bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from FAM46C and FNDC3A Are Multiple Myeloma Tumor Suppressors That Act in Concert to Impair Clearing of Protein Aggregates and Autophagy
Authors: Manfrini Nicola , Mancino Marilena , Miluzio Annarita , Oliveto Stefania , Balestra Matteo , Calamita Piera , Alfieri Roberta , Rossi Riccardo L. , Sassoè-Pognetto Marco , Salio Chiara , Cuomo Alessandro , Bonaldi Tiziana , Manfredi Marcello , Marengo Emilio , Ranzato Elia , Martinotti Simona , Cittaro Davide , Tonon Giovanni , Biffo Stefano
Published: March 2023

Abstract
Multiple myeloma is a plasma cell neoplasm characterized by the production of unfolded immunoglobulins, which cause endoplasmic reticulum (ER) stress and sensitivity to proteasome inhibition. The genomic landscape of multiple myeloma is characterized by the loss of several genes rarely mutated in other cancers that may underline specific weaknesses of multiple myeloma cells. One of these is FAM46C that is lost in more than 10% of patients with multiple myeloma. We show here that FAM46C is part of a new complex containing the ER-associated protein FNDC3A, which regulates trafficking and secretion and, by impairing autophagy, exacerbates proteostatic stress. Reconstitution of FAM46C in multiple myeloma cells that had lost it induced apoptosis and ER stress. Apoptosis was preceded by an increase of intracellular aggregates, which was not linked to increased translation of IgG mRNA, but rather to impairment of autophagy. Biochemical analysis showed that FAM46C requires interaction with ER bound protein FNDC3A to reside in the cytoplasmic side of the ER. FNDC3A was lost in some multiple myeloma cell lines. Importantly, depletion of FNDC3A increased the fitness of FAM46C-expressing cells and expression of FNDC3A in cells that had lost it recapitulated the effects of FAM46C, inducing aggregates and apoptosis. FAM46C and FNDC3A formed a complex that modulates secretion routes, increasing lysosome exocytosis. The cellular landscape generated by FAM46C/FNDC3A expression predicted sensitivity to sphingosine kinase inhibition. These results suggest that multiple myeloma cells remodel their trafficking machinery to cope with ER stress.
Significance:
This study identifies a new multiple myeloma–specific tumor suppressor complex that regulates autophagy and unconventional secretion, highlighting the sensitivity of multiple myeloma cells to the accumulation of protein aggregates.
Data from Combined Blockade of IL6 and PD-1/PD-L1 Signaling Abrogates Mutual Regulation of Their Immunosuppressive Effects in the Tumor Microenvironment
Authors: Tsukamoto Hirotake , Fujieda Koji , Miyashita Azusa , Fukushima Satoshi , Ikeda Tokunori , Kubo Yosuke , Senju Satoru , Ihn Hironobu , Nishimura Yasuharu , Oshiumi Hiroyuki
Published: March 2023

Abstract
Recently emerging cancer immunotherapies combine the applications of therapeutics to disrupt the immunosuppressive conditions in tumor-bearing hosts. In this study, we found that targeting the proinflammatory cytokine IL6 enhances tumor-specific Th1 responses and subsequent antitumor effects in tumor-bearing mice. IL6 blockade upregulated expression of the immune checkpoint molecule programmed death-ligand 1 (PD-L1) on melanoma cells. This PD-L1 induction was canceled in IFNγ-deficient mice or CD4+ T cell–depleted mice, suggesting that CD4+ T cell–derived IFNγ is important for PD-L1 induction in tumor-bearing hosts. In some patients with melanoma, however, treatment with the anti–PD-1 antibody nivolumab increased systemic levels of IL6, which was associated with poor clinical responses. This PD-L1 blockade-evoked induction of IL6 was reproducible in melanoma-bearing mice. We found that PD-1/PD-L1 blockade prompted PD-1+ macrophages to produce IL6 in the tumor microenvironment. Depletion of macrophages in melanoma-bearing mice reduced the levels of IL6 during PD-L1 blockade, suggesting macrophages are responsible for the IL6-mediated defective CD4+ Th1 response. Combined blockade of the mutually regulated immunosuppressive activities of IL6 and PD-1/PD-L1 signals enhanced expression of T cell–attracting chemokines and promoted infiltration of IFNγ-producing CD4+ T cells in tumor tissues, exerting a synergistic antitumor effect, whereas PD-L1 blockade alone did not promote Th1 response. Collectively, these findings suggest that IL6 is a rational immunosuppressive target for overcoming the narrow therapeutic window of anti–PD-1/PD-L1 therapy.

Significance: These findings advance our understanding of IL6-PD1/PD-L1 cross-talk in the tumor microenvironment and provide clues for targeted interventional therapy that may prove more effective against cancer. Cancer Res; 78(17); 5011–22. ©2018 AACR.
Data from Notch-Induced Myeloid Reprogramming in Spontaneous Pancreatic Ductal Adenocarcinoma by Dual Genetic Targeting
Authors: Cheung Phyllis F. , Neff Florian , Neander Christian , Bazarna Anna , Savvatakis Konstantinos , Liffers Sven-Thorsten , Althoff Kristina , Lee Chang-Lung , Moding Everett J. , Kirsch David G , Saur Dieter , Bazhin Alexandr V. , Trajkovic-Arsic Marija , Heikenwalder Mathias F. , Siveke Jens T.
Published: March 2023

Abstract
Despite advances in our understanding of the genetics of pancreatic ductal adenocarcinoma (PDAC), the efficacy of therapeutic regimens targeting aberrant signaling pathways remains highly limited. Therapeutic strategies are greatly hampered by the extensive desmoplasia that comprises heterogeneous cell populations. Notch signaling is a contentious pathway exerting opposite roles in tumorigenesis depending on cellular context. Advanced model systems are needed to gain more insights into complex signaling in the multilayered tumor microenvironment. In this study, we employed a dual recombinase-based in vivo strategy to modulate Notch signaling specifically in myeloid cells to dissect the tumorigenic role of Notch in PDAC stroma. Pancreas-specific KrasG12D activation and loss of Tp53 was induced using a Pdx1-Flp transgene, whereas Notch signaling was genetically targeted using a myeloid-targeting Lyz2-Cre strain for either activation of Notch2-IC or deletion of Rbpj. Myeloid-specific Notch activation significantly decreased tumor infiltration by protumorigenic M2 macrophages in spontaneous endogenous PDAC, which translated into significant survival benefit. Further characterization revealed upregulated antigen presentation and cytotoxic T effector phenotype upon Notch-induced M2 reduction. This approach is the first proof of concept for genetic targeting and reprogramming of myeloid cells in a complex disease model of PDAC and provides evidence for a regulatory role of Notch signaling in intratumoral immune phenotypes.

Significance: This study provides insight into the role of myeloid-dependent NOTCH signaling in PDAC and accentuates the need to dissect differential roles of signaling pathways in different cellular components within the tumor microenvironment. Cancer Res; 78(17); 4997–5010. ©2018 AACR.
Data from Subcellular Distribution of p53 by the p53-Responsive lncRNA NBAT1 Determines Chemotherapeutic Response in Neuroblastoma
Authors: Mitra Sanhita , Muralidharan Somsundar Veppil , Di Marco Mirco , Juvvuna Prasanna Kumar , Kosalai Subazini Thankaswamy , Reischl Silke , Jachimowicz Daniel , Subhash Santhilal , Raimondi Ivan , Kurian Leo , Huarte Maite , Kogner Per , Fischer Matthias , Johnsen John Inge , Mondal Tanmoy , Kanduri Chandrasekhar
Published: March 2023

Abstract
Neuroblastoma has a low mutation rate for the p53 gene. Alternative ways of p53 inactivation have been proposed in neuroblastoma, such as abnormal cytoplasmic accumulation of wild-type p53. However, mechanisms leading to p53 inactivation via cytoplasmic accumulation are not well investigated. Here we show that the neuroblastoma risk-associated locus 6p22.3-derived tumor suppressor NBAT1 is a p53-responsive lncRNA that regulates p53 subcellular levels. Low expression of NBAT1 provided resistance to genotoxic drugs by promoting p53 accumulation in cytoplasm and loss from mitochondrial and nuclear compartments. Depletion of NBAT1 altered CRM1 function and contributed to the loss of p53-dependent nuclear gene expression during genotoxic drug treatment. CRM1 inhibition rescued p53-dependent nuclear functions and sensitized NBAT1-depleted cells to genotoxic drugs. Combined inhibition of CRM1 and MDM2 was even more effective in sensitizing aggressive neuroblastoma cells with p53 cytoplasmic accumulation. Thus, our mechanistic studies uncover an NBAT1-dependent CRM1/MDM2-based potential combination therapy for patients with high-risk neuroblastoma.
Significance:
This study shows how a p53-responsive lncRNA mediates chemotherapeutic response by modulating nuclear p53 pathways and identifies a potential treatment strategy for patients with high-risk neuroblastoma.
Data from De Novo Lipogenesis Alters the Phospholipidome of Esophageal Adenocarcinoma
Authors: Abbassi-Ghadi Nima , Antonowicz Stefan S. , McKenzie James S. , Kumar Sacheen , Huang Juzheng , Jones Emrys A. , Strittmatter Nicole , Petts Gemma , Kudo Hiromi , Court Stephen , Hoare Jonathan M. , Veselkov Kirill , Goldin Robert , Takáts Zoltán , Hanna George B.
Published: March 2023

Abstract
The incidence of esophageal adenocarcinoma is rising, survival remains poor, and new tools to improve early diagnosis and precise treatment are needed. Cancer phospholipidomes quantified with mass spectrometry imaging (MSI) can support objective diagnosis in minutes using a routine frozen tissue section. However, whether MSI can objectively identify primary esophageal adenocarcinoma is currently unknown and represents a significant challenge, as this microenvironment is complex with phenotypically similar tissue-types. Here, we used desorption electrospray ionization-MSI (DESI-MSI) and bespoke chemometrics to assess the phospholipidomes of esophageal adenocarcinoma and relevant control tissues. Multivariate models derived from phospholipid profiles of 117 patients were highly discriminant for esophageal adenocarcinoma both in discovery (AUC = 0.97) and validation cohorts (AUC = 1). Among many other changes, esophageal adenocarcinoma samples were markedly enriched for polyunsaturated phosphatidylglycerols with longer acyl chains, with stepwise enrichment in premalignant tissues. Expression of fatty acid and glycerophospholipid synthesis genes was significantly upregulated, and characteristics of fatty acid acyls matched glycerophospholipid acyls. Mechanistically, silencing the carbon switch ACLY in esophageal adenocarcinoma cells shortened glycerophospholipid chains, linking de novo lipogenesis to the phospholipidome. Thus, DESI-MSI can objectively identify invasive esophageal adenocarcinoma from a number of premalignant tissues and unveils mechanisms of phospholipidomic reprogramming.
Significance:
These results call for accelerated diagnosis studies using DESI-MSI in the upper gastrointestinal endoscopy suite, as well as functional studies to determine how polyunsaturated phosphatidylglycerols contribute to esophageal carcinogenesis.
Data from Allosteric SHP2 Inhibitor, IACS-13909, Overcomes EGFR-Dependent and EGFR-Independent Resistance Mechanisms toward Osimertinib
Authors: Sun Yuting , Meyers Brooke A. , Czako Barbara , Leonard Paul , Mseeh Faika , Harris Angela L. , Wu Qi , Johnson Sarah , Parker Connor A. , Cross Jason B. , Di Francesco Maria Emilia , Bivona Benjamin J. , Bristow Christopher A. , Burke Jason P. , Carrillo Caroline C. , Carroll Christopher L. , Chang Qing , Feng Ningping , Gao Guang , Gera Sonal , Giuliani Virginia , Huang Justin K. , Jiang Yongying , Kang Zhijun , Kovacs Jeffrey J. , Liu Chiu-Yi , Lopez Anastasia M. , Ma Xiaoyan , Mandal Pijus K. , McAfoos Timothy , Miller Meredith A. , Mullinax Robert A. , Peoples Michael , Ramamoorthy Vandhana , Seth Sahil , Spencer Nakia D. , Suzuki Erika , Williams Christopher C. , Yu Simon S. , Zuniga Andy M. , Draetta Giulio F. , Marszalek Joseph R. , Heffernan Timothy P. , Kohl Nancy E. , Jones Philip
Published: March 2023

Abstract
Src homology 2 domain-containing phosphatase (SHP2) is a phosphatase that mediates signaling downstream of multiple receptor tyrosine kinases (RTK) and is required for full activation of the MAPK pathway. SHP2 inhibition has demonstrated tumor growth inhibition in RTK-activated cancers in preclinical studies. The long-term effectiveness of tyrosine kinase inhibitors such as the EGFR inhibitor (EGFRi), osimertinib, in non–small cell lung cancer (NSCLC) is limited by acquired resistance. Multiple clinically identified mechanisms underlie resistance to osimertinib, including mutations in EGFR that preclude drug binding as well as EGFR-independent activation of the MAPK pathway through alternate RTK (RTK-bypass). It has also been noted that frequently a tumor from a single patient harbors more than one resistance mechanism, and the plasticity between multiple resistance mechanisms could restrict the effectiveness of therapies targeting a single node of the oncogenic signaling network. Here, we report the discovery of IACS-13909, a specific and potent allosteric inhibitor of SHP2, that suppresses signaling through the MAPK pathway. IACS-13909 potently impeded proliferation of tumors harboring a broad spectrum of activated RTKs as the oncogenic driver. In EGFR-mutant osimertinib-resistant NSCLC models with EGFR-dependent and EGFR-independent resistance mechanisms, IACS-13909, administered as a single agent or in combination with osimertinib, potently suppressed tumor cell proliferation in vitro and caused tumor regression in vivo. Together, our findings provide preclinical evidence for using a SHP2 inhibitor as a therapeutic strategy in acquired EGFRi-resistant NSCLC.
Significance:
These findings highlight the discovery of IACS-13909 as a potent, selective inhibitor of SHP2 with drug-like properties, and targeting SHP2 may serve as a therapeutic strategy to overcome tumor resistance to osimertinib.
Data from Integrated Genomic Characterization of the Human Immunome in Cancer
Authors: Li Yongsheng , Burgman Brandon , McGrail Daniel J. , Sun Ming , Qi Dan , Shukla Sachet A. , Wu Erxi , Capasso Anna , Lin Shiaw-Yih , Wu Catherine J. , Eckhardt S. Gail , Mills Gordon B. , Li Bo , Sahni Nidhi , Yi S. Stephen
Published: March 2023

Abstract
Alterations in immune-related pathways are common hallmarks of cancer. A comprehensive understanding of how cancer mutations rewire immune signaling networks and functional output across cancer types is instrumental to realize the full potential of immunotherapy. Here, we systematically interrogated somatic mutations involved in immune signaling that alter immune responses in patients with cancer. To do so, we developed a Network-based Integrative model to Prioritize Potential immune respondER genes (NIPPER). Identified mutations were enriched in essential protein domains and genes identified by NIPPER were associated with responsiveness to multiple immunotherapy modalities. These genes were used to devise an interactome network propagation framework integrated with drug-associated gene signatures to identify potential immunomodulatory drug candidates. Together, our systems-level analysis results help interpret the heterogeneous immune responses among patients and serve as a resource for future functional studies and targeted therapeutics.
Significance:
This study demonstrates that integration of multi-omics data can help identify critical molecular determinants for effective targeted therapeutics.
Data from Erbin Suppresses KSR1-Mediated RAS/RAF Signaling and Tumorigenesis in Colorectal Cancer
Authors: Stevens Payton D. , Wen Yang-An , Xiong Xiaopeng , Zaytseva Yekaterina Y. , Li Austin T. , Wang Chi , Stevens Ashley T. , Farmer Trevor N. , Gan Tong , Weiss Heidi L. , Inagaki Masaki , Marchetto Sylvie , Borg Jean-Paul , Gao Tianyan
Published: March 2023

Abstract
Erbin belongs to the LAP (leucine-rich repeat and PDZ domain) family of scaffolding proteins that plays important roles in orchestrating cell signaling. Here, we show that Erbin functions as a tumor suppressor in colorectal cancer. Analysis of Erbin expression in colorectal cancer patient specimens revealed that Erbin was downregulated at both mRNA and protein levels in tumor tissues. Knockdown of Erbin disrupted epithelial cell polarity and increased cell proliferation in 3D culture. In addition, silencing Erbin resulted in increased amplitude and duration of signaling through Akt and RAS/RAF pathways. Erbin loss induced epithelial–mesenchymal transition, which coincided with a significant increase in cell migration and invasion. Erbin interacted with kinase suppressor of Ras 1 (KSR1) and displaced it from the RAF/MEK/ERK complex to prevent signal propagation. Furthermore, genetic deletion of Erbin in Apc knockout mice promoted tumorigenesis and significantly reduced survival. Tumor organoids derived from Erbin/Apc double knockout mice displayed increased tumor initiation potential and activation of Wnt signaling. Results from gene set enrichment analysis revealed that Erbin expression associated positively with the E-cadherin adherens junction pathway and negatively with Wnt signaling in human colorectal cancer. Taken together, our study identifies Erbin as a negative regulator of tumor initiation and progression by suppressing Akt and RAS/RAF signaling in vivo.

Significance: These findings establish the scaffold protein Erbin as a negative regulator of EMT and tumorigenesis in colorectal cancer through direct suppression of Akt and RAS/RAF signaling. Cancer Res; 78(17); 4839–52. ©2018 AACR.
Data from Epigenetic Control of Cdkn2a.Arf Protects Tumor-Infiltrating Lymphocytes from Metabolic Exhaustion
Authors: Koss Brian , Shields Bradley D. , Taylor Erin M. , Storey Aaron J. , Byrum Stephanie D. , Gies Allen J. , Washam Charity L. , Choudhury Samrat Roy , Hyun Ahn Jeong , Uryu Hidetaka , Williams Jason B. , Krager Kimberly J. , Chiang Tung-Chin , Mackintosh Samuel G. , Edmondson Rick D. , Aykin-Burns Nukhet , Gajewski Thomas F. , Wang Gang Greg , Tackett Alan J.
Published: March 2023

Abstract
T-cell exhaustion in cancer is linked to poor clinical outcomes, where evidence suggests T-cell metabolic changes precede functional exhaustion. Direct competition between tumor-infiltrating lymphocytes (TIL) and cancer cells for metabolic resources often renders T cells dysfunctional. Environmental stress produces epigenome remodeling events within TIL resulting from loss of the histone methyltransferase EZH2. Here, we report an epigenetic mechanism contributing to the development of metabolic exhaustion in TIL. A multiomics approach revealed a Cdkn2a.Arf-mediated, p53-independent mechanism by which EZH2 inhibition leads to mitochondrial dysfunction and the resultant exhaustion. Reprogramming T cells to express a gain-of-function EZH2 mutant resulted in an enhanced ability of T cells to inhibit tumor growth in vitro and in vivo. Our data suggest that manipulation of T-cell EZH2 within the context of cellular therapies may yield lymphocytes that are able to withstand harsh tumor metabolic environments and collateral pharmacologic insults.
Significance:
These findings demonstrate that manipulation of T-cell EZH2 in cellular therapies may yield cellular products able to withstand solid tumor metabolic–deficient environments.
Data from A DNA Hypomethylating Drug Alters the Tumor Microenvironment and Improves the Effectiveness of Immune Checkpoint Inhibitors in a Mouse Model of Pancreatic Cancer
Authors: Gonda Tamas A. , Fang Jarwei , Salas Martha , Do Catherine , Hsu Emily , Zhukovskaya Anna , Siegel Ariel , Takahashi Ryota , Lopez-Bujanda Zoila A. , Drake Charles G. , Manji Gulam A. , Wang Timothy C. , Olive Kenneth P. , Tycko Benjamin
Published: March 2023

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer that has proven refractory to immunotherapy. Previously, treatment with the DNA hypomethylating drug decitabine (5-aza-dC; DAC) extended survival in the KPC-Brca1 mouse model of PDAC. Here we investigated the effects of DAC in the original KPC model and tested combination therapy with DAC followed by immune checkpoint inhibitors (ICI). Four protocols were tested: PBS vehicle, DAC, ICI (anti-PD-1 or anti-VISTA), and DAC followed by ICI. For each single-agent and combination treatment, tumor growth was measured by serial ultrasound, tumor-infiltrating lymphoid and myeloid cells were characterized, and overall survival was assessed. Single-agent DAC led to increased CD4+ and CD8+ tumor-infiltrating lymphocytes (TIL), PD1 expression, and tumor necrosis while slowing tumor growth and modestly increasing mouse survival without systemic toxicity. RNA-sequencing of DAC-treated tumors revealed increased expression of Chi3l3 (Ym1), reflecting an increase in a subset of tumor-infiltrating M2-polarized macrophages. While ICI alone had modest effects, DAC followed by either of ICI therapies additively inhibited tumor growth and prolonged mouse survival. The best results were obtained using DAC followed by anti-PD-1, which extended mean survival from 26 to 54 days (P < 0.0001). In summary, low-dose DAC inhibits tumor growth and increases both TILs and a subset of tumor-infiltrating M2-polarized macrophages in the KPC model of PDAC, and DAC followed by anti-PD-1 substantially prolongs survival. Because M2-polarized macrophages are predicted to antagonize antitumor effects, targeting these cells may be important to enhance the efficacy of combination therapy with DAC plus ICI.
Significance:
In a pancreatic cancer model, a DNA hypomethylating drug increases tumor-infiltrating effector T cells, increases a subset of M2 macrophages, and significantly prolongs survival in combination with immune checkpoint inhibitors.

See related commentary by Nephew, p. 4610
Data from Remission of Spontaneous Canine Tumors after Systemic Cellular Viroimmunotherapy
Authors: Cejalvo Teresa , Perisé-Barrios Ana Judith , del Portillo Isabel , Laborda Eduardo , Rodriguez-Milla Miguel A. , Cubillo Isabel , Vázquez Fernando , Sardón David , Ramirez Manuel , Alemany Ramon , del Castillo Noemí , García-Castro Javier
Published: March 2023

Abstract
Dogs with spontaneous tumors treated in veterinary hospitals offer an excellent opportunity for studying immunotherapies, including oncolytic viruses. Oncolytic viruses have advanced into the clinic as an intratumorally administered therapeutic; however, intravenous delivery has been hindered by neutralization in the blood. To circumvent this hurdle, mesenchymal stem cells have been used as a "Trojan horse." Here, we present the treatment of 27 canine patients with cancer with canine mesenchymal stem cells infected with ICOCAV17, a canine oncolytic adenovirus. No significant adverse effects were found. The response rate was 74%, with 14.8% showing complete responses, including total remissions of lung metastasis. We detected virus infection, stromal degeneration, and immune cell infiltration in tumor biopsies after 4 weeks of treatment. The increased presence of antiadenoviral antibodies in the peripheral blood of treated dogs did not appear to prevent the clinical benefit of this therapy. These data indicate that oncolytic viruses loaded in mesenchymal stem cells represent an effective cancer immunotherapy.

Significance: The classical clinical limitations of antitumoral viroimmunotherapy can be overcome by use of mesenchymal stem cells.

Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/17/4891/F1.large.jpg. Cancer Res; 78(17); 4891–901. ©2018 AACR.
Data from A Transcriptome-Wide Association Study Identifies Candidate Susceptibility Genes for Pancreatic Cancer Risk
Authors: Liu Duo , Zhou Dan , Sun Yanfa , Zhu Jingjing , Ghoneim Dalia , Wu Chong , Yao Qizhi , Gamazon Eric R. , Cox Nancy J. , Wu Lang
Published: March 2023

Abstract
Pancreatic cancer is among the most well-characterized cancer types, yet a large proportion of the heritability of pancreatic cancer risk remains unclear. Here, we performed a large transcriptome-wide association study to systematically investigate associations between genetically predicted gene expression in normal pancreas tissue and pancreatic cancer risk. Using data from 305 subjects of mostly European descent in the Genotype-Tissue Expression Project, we built comprehensive genetic models to predict normal pancreas tissue gene expression, modifying the UTMOST (unified test for molecular signatures). These prediction models were applied to the genetic data of 8,275 pancreatic cancer cases and 6,723 controls of European ancestry. Thirteen genes showed an association of genetically predicted expression with pancreatic cancer risk at an FDR ≤ 0.05, including seven previously reported genes (INHBA, SMC2, ABO, PDX1, RCCD1, CFDP1, and PGAP3) and six novel genes not yet reported for pancreatic cancer risk [6q27: SFT2D1 OR (95% confidence interval (CI), 1.54 (1.25–1.89); 13q12.13: MTMR6 OR (95% CI), 0.78 (0.70–0.88); 14q24.3: ACOT2 OR (95% CI), 1.35 (1.17–1.56); 17q12: STARD3 OR (95% CI), 6.49 (2.96–14.27); 17q21.1: GSDMB OR (95% CI), 1.94 (1.45–2.58); and 20p13: ADAM33 OR (95% CI): 1.41 (1.20–1.66)]. The associations for 10 of these genes (SFT2D1, MTMR6, ACOT2, STARD3, GSDMB, ADAM33, SMC2, RCCD1, CFDP1, and PGAP3) remained statistically significant even after adjusting for risk SNPs identified in previous genome-wide association study. Collectively, this analysis identified novel candidate susceptibility genes for pancreatic cancer that warrant further investigation.
Significance:
A transcriptome-wide association analysis identified seven previously reported and six novel candidate susceptibility genes for pancreatic cancer risk.
Data from 5-Fluorouracil Enhances the Antitumor Activity of the Glutaminase Inhibitor CB-839 against PIK3CA-Mutant Colorectal Cancers
Authors: Zhao Yiqing , Feng Xiujing , Chen Yicheng , Selfridge J. Eva , Gorityala Shashank , Du Zhanwen , Wang Janet M. , Hao Yujun , Cioffi Gino , Conlon Ronald A. , Barnholtz-Sloan Jill S. , Saltzman Joel , Krishnamurthi Smitha S. , Vinayak Shaveta , Veigl Martina , Xu Yan , Bajor David L. , Markowitz Sanford D. , Meropol Neal J. , Eads Jennifer R. , Wang Zhenghe
Published: March 2023

Abstract
PIK3CA encodes the p110α catalytic subunit of PI3K and is frequently mutated in human cancers, including ∼30% of colorectal cancer. Oncogenic mutations in PIK3CA render colorectal cancers more dependent on glutamine. Here we report that the glutaminase inhibitor CB-839 preferentially inhibits xenograft growth of PIK3CA-mutant, but not wild-type (WT), colorectal cancers. Moreover, the combination of CB-839 and 5-fluorouracil (5-FU) induces PIK3CA-mutant tumor regression in xenograft models. CB-839 treatment increased reactive oxygen species and caused nuclear translocation of Nrf2, which in turn upregulated mRNA expression of uridine phosphorylase 1 (UPP1). UPP1 facilitated the conversion of 5-FU to its active compound, thereby enhancing the inhibition of thymidylate synthase. Consistently, knockout of UPP1 abrogated the tumor inhibitory effect of combined CB-839 and 5-FU administration. A phase I clinical trial showed that the combination of CB-839 and capecitabine, a prodrug of 5-FU, was well tolerated at biologically-active doses. Although not designed to test efficacy, an exploratory analysis of the phase I data showed a trend that PIK3CA-mutant patients with colorectal cancer might derive greater benefit from this treatment strategy as compared with PIK3CA WT patients with colorectal cancer. These results effectively demonstrate that targeting glutamine metabolism may be an effective approach for treating patients with PIK3CA-mutant colorectal cancers and warrants further clinical evaluation.
Significance:
Preclinical and clinical trial data suggest that the combination of CB-839 with capecitabine could serve as an effective treatment for PIK3CA-mutant colorectal cancers.
Data from Palmitoylated Proteins on AML-Derived Extracellular Vesicles Promote Myeloid-Derived Suppressor Cell Differentiation via TLR2/Akt/mTOR Signaling
Authors: Tohumeken Sehmus , Baur Rebecca , Böttcher Martin , Stoll Andrej , Loschinski Romy , Panagiotidis Konstantinos , Braun Martina , Saul Domenica , Völkl Simon , Baur Andreas S. , Bruns Heiko , Mackensen Andreas , Jitschin Regina , Mougiakakos Dimitrios
Published: March 2023

Abstract
Acute myeloid leukemia (AML) represents the most common acute leukemia among adults. Despite recent progress in diagnosis and treatment, long-term outcome remains unsatisfactory. The success of allogeneic stem cell transplantation underscores the immunoresponsive nature of AML, creating the basis for further exploiting immunotherapies. However, emerging evidence suggests that AML, similar to other malignant entities, employs a variety of mechanisms to evade immunosurveillance. In light of this, T-cell inhibitory myeloid-derived suppressor cells (MDSC) are gaining interest as key facilitators of immunoescape. Accumulation of CD14+HLA-DRlow monocytic MDSCs has been described in newly diagnosed AML patients, and deciphering the underlying mechanisms could help to improve anti-AML immunity. Here, we report that conventional monocytes readily take-up AML-derived extracellular vesicles (EV) and subsequently undergo MDSC differentiation. They acquired an CD14+HLA-DRlow phenotype, expressed the immunomodulatory indoleamine-2,3-dioxygenase, and upregulated expression of genes characteristic for MDSCs, such as S100A8/9 and cEBPβ. The Akt/mTOR pathway played a critical role in the AML-EV–induced phenotypical and functional transition of monocytes. Generated MDSCs displayed a glycolytic switch, which rendered them more susceptible toward glycolytic inhibitors. Furthermore, palmitoylated proteins on the AML-EV surface activated Toll-like receptor 2 as the initiating event of Akt/mTOR-dependent induction of MDSC. Therefore, targeting protein palmitoylation in AML blasts could block MDSC accumulation to improve immune responses.
Significance:
These findings indicate that targeting protein palmitoylation in AML could interfere with the leukemogenic potential and block MDSC accumulation to improve immunity.
Data from Loss of ARID1A Promotes Epithelial–Mesenchymal Transition and Sensitizes Pancreatic Tumors to Proteotoxic Stress
Authors: Tomihara Hideo , Carbone Federica , Perelli Luigi , Huang Justin K. , Soeung Melinda , Rose Johnathon L. , Robinson Frederick S. , Lissanu Deribe Yonathan , Feng Ningping , Takeda Mitsunobu , Inoue Akira , Poggetto Edoardo Del , Deem Angela K. , Maitra Anirban , Msaouel Pavlos , Tannir Nizar M. , Draetta Giulio F. , Viale Andrea , Heffernan Timothy P. , Bristow Christopher A. , Carugo Alessandro , Genovese Giannicola
Published: March 2023

Abstract
Cellular dedifferentiation is a key mechanism driving cancer progression. Acquisition of mesenchymal features has been associated with drug resistance, poor prognosis, and disease relapse in many tumor types. Therefore, successful targeting of tumors harboring these characteristics is a priority in oncology practice. The SWItch/Sucrose non-fermentable (SWI/SNF) chromatin remodeling complex has also emerged as a critical player in tumor progression, leading to the identification of several SWI/SNF complex genes as potential disease biomarkers and targets of anticancer therapies. AT-rich interaction domain-containing protein 1A (ARID1A) is a component of SWI/SNF, and mutations in ARID1A represent one of the most frequent molecular alterations in human cancers. ARID1A mutations occur in approximately 10% of pancreatic ductal adenocarcinomas (PDAC), but whether these mutations confer a therapeutic opportunity remains unclear. Here, we demonstrate that loss of ARID1A promotes an epithelial–mesenchymal transition (EMT) phenotype and sensitizes PDAC cells to a clinical inhibitor of HSP90, NVP-AUY922, both in vitro and in vivo. Although loss of ARID1A alone did not significantly affect proliferative potential or rate of apoptosis, ARID1A-deficient cells were sensitized to HSP90 inhibition, potentially by promoting the degradation of intermediate filaments driving EMT, resulting in cell death. Our results describe a mechanistic link between ARID1A defects and a quasi-mesenchymal phenotype, suggesting that deleterious mutations in ARID1A associated with protein loss exhibit potential as a biomarker for patients with PDAC who may benefit by HSP90-targeting drugs treatment.
Significance:
This study identifies ARID1A loss as a promising biomarker for the identification of PDAC tumors that are potentially responsive to treatment with proteotoxic agents.
Data from Inhibition of Histone H3K27 Demethylases Inactivates Brachyury (TBXT) and Promotes Chordoma Cell Death
Authors: Cottone Lucia , Cribbs Adam P. , Khandelwal Garima , Wells Graham , Ligammari Lorena , Philpott Martin , Tumber Anthony , Lombard Patrick , Hookway Edward S. , Szommer Tamas , Johansson Catrine , Brennan Paul E. , Pillay Nischalan , Jenner Richard G. , Oppermann Udo , Flanagan Adrienne M.
Published: March 2023

Abstract
Expression of the transcription factor brachyury (TBXT) is normally restricted to the embryo, and its silencing is epigenetically regulated. TBXT promotes mesenchymal transition in a subset of common carcinomas, and in chordoma, a rare cancer showing notochordal differentiation, TBXT acts as a putative oncogene. We hypothesized that TBXT expression is controlled through epigenetic inhibition to promote chordoma cell death. Screening of five human chordoma cell lines revealed that pharmacologic inhibition of the histone 3 lysine 27 demethylases KDM6A (UTX) and KDM6B (JMJD3) leads to cell death. This effect was phenocopied by dual genetic inactivation of KDM6A/B using CRISPR/Cas9. Inhibition of KDM6A/B with a novel compound KDOBA67 led to a genome-wide increase in repressive H3K27me3 marks with concomitant reduction in active H3K27ac, H3K9ac, and H3K4me3 marks. TBXT was a KDM6A/B target gene, and chromatin changes at TBXT following KDOBA67 treatment were associated with a reduction in TBXT protein levels in all models tested, including primary patient-derived cultures. In all models tested, KDOBA67 treatment downregulated expression of a network of transcription factors critical for chordoma survival and upregulated pathways dominated by ATF4-driven stress and proapoptotic responses. Blocking the AFT4 stress response did not prevent suppression of TBXT and induction of cell death, but ectopic overexpression of TBXT increased viability, therefore implicating TBXT as a potential therapeutic target of H3K27 demethylase inhibitors in chordoma. Our work highlights how knowledge of normal processes in fetal development can provide insight into tumorigenesis and identify novel therapeutic approaches.
Significance:
Pharmacologic inhibition of H3K27-demethylases in human chordoma cells promotes epigenetic silencing of oncogenic TBXT, alters gene networks critical to survival, and represents a potential novel therapy.
Data from In Silico Models Accurately Predict In Vivo Response for IL6 Blockade in Head and Neck Cancer
Authors: Nazari Fereshteh , Oklejas Alexandra E. , Nör Jacques E. , Pearson Alexander T. , Jackson Trachette L.
Published: March 2023

Abstract
Malignant features of head and neck squamous cell carcinoma (HNSCC) may be derived from the presence of stem-like cells that are characterized by uniquely high tumorigenic potential. These cancer stem cells (CSC) function as putative drivers of tumor initiation, therapeutic evasion, metastasis, and recurrence. Although they are an appealing conceptual target, CSC-directed cancer therapies remain scarce. One promising CSC target is the IL6 pathway, which is strongly correlated with poor patient survival. In this study we created and validated a multiscale mathematical model to investigate the impact of cross-talk between tumor cell- and endothelial cell (EC)-secreted IL6 on HNSCC growth and the CSC fraction. We then predicted and analyzed the responses of HNSCC to tocilizumab (TCZ) and cisplatin combination therapy. The model was validated with in vivo experiments involving human ECs coimplanted with HNSCC cell line xenografts. Without artificial tuning to the laboratory data, the model showed excellent predictive agreement with the decrease in tumor volumes observed in TCZ-treated mice, as well as a decrease in the CSC fraction. This computational platform provides a framework for preclinical cisplatin and TCZ dose and frequency evaluation to be tested in future clinical studies.
Significance:
A mathematical model is used to rapidly evaluate dosing strategies for IL6 pathway modulation. These results may lead to nonintuitive dosing or timing treatment schedules to optimize synergism between drugs.
Data from A Hyperactive RelA/p65-Hexokinase 2 Signaling Axis Drives Primary Central Nervous System Lymphoma
Authors: Tateishi Kensuke , Miyake Yohei , Kawazu Masahito , Sasaki Nobuyoshi , Nakamura Taishi , Sasame Jo , Yoshii Yukie , Ueno Toshihide , Miyake Akio , Watanabe Jun , Matsushita Yuko , Shiba Norio , Udaka Naoko , Ohki Kentaro , Fink Alexandria L. , Tummala Shilpa S. , Natsumeda Manabu , Ikegaya Naoki , Nishi Mayuko , Ohtake Makoto , Miyazaki Ryohei , Suenaga Jun , Murata Hidetoshi , Aoki Ichio , Miller Julie J. , Fujii Yukihiko , Ryo Akihide , Yamanaka Shoji , Mano Hiroyuki , Cahill Daniel P. , Wakimoto Hiroaki , Chi Andrew S. , Batchelor Tracy T. , Nagane Motoo , Ichimura Koichi , Yamamoto Tetsuya
Published: March 2023

Abstract
Primary central nervous system lymphoma (PCNSL) is an isolated type of lymphoma of the central nervous system and has a dismal prognosis despite intensive chemotherapy. Recent genomic analyses have identified highly recurrent mutations of MYD88 and CD79B in immunocompetent PCNSL, whereas LMP1 activation is commonly observed in Epstein–Barr virus (EBV)-positive PCNSL. However, a lack of clinically representative preclinical models has hampered our understanding of the pathogenic mechanisms by which genetic aberrations drive PCNSL disease phenotypes. Here, we establish a panel of 12 orthotopic, patient-derived xenograft (PDX) models from both immunocompetent and EBV-positive PCNSL and secondary CNSL biopsy specimens. PDXs faithfully retained their phenotypic, metabolic, and genetic features, with 100% concordance of MYD88 and CD79B mutations present in PCNSL in immunocompetent patients. These models revealed a convergent functional dependency upon a deregulated RelA/p65-hexokinase 2 signaling axis, codriven by either mutated MYD88/CD79B or LMP1 with Pin1 overactivation in immunocompetent PCNSL and EBV-positive PCNSL, respectively. Notably, distinct molecular alterations used by immunocompetent and EBV-positive PCNSL converged to deregulate RelA/p65 expression and to drive glycolysis, which is critical for intracerebral tumor progression and FDG-PET imaging characteristics. Genetic and pharmacologic inhibition of this key signaling axis potently suppressed PCNSL growth in vitro and in vivo. These patient-derived models offer a platform for predicting clinical chemotherapeutics efficacy and provide critical insights into PCNSL pathogenic mechanisms, accelerating therapeutic discovery for this aggressive disease.
Significance:
A set of clinically relevant CNSL xenografts identifies a hyperactive RelA/p65-hexokinase 2 signaling axis as a driver of progression and potential therapeutic target for treatment and provides a foundational preclinical platform.
Data from The Inhibitor of Apoptosis Protein Livin Confers Resistance to Fas-Mediated Immune Cytotoxicity in Refractory Lymphoma
Authors: Sugihara Eiji , Hashimoto Norisato , Osuka Satoru , Shimizu Takatsune , Ueno Sayaka , Okazaki Shogo , Yaguchi Tomonori , Kawakami Yutaka , Kosaki Kenjiro , Sato Taka-Aki , Okamoto Shinichiro , Saya Hideyuki
Published: March 2023

Abstract
Death receptor Fas-mediated apoptosis not only eliminates nonspecific and autoreactive B cells but also plays a major role in antitumor immunity. However, the possible mechanisms underlying impairment of Fas-mediated induction of apoptosis during lymphomagenesis remain unknown. In this study, we employed our developed syngeneic lymphoma model to demonstrate that downregulation of Fas is required for both lymphoma development and lymphoma cell survival to evade immune cytotoxicity. CD40 signal activation significantly restored Fas expression and thereby induced apoptosis after Fas ligand treatment in both mouse and human lymphoma cells. Nevertheless, certain human lymphoma cell lines were found to be resistant to Fas-mediated apoptosis, with Livin (melanoma inhibitor of apoptosis protein; ML-IAP) identified as a driver of such resistance. High expression of Livin and low expression of Fas were associated with poor prognosis in patients with aggressive non-Hodgkin's lymphoma. Livin expression was tightly driven by bromodomain and extraterminal (BET) proteins BRD4 and BRD2, suggesting that Livin expression is epigenetically regulated in refractory lymphoma cells to protect them from Fas-mediated apoptosis. Accordingly, the combination of CD40-mediated Fas restoration with targeting of the BET proteins–Livin axis may serve as a promising immunotherapeutic strategy for refractory B-cell lymphoma.
Significance:
These findings yield insights into identifying risk factors in refractory lymphoma and provide a promising therapy for tumors resistant to Fas-mediated antitumor immunity.
Data from RIG-I–Like Receptor LGP2 Is Required for Tumor Control by Radiotherapy
Authors: Zheng Wenxin , Ranoa Diana Rose E. , Huang Xiaona , Hou Yuzhu , Yang Kaiting , Poli Elizabeth C. , Beckett Michael A. , Fu Yang-Xin , Weichselbaum Ralph R.
Published: March 2023

Abstract
Dendritic cells (DC) play an essential role in innate immunity and radiation-elicited immune responses. LGP2 is a RIG-I–like receptor involved in cytoplasmic RNA recognition and antiviral responses. Although LGP2 has also been linked to cell survival of both tumor cells and T cells, the role of LGP2 in mediating DC function and antitumor immunity elicited by radiotherapy remains unclear. Here, we report that tumor DCs are linked to the clinical outcome of patients with breast cancer who received radiotherapy, and the presence of DC correlates with gene expression of LGP2 in the tumor microenvironment. In preclinical models, host LGP2 was essential for optimal antitumor control by ionizing radiation (IR). The absence of LGP2 in DC dampened type I IFN production and the priming capacity of DC. In the absence of LGP2, MDA5-mediated activation of type I IFN signaling was abrogated. The MDA5/LGP2 agonist high molecular weight poly I:C improved the antitumor effect of IR. This study reveals a previously undefined role of LGP2 in host immunity and provides a new strategy to improve the efficacy of radiotherapy.
Significance:
These findings reveal an essential role of LGP2 in promoting antitumor immunity after radiotherapy and provide a new strategy to enhance radiotherapy.
Data from Combined Inhibition of SHP2 and MEK Is Effective in Models of NF1-Deficient Malignant Peripheral Nerve Sheath Tumors
Authors: Wang Jiawan , Pollard Kai , Allen Amy N. , Tomar Tushar , Pijnenburg Dirk , Yao Zhan , Rodriguez Fausto J. , Pratilas Christine A.
Published: March 2023

Abstract
Loss of the RAS GTPase-activating protein (RAS-GAP) NF1 drives aberrant activation of RAS/MEK/ERK signaling and other effector pathways in the majority of malignant peripheral nerve sheath tumors (MPNST). These dysregulated pathways represent potential targets for therapeutic intervention. However, studies of novel single agents including MEK inhibitors (MEKi) have demonstrated limited efficacy both preclinically and clinically, with little advancement in overall patient survival. By interrogation of kinome activity through an unbiased screen and targeted evaluation of the signaling response to MEK inhibition, we have identified global activation of upstream receptor tyrosine kinases (RTK) that converges on activation of RAS as a mechanism to limit sensitivity to MEK inhibition. As no direct inhibitors of pan-RAS were available, an inhibitor of the protein tyrosine phosphatase SHP2, a critical mediator of RAS signal transduction downstream of multiple RTK, represented an alternate strategy. The combination of MEKi plus SHP099 was superior to MEKi alone in models of NF1-MPNST, including those with acquired resistance to MEKi. Our findings have immediate translational implications and may inform future clinical trials for patients with MPNST harboring alterations in NF1.
Significance:
Combined inhibition of MEK and SHP2 is effective in models of NF1-MPNST, both those naïve to and those resistant to MEKi, as well as in the MPNST precursor lesion plexiform neurofibroma.
Data from Hormonal Regulation of Semaphorin 7a in ER+ Breast Cancer Drives Therapeutic Resistance
Authors: Crump Lyndsey S. , Wyatt Garhett L. , Rutherford Taylor R. , Richer Jennifer K. , Porter Weston W. , Lyons Traci R.
Published: March 2023

Abstract
Approximately 70% of all breast cancers are estrogen receptor–positive (ER+ breast cancer), and endocrine therapy has improved survival for patients with ER+ breast cancer. However, up to half of these tumors recur within 20 years. Recurrent ER+ breast cancers develop resistance to endocrine therapy; thus, novel targets are needed to treat recurrent ER+ breast cancer. Here we report that semaphorin 7A (SEMA7A) confers significantly decreased patient survival rates in ER+ breast cancer. SEMA7A was hormonally regulated in ER+ breast cancer, but its expression did not uniformly decrease with antiestrogen treatments. Additionally, overexpression of SEMA7A in ER+ cell lines drove increased in vitro growth in the presence of estrogen deprivation, tamoxifen, and fulvestrant. In vivo, SEMA7A conferred primary tumor resistance to fulvestrant and induced lung metastases. Prosurvival signaling was identified as a therapeutic vulnerability of ER+SEMA7A+ tumors. We therefore propose that targeting this pathway with inhibitors of survival signaling such as venetoclax may prove efficacious for treating SEMA7A+ tumors.
Significance:
SEMA7A predicts for and likely contributes to poor response to standard-of-care therapies, suggesting that patients with SEMA7A+ER+ tumors may benefit from alternative therapeutic strategies.
Data from Racial/Ethnic Disparities in All-Cause Mortality among Patients Diagnosed with Triple-Negative Breast Cancer
Authors: Wang Fei , Zheng Wei , Bailey Christina E. , Mayer Ingrid A. , Pietenpol Jennifer A. , Shu Xiao-Ou
Published: March 2023

Abstract
It is unclear whether racial/ethnic disparities in triple-negative breast cancer (TNBC) mortality remain after accounting for clinical characteristics, treatment, and access-to-care–related factors. In this study, women with a primary diagnosis of TNBC during 2010–2014 were identified from the National Cancer Database. Hazard ratios (HR) and 95% confidence intervals (CI) for 3- and 5-year all-cause mortality associated with race/ethnicity were estimated using Cox proportional hazards models with stepwise adjustments for age, clinical characteristics, treatment, and access-to-care–related factors. Of 78,708 patients, non-Hispanic (NH) black women had the lowest 3-year overall survival rates (79.4%), followed by NH-whites (83.1%), Hispanics (86.0%), and Asians (87.1%). After adjustment for clinical characteristics, NH-blacks had a 12% higher risk of dying 3 years post-diagnosis (HR, 1.12; 95% CI, 1.07–1.17), whereas Hispanics and Asians had a 24% (HR, 0.76; 95% CI, 0.70–0.83) and 17% (HR, 0.83; 95% CI, 0.73–0.94) lower risk than their NH-white counterparts. The black–white disparity became non-significant after combined adjustment for treatment and access-to-care–related factors (HR, 1.04; 95% CI, 0.99–1.09), whereas the white-Hispanic and white-Asian differences remained. Stratified analyses revealed that among women aged less than or equal to 50 with stage III cancer, the elevated risk among NH-blacks persisted (HR, 1.20; 95% CI, 1.04–1.39) after full adjustments. Similar results were seen for 5-year mortality. Overall, clinical characteristics, treatment, and access-to-care–related factors accounted for most of the white–black differences in all-cause mortality of TNBC but explained little about Hispanic- and Asian-white differences.
Significance:
These findings highlight the need for equal healthcare to mitigate the black–white disparity and for investigations of contributors beyond healthcare for lower mortality among Asians and Hispanics.