Oncologies
Abstract
The role of aberrant glycosylation in pancreatic ductal adenocarcinoma (PDAC) remains an under-investigated area of research. In this study, we determined that the ST6GAL1 sialyltransferase, which adds α2,6-linked sialic acids to N-glycosylated proteins, is upregulated in patients with early-stage PDAC, and further increased in advanced disease. A tumor-promoting function for ST6GAL1 was elucidated using tumor xenograft experiments with human PDAC cells. Additionally, we developed a genetically-engineered mouse (GEM) with transgenic expression of ST6GAL1 in the pancreas, and found that mice with dual expression of ST6GAL1 and oncogenic KRASG12D have greatly accelerated PDAC progression compared with mice expressing KRASG12D alone. As ST6GAL1 imparts progenitor-like characteristics, we interrogated ST6GAL1's role in acinar to ductal metaplasia (ADM), a process that fosters neoplasia by reprogramming acinar cells into ductal, progenitor-like cells. We confirmed ST6GAL1 promotes ADM using multiple models including the 266-6 cell line, GEM-derived organoids and tissues, and an in vivo model of inflammation-induced ADM. EGFR is a key driver of ADM and is known to be activated by ST6GAL1-mediated sialylation. Importantly, EGFR activation was dramatically increased in acinar cells and organoids from mice with transgenic ST6GAL1 expression. These collective results highlight a glycosylation-dependent mechanism involved in early stages of pancreatic neoplasia.
Authors
Nikita Bhalerao, Asmi Chakraborty, Michael P. Marciel, Jihye Hwang, Colleen M. Britain, Austin D. Silva, Isam E. Eltoum, Robert B. Jones, Katie L. Alexander, Lesley E. Smythies, Phillip D. Smith, David K. Crossman, Michael R. Crowley, Boyoung Shin, Laurie E. Harrington, Zhaoqi Yan, Maigen M. Bethea, Chad S. Hunter, Christopher A. Klug, Donald J. Buchsbaum, Susan L. Bellis
Abstract
Pancreatic ductal adenocarcinoma (PDAC) progresses in an organ with a unique pH landscape, where the stroma acidifies after each meal. We hypothesized that disrupting this pH landscape during PDAC progression triggers pancreatic stellate cells (PSCs) and cancer-associated fibroblasts (CAFs) to induce PDAC fibrosis. We revealed that alkaline environmental pH is sufficient to induce PSC differentiation to a myofibroblastic phenotype. We then mechanistically dissected this finding focusing on the involvement of the Na+/H+ exchanger NHE1. Perturbing cellular pH homeostasis by inhibiting NHE1 with cariporide partially alters the myofibroblastic PSC phenotype. To show the relevance of this finding in vivo, we targeted NHE1 in murine PDAC (KPfC). Indeed, tumor fibrosis decreases when mice receive the NHE1-inhibitor cariporide in addition to gemcitabine treatment. Moreover, the tumor immune infiltrate shifts from granulocyte-rich to more lymphocytic. Taken together, our study provides mechanistic evidence on how the pancreatic pH landscape shapes pancreatic cancer through tuning PSC differentiation.
Authors
Zoltán Pethő, Karolina Najder, Stephanie Beel, Benedikt Fels, Ilka Neumann, Sandra Schimmelpfennig, Sarah Sargin, Maria Wolters, Klavs Grantins, Eva Wardelmann, Miso Mitkovski, Andrea Oeckinghaus, Albrecht Schwab
Abstract
Spatially resolved metabolomics enables the investigation of tumoral metabolites in situ. Inter- and intratumor heterogeneity are key factors associated with patient outcomes. Adrenocortical carcinoma (ACC) is an exceedingly rare tumor associated with poor survival. Its clinical prognosis is highly variable, but the contributions of tumor metabolic heterogeneity have not been investigated thus far to our knowledge. An in-depth understanding of tumor heterogeneity requires molecular feature-based identification of tumor subpopulations associated with tumor aggressiveness. Here, using spatial metabolomics by high–mass resolution MALDI Fourier transform ion cyclotron resonance mass spectrometry imaging, we assessed metabolic heterogeneity by de novo discovery of metabolic subpopulations and Simpson’s diversity index. After identification of tumor subpopulations in 72 patients with ACC, we additionally performed a comparison with 25 tissue sections of normal adrenal cortex to identify their common and unique metabolic subpopulations. We observed variability of ACC tumor heterogeneity and correlation of high metabolic heterogeneity with worse clinical outcome. Moreover, we identified tumor subpopulations that served as independent prognostic factors and, furthermore, discovered 4 associated anticancer drug action pathways. Our research may facilitate comprehensive understanding of the biological implications of tumor subpopulations in ACC and showed that metabolic heterogeneity might impact chemotherapy.
Authors
Qian Wang, Na Sun, Raphael Meixner, Ronan Le Gleut, Thomas Kunzke, Annette Feuchtinger, Jun Wang, Jian Shen, Stefan Kircher, Ulrich Dischinger, Isabel Weigand, Felix Beuschlein, Martin Fassnacht, Matthias Kroiss, Axel Walch
Abstract
CD8+ T cells can recognize tumor antigens displayed by HLA class I molecules and eliminate tumor cells. Despite their low tumor mutation burden, immune checkpoint blockade (ICB) is often beneficial in patients with renal cell carcinoma (RCC). Here, using a proteogenomic approach, we directly and comprehensively explored the HLA class I–presenting peptidome of RCC tissues and demonstrated that the immunopeptidomes contain a small subset of peptides derived from human endogenous retroviruses (hERV). A comparison between tumor and normal kidney tissues revealed tumor-associated hERV antigens, one of which was immunogenic and recognized by host tumor-infiltrating lymphocytes (TIL). Stimulation with the hERV antigen induced reactive CD8+ T cells in healthy donor–derived (HD-derived) peripheral blood mononuclear cells (PBMC). These results highlight the presence of antitumor CD8+ T cell surveillance against hERV3895 antigens, suggesting their clinical applications in patients with RCC.
Authors
Shin Kobayashi, Serina Tokita, Keigo Moniwa, Katsuyuki Kitahara, Hiromichi Iuchi, Kazuhiko Matsuo, Hidehiro Kakizaki, Takayuki Kanaseki, Toshihiko Torigoe
Abstract
Patients with triple negative breast cancer remain at risk for metastatic disease despite treatment. The acquisition of chemoresistance is a major cause of tumor relapse and death, but the mechanisms are far from understood. We have demonstrated that breast cancer cells (BCCs) can engulf mesenchymal stem/stromal cells (MSCs), leading to enhanced dissemination. Here, we show that clinical samples of primary invasive carcinoma and chemoresistant breast cancer metastasis contain a unique hybrid cancer cell population co-expressing pan-cytokeratin and the MSC marker fibroblast activation protein-alpha. We show that hybrid cells form in primary tumors and that they promote breast cancer metastasis and chemoresistance. Using single cell microfluidics and in vivo models, we found that within the hybrid cell population are polyploid senescent cells that contribute to metastatic dissemination. Our data reveal that WNT5A plays a crucial role in supporting the chemoresistance properties of hybrid cells. Furthermore, we identify that WNT5A mediates hybrid cell formation through a phagocytosis-like mechanism that requires BCC-derived Interleukin 6 and MSC-derived C-C Motif Chemokine Ligand 2. These findings reveal hybrid cell formation as a novel mechanism of chemoresistance and suggest that interrupting this mechanism may be a potential strategy to overcome breast cancer drug resistance.
Authors
Giuseppina Augimeri, Maria E. Gonzalez, Alessandro Paolì, Ahmad Eido, Yehyun Choi, Boris Burman, Sabra Djomehri, Santhosh Kumar Karthikeyan, Sooryanarayana Varambally, Johanna M. Buschhaus, Yu-Chih Chen, Loredana Mauro, Daniela Bonofiglio, Alexey I. Nesvizhskii, Gary D. Luker, Sebastiano Andò, Euisik Yoon, Celina G. Kleer
Abstract
Cancer stem cells (CSCs) are responsible for tumor progression and recurrence. However, the mechanisms regulating hepatocellular carcinoma (HCC) stemness remain unclear. Applying a genome-scale CRISPR knockout screen, we identify that the H3K4 methyltransferase SETD1A and other members of Trithorax group proteins drive cancer stemness in HCC. SETD1A is positively correlated with poor clinical outcome in HCC patients. Combination of SETD1A and serum AFP significantly improves the accuracy of predicting HCC relapse. Mechanistically, SETD1A mediates transcriptional activation of various histone-modifying enzymes, facilitates deposition of H3K4me3 and H3K27me3 and activates oncogenic enhancers and super-enhancers, leading to activation of oncogenes and inactivation of tumor suppressor genes simultaneously in HCC CSCs. In addition, SETD1A cooperates with PABPC1 to regulate H3K4me3 modification on oncogenes. Our data pinpoint SETD1A as a key epigenetic regulator driving HCC stemness and progression, highlighting the potential of SETD1A as a candidate target for HCC intervention and therapy.
Authors
Jianxu Chen, Zhijie Xu, Hongbin Huang, Yao Tang, Hong Shan, Fei Xiao
Abstract
DNASE1L3, an enzyme highly expressed in dendritic cells, is functionally important for regulating autoimmune responses to self-DNA and chromatin. Deficiency of DNASE1L3 leads to development of autoimmune diseases in both humans and mice. However, despite the well-established causal relationship between DNASE1L3 and immunity, little is known about the involvement of DNASE1L3 in regulation of anti-tumor immunity, the foundation of modern anti-tumor immunotherapy. In this study, we identify DNASE1L3 as a new regulator of anti-tumor immunity and a tumor suppressor in colon cancer. In humans, DNASE1L3 is downregulated in tumor-infiltrating dendritic cells, and this downregulation is associated with poor patient prognosis and reduced tumor immune cell infiltration in many cancer types. In mice, Dnase1l3 deficiency in the tumor microenvironment enhances tumor formation and growth in several colon cancer models. Notably, the increased tumor formation and growth in Dnase1l3-deficient mice are associated with impaired anti-tumor immunity, including a substantial reduction of cytotoxic T cells and a unique subset of dendritic cells. Consistently, Dnase1l3-deficient dendritic cells directly modulate cytotoxic T cells in vitro. Collectively, our study unveils a previously unknown link between DNASE1L3 and anti-tumor immunity, and further suggests that restoration of DNASE1L3 activity may represent a potential therapeutic approach for anti-cancer therapy.
Authors
Wenling Li, Hideki Nakano, Wei Fan, Yuanyuan Li, Payel Sil, Keiko Nakano, Fei Zhao, Peer W. Karmaus, Sara A. Grimm, Min Shi, Xin Xu, Ryushin Mizuta, Daisuke Kitamura, Yisong Wan, Michael B. Fessler, Donald N. Cook, Igor Shats, Xiaoling Li, Leping Li
Abstract
Lysine-specific demethylase 1 (LSD1) is a histone demethylase that promotes stemness and cancer cell survival, including in prostate cancer. Most prostate malignancies are adenocarcinomas with luminal differentiation. However, some tumors undergo cellular reprogramming to a more lethal subset termed neuroendocrine prostate cancer (NEPC) with neuronal differentiation. The frequency of NEPC is increasing since widespread use of potent androgen receptor signaling inhibitors. Currently, there are no effective treatments for NEPC. We previously determined that LSD1 promotes survival of prostate adenocarcinoma tumors. However, the role of LSD1 in NEPC is unknown. Here, we determined that LSD1 is highly upregulated in NEPC vs. adenocarcinoma patient tumors. LSD1 suppression with RNAi or allosteric LSD1 inhibitors—but not catalytic inhibitors—reduced NEPC cell survival. RNA-seq analysis revealed that LSD1 represses pathways linked to luminal differentiation, and TP53 was the top reactivated pathway. We confirmed that LSD1 suppressed the TP53 pathway by reducing TP53 occupancy at target genes while LSD1’s catalytic function was dispensable for this effect. Mechanistically, LSD1 inhibition disrupted LSD1-HDAC interactions, increasing histone acetylation at TP53 targets. Finally, LSD1 inhibition suppressed NEPC tumor growth in vivo. These findings suggest that blocking LSD1’s non-catalytic function may be a promising new treatment strategy for NEPC.
Authors
Anbarasu Kumaraswamy, Zhi Duan, Diana Flores, Chao Zhang, Archana Sehrawat, Ya-Mei Hu, Olivia A. Swaim, Eva Rodansky, William K. Storck, Joshua A. Kuleape, Karan Bedi, Rahul Mannan, Xiao-Ming Wang, Aaron M. Udager, Visweswaran Ravikumar, Armand Bankhead III, Ilsa Coleman, John K. Lee, Colm Morrissey, Peter S. Nelson, Arul Chinnaiyan, Arvind Rao, Zheng Xia, Joel A. Yates, Joshi J. Alumkal
Abstract
Glioblastomas (GBM) are aggressive tumors that lack effective treatments. Here, we show that the Rho family guanine nucleotide exchange factor Syx promotes GBM cell growth both in vitro and in orthotopic xenografts derived from patients with GBM. Growth defects upon Syx depletion are attributed to prolonged mitosis, increased DNA damage, G2/M cell cycle arrest, and cell apoptosis, mediated by altered mRNA and protein expression of various cell cycle regulators. These effects are phenocopied by depletion of the Rho downstream effector Dia1 and are due, at least in part, to increased phosphorylation, cytoplasmic retention, and reduced activity of the YAP/TAZ transcriptional coactivators. Furthermore, targeting Syx signaling cooperates with radiation treatment and temozolomide (TMZ) to decrease viability in GBM cells, irrespective of their inherent response to TMZ. The data indicate that a Syx-RhoA-Dia1-YAP/TAZ signaling axis regulates cell cycle progression, DNA damage, and therapy resistance in GBM and argue for its targeting for cancer treatment.
Authors
Wan-Hsin Lin, Ryan W. Feathers, Lisa M. Cooper, Laura J. Lewis-Tuffin, Jiaxiang Chen, Jann N. Sarkaria, Panos Z. Anastasiadis
Abstract
Epigenetic aberrations, including posttranslational modifications of core histones, are major contributors to cancer. Here, we define the status of histone H2B monoubiquitylation (H2Bub1) in clear cell ovarian carcinoma (CCOC), low-grade serous carcinoma, and endometrioid carcinomas. We report that clear cell carcinomas exhibited profound loss, with nearly all cases showing low or negative H2Bub1 expression. Moreover, we found that H2Bub1 loss occurred in endometriosis and atypical endometriosis, which are established precursors to CCOCs. To examine whether dysregulation of a specific E3 ligase contributes to the loss of H2Bub1, we explored expression of ring finger protein 40 (RNF40), ARID1A, and UBR7 in the same case cohort. Loss of RNF40 was significantly and profoundly correlated with loss of H2Bub1. Using genome-wide DNA methylation profiles of 230 patients with CCOC, we identified hypermethylation of RNF40 in CCOC as a likely mechanism underlying the loss of H2Bub1. Finally, we demonstrated that H2Bub1 depletion promoted cell proliferation and clonogenicity in an endometriosis cell line. Collectively, our results indicate that H2Bub1 plays a tumor-suppressive role in CCOCs and that its loss contributes to disease progression.
Authors
Adam J. Ferrari, Priyanka Rawat, Hannah S. Rendulich, Akshaya V. Annapragada, Yasuto Kinose, Xiaoming Zhang, Kyle Devins, Anna Budina, Robert B. Scharpf, Marilyn A. Mitchell, Janos L. Tanyi, Mark A. Morgan, Lauren E. Schwartz, T. Rinda Soong, Victor E. Velculescu, Ronny Drapkin
No posts were found with this tag.
