., Ramineni, M., Schiavinato Eberlin, L.The combination of spatial metabolomics and spatial transcriptomics can reveal powerful connections between gene expression and metabolism in heterogeneous tissues, but section-to-section variability can convolute data integration. We present a novel method combining Desorption Electrospray Ionization Mass Spectrometry Imaging spatial metabolomics and spatial transcriptomics on the same tissue sections. We demonstrate this workflow on human breast and lung cancer tissues identifying correlations between metabolites and cancer-related RNA transcripts.
- by Berico, P., Flores Yanke, A. F., Vand Rajabpour, F., Do, C., Simonin Wilmer, I., Sakellaropoulos, T., Delclaux Obieta, I., Stagnitta, R., Vazquez Cruz, E., Osman, I., Skok, J., Robles-Espinoza, C. D., Lund, A. W., Schober, M., Hernando, E.Ultraviolet (UV)-induced DNA mutations produce genetic drivers of cutaneous melanoma initiation and numerous neoantigens that can trigger anti-tumor immune responses in the host. Consequently, melanoma cells must rapidly evolve to evade immune detection by simultaneously modulating cell-autonomous epigenetic mechanisms and tumor-microenvironment interactions. Angiogenesis has been implicated in this process; although an increase of vasculature initiates the immune response in normal tissue, solid tumors manage to somehow enhance blood flow while preventing immune cell infiltration. By comparing the expression of transcription […]
- by Zhu, L.Targeting glucose metabolism for cancer therapy is a long-lasting pursuit but with disappointing translational success. Revelation of actionable distinctions between the malignancy traits to achieve selectivity is a prerequisite for fulfilling a therapeutic window. We discover a non-canonical glucose transporter GLUT6-facilitated, lactate-independent, glucose metabolic rewiring that selectively enables resistance to targeted therapy in lung cancer. Downstream, GLUT6 facilitated glucose influx and straying to methylglyoxal which dimerized KEAP1 and upregulated NRF2 pathway to confer resistance. Upstream, GLUT6 was transcriptionally upregulated by […]
- by Wood, D. E., Roy, J., Ballew, B. J.Ovarian cancer remains a danger to women's health, and accurate screening tests would likely increase survival. Two established protein biomarkers, CA125 and HE4, have been shown to work well in isolation, but achieve even higher accuracy when combined using logistic regression (LR). We show here that this LR-based combination of protein concentrations achieves high accuracy when distinguishing healthy samples from cancer samples (AUC = 0.99) and benign masses from cancer (AUC = 0.86). This approach exhibits superior performance on an […]
- by Hancock, S. E., Garthwaite, L., Harellis, K., Susetio, M., Ding, E., Choong, L., Contreras, O., Nguyen, A., Lising, J., Hansen, F. K., Wongsomboon, P., Menzel, J. P., Poad, B. L., Mitchell, T. W., Blanksby, S. J., Turner, N.Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with few treatment options and poor survivability. In this work we sought to characterise metabolic adaptions to gemcitabine (GEMC)-based chemotherapy exposure to discover new therapeutic targets for improving treatment efficacy. We show that GEMC resistance (GEMR) upregulates de novo lipogenesis in Panc1 and MiaPaCa2 cells through increased activity and expression of acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS) and stearoyl-CoA desaturase 1 (SCD1). We also discovered alternate fatty acid desaturase 2 […]
- by Jaiswal, S., Mishra, V., Majumder, S., Wangikar, P. P., Sengupta, S.Despite the availability of new therapies for cervical cancer, innovative strategies are essential to address challenges related to drug resistance and high toxicity. The present study focuses on the metabolic profiling of cervical carcinoma using non-targeted metabolomics approach using liquid chromatography-mass spectrometry. Our study identified over 100 metabolites in cervical tissue samples (both cancerous and adjacent normal) using HILIC and reversed-phase chromatography in the positive and negative ionization modes. The major metabolic alterations included changes in glycolysis, the citric acid […]
- by Nagel, L., Wenzel, M., Hoppe, S., Plum, P. S., Karimpour, M., Franitza, M., Wahba, R., Bludau, M., Bruns, C. J., Quaas, A., Beyer, A., Hillmer, A.The adaptation of metastatic cells to their host tissue critically determines the pathogenicity of a cancer and therefore patient survival. Yet, it remains elusive to what extent the host environment drives gene expression programs in metastatic cells. Here we identify adaptive mechanisms that enable metastases to establish themselves in a novel tissue context. We performed single-cell RNA-sequencing on malignant and benign tissue samples from untreated donors with colorectal adenocarcinoma and liver metastasis to deduce tissue adaptive expression patterns. A novel […]
- by Kakati, R. T., Whitman, A. A., Haase, S., Szenasi, A. T., Thai, C. H., Brunk, E. C., Okumu, D. O., East, M. P., Perou, C. M., Johnson, G. L., Spanheimer, P. M.Resistance to endocrine therapy (ET) is common in estrogen receptor (ER) positive breast cancer. Multiple studies have demonstrated that upregulation of MAPK signaling pathways contributes to ET resistance. Herein we show that vandetanib treatment enhances sensitivity to ET in ET-sensitive and -resistant ER+ breast cancer models. Using a CRISPR knockout model, we demonstrate that vandetanib effects are partially mediated by RET receptor tyrosine kinase. Vandetanib treatment alters the gene expression program of ER+ breast cancer cells resulting in a less […]
- by Yazgili, A. S., Zivkovic, D., Sanchez Dafun, A., Giotopoulou, G. G., Behrend, S., Koops, F., Zemke, L., Stacher-Priehse, E., Goldmann, T., Reiling, N., Stathopoulos, G. T., Marcoux, J., Bousquet, M.-P., Meiners, S.The proteasome is a well-identified therapeutic target for cancer treatment but the efficacy of proteasome inhibitors for solid tumors is severely hampered by cytotoxic side effects due to broad proteasome inhibition in non-tumor tissues. We and others observed significant upregulation of proteasome activator 200 (PA200) specifically in non-small cell lung cancer (NSCLC) tissues correlating with poor prognosis. To understand the functional role of PA200, we genetically depleted PA200 in two different NSCLC cell lines and characterized its functional effects in […]
- by Ojala, V. K., Ahonen, S., Tuohisto-Kokko, A., Esparta, O., Suominen, P., Jokilammi, A., Farahani, I., Chakroborty, D., Dibus, N., Boettcher, S., Airenne, T. T., Johnson, M. S., Eli, L. D., Elenius, K., Kurppa, K. J.Receptor tyrosine kinase ERBB4 (HER4) is frequently mutated in human cancer, and ERBB4 mutations have been identified in patients relapsing on targeted therapy. Here, we addressed the functional consequences of recurrent cancer-associated ERBB4 mutations that are located at regions important for dimer interactions and/or are paralogous to known oncogenic hotspot mutations in other ERBB genes. Eleven out of 18 analyzed mutations were transforming in cell models, thus suggesting oncogenic potential for more than half of the recurrent ERBB4 mutations. More […]
- by Gothwal, S. K., Barlow, J. H.B cell receptor signaling, NF-kappaB signaling, BCL6 and p53 regulation are essential for germinal center (GC) B cell fate. Dysregulation of these pathways drives the pathogenesis and treatment resistance of GC-derived B-lymphomas (GCDBL). To explore how these pathways affect GCDBL fate and pathogenesis, we treated Raji cells (a GCDBL and Burkitt lymphoma) with mild hydroxyurea (HU) to simulate genotoxic stress encountered by GC B cells. Genome- wide mapping of histone H3K4me3 and p53 target analysis in HU-treated Raji cells combined […]
- by Lin-Rahardja, K., Scarborough, J., Scott, J. G.Gene expression signatures predictive of chemotherapeutic response have the potential to greatly extend the reach of precision medicine by allowing medical providers to plan treatment regimens on an individual basis for patients with and without actionable mutations. Most published gene signatures are only capable of predicting response for individual drugs, but currently, a majority of chemotherapy regimens utilize combinations of different agents. We propose a unified framework, called the chemogram, that uses predictive gene signatures to rank the relative predicted […]
- by Bashtanova, U., Kuraite, A., Rajan, R., Duer, M.Extracellular hyaluronic acid (HA) has been shown to be important in cancer; low molecular weight HA typically correlates with cancer progression, high molecular weight HA with homeostasis. Here we show that even high molecular weight HA can induce cancer cell migration when it is highly diluted. HA-induced cell signalling is primarily through HA binding to the cell surface receptor, CD44. We show by NMR spectroscopy that at high dilution, high molecular weight HA molecules access the conformations needed for strong […]
- by Basappa, J., Goldman, A., Lobello, C., Wang, S., Rushmore, D., Melnikova, O., Sen, N., Mallikarjuna, V., Jain, P., Edalati, M., Cai, K., Lu, P., Nejati, R., Borghaei, H., Wellen, K., Wasik, M.The mitochondrial Acetyl-CoA synthetase short-chain family member 1 (ACSS1) converts acetate, an energy source in nutrient-deprived conditions1,2, to mitochondrial acetyl-CoA. However, the specific mechanism behind this process remains unknown. Here, we show that ACSS1 is overexpressed in patients with mantle cell lymphoma (MCL), diffuse large B cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), and Ibrutinib (IBR)-resistant cell lines. The mitochondrial stress test showed reduced oxygen consumption in ACSS1 knockdown (KD) cell lines. 13C-acetate stable isotope tracing revealed that ACSS1 knockdown […]
- by Gizaw, N. Y., Kolari, K., alitalo, K., Kivela, R.Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children, but the outcomes of high-grade RMS patients remain poor, underscoring the critical need for novel therapeutic strategies. Although metabolic pathways in RMS are incompletely characterized, emerging evidence suggests that metabolic adaptations in RMS resemble those in other malignancies. Here, we identify elevated cholesterol biosynthesis driven by the PROX1 transcription factor as a defining feature of RMS. Our findings demonstrate that the cholesterol biosynthesis pathway is essential for RMS cell […]
- by Klebba, J. E., Roy, N., Bernard, S. M., Grabow, S., Hoffman, M. A., Miao, H., Tamiya, J., Wang, J., Berry, C., Esparza-Oros, A., Lin, R., Liu, Y., Pariollaud, M., Parker, H., Mochalkin, I., Rana, S., Snead, A. N., Walton, E. J., Wyrick, T. E., Aitichson, E., Bedke, K., Brannon, J. C., Chick, J. M., Hee, K., Horning, B. D., Ismail, M., Lamb, K. N., Lin, W., Metzger, J., Pastuszka, M. K., Pollock, J., Sigler, J. J., Tomaschko, M., Tran, E., Kinsella, T. M., Molina-Arcas, M., Simon, G. M., Weinstein, D. S., Downward, J., Patricelli, M. P.Genetic disruption of the RAS binding domain (RBD) of PI 3-kinase (PI3K) prevents the growth of mutant RAS driven tumors in mice and does not impact PI3Ks role in insulin mediated control of glucose homeostasis. Selectively blocking the RAS-PI3K interaction may represent an attractive strategy for treating RAS-dependent cancers as it would avoid the toxicity associated with inhibitors of PI3K lipid kinase activity such as alpelisib. Here we report compounds that bind covalently to cysteine 242 in the RBD of […]
- by Morsy, Y., Walberg, A., Wawrzyniak, P., Hubeli, B., Truscello, L., Mamie, C., Niechcial, A., Gueguen, E., Manzini, R., Gottier, C., Lang, S., Sylvie, S., Bluemel, S., Biedermann, L., Rogler, G., Turina, M., Ramser, M., Petrowsky, H., Arnold, I., Zeissig, S., Zamboni, N., Egli, A., Niess, J., Hruz, P., Knuth, A., Fritsch, R., Manz, M., Wawrzyniak, M., Scharl, M.The involvement of the human intestinal microbiome in the regulation of immune cell homeostasis, as well as in the pathogenesis of inflammatory bowel disease (IBD) and colorectal cancer (CRC), are well-established1-4. Bacteria interact with immune cells at the sites of intestinal inflammation, but also in the CRC tumor microenvironment1-6. Indeed, bacterial remnants have recently been detected in human intestinal tissue in patients with IBD, at primary tumor sites and in the metastases of patients with CRC, and in whole blood3,7,8. […]
- by Sutton, M. N., Glazer, S. E., Al Zaki, A., Napoli, A., Yang, P., Bhosale, P., Liu, J., Gammon, S. T., Piwnica-Worms, D.B7-H3 (CD276), a member of the B7-family of immune checkpoint proteins, has been shown to have immunological and non-immunological effects promoting tumorigenesis [1, 2] and expression correlates with poor prognosis for many solid tumors, including cervical, ovarian and breast cancers [3-6]. We recently identified a tumor-cell autochthonous tumorigenic role for dimerization of the 4Ig isoform of B7-H3 (4Ig-B7-H3) [7], where 4Ig-B7-H3 dimerization in cis activated tumor-intrinsic cellular proliferation and tumorigenesis pathways, providing a novel opportunity for therapeutic intervention. Herein, a […]
- by Ill, C. R., Marikar, N. C., Nguyen, V., Nangia, V., Darnell, A. M., Vander Heiden, M. G., Reigan, P., Spencer, S. L.Targeted kinase inhibitors are well known for their promiscuity and off-target effects. Herein, we define an off-target effect in which several clinical BRAFV600 inhibitors, including the widely used dabrafenib and encorafenib, interact directly with GCN2 to activate the Integrated Stress Response and ATF4. Blocking this off-target effect by co-drugging with a GCN2 inhibitor in A375 melanoma cells causes enhancement rather than suppression of cancer cell outgrowth, suggesting that the off-target activation of GCN2 is detrimental to these cells. This result […]
- by Fowler, C. E., O'Hearn, N. A., Salus, G. J., Singh, A., Boutz, P. L., Lees, J. A.Protein arginine methyltransferase 5 (PRMT5) is a promising cancer target, yet it's unclear which PRMT5 roles underlie this vulnerability. Here, we establish that PRMT5 inhibition induces a special class of unspliced introns, called detained introns (DIs). To interrogate the impact of DIs, we depleted CLNS1A, a PRMT5 cofactor that specifically enables Sm protein methylation. We found that many, but not all, cell lines are CLNS1A-dependent and established that loss of viability is linked to loss of Sm protein methylation and […]
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