bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from S100A10 Is a Critical Mediator of GAS6/AXL–Induced Angiogenesis in Renal Cell Carcinoma
Authors: Xiao Yiren , Zhao Hongjuan , Tian Lei , Nolley Rosalie , Diep Anh N. , Ernst Anne , Fuh Katherine C. , Miao Yu Rebecca , von Eyben Rie , Leppert John T. , Brooks James D. , Peehl Donna M. , Giaccia Amato J. , Rankin Erinn B.
Published: March 2023

Abstract
Angiogenesis is a hallmark of cancer that promotes tumor progression and metastasis. However, antiangiogenic agents have limited efficacy in cancer therapy due to the development of resistance. In clear cell renal cell carcinoma (ccRCC), AXL expression is associated with antiangiogenic resistance and poor survival. Here, we establish a role for GAS6/AXL signaling in promoting the angiogenic potential of ccRCC cells through the regulation of the plasminogen receptor S100A10. Genetic and therapeutic inhibition of AXL signaling in ccRCC tumor xenografts reduced tumor vessel density and growth under the renal capsule. GAS6/AXL signaling activated the expression of S100A10 through SRC to promote plasmin production, endothelial cell invasion, and angiogenesis. Importantly, treatment with the small molecule AXL inhibitor cabozantinib or an ultra-high affinity soluble AXL Fc fusion decoy receptor (sAXL) reduced the growth of a pazopanib-resistant ccRCC patient-derived xenograft. Moreover, the combination of sAXL synergized with pazopanib and axitinib to reduce ccRCC patient-derived xenograft growth and vessel density. These findings highlight a role for AXL/S100A10 signaling in mediating the angiogenic potential of ccRCC cells and support the combination of AXL inhibitors with antiangiogenic agents for advanced ccRCC.
Significance:
These findings show that angiogenesis in renal cell carcinoma (RCC) is regulated through AXL/S100A10 signaling and support the combination of AXL inhibitors with antiangiogenic agents for the treatment of RCC.
Data from Time-Resolved MRI Assessment of Convection-Enhanced Delivery by Targeted and Nontargeted Nanoparticles in a Human Glioblastoma Mouse Model
Authors: Stephen Zachary R. , Chiarelli Peter A. , Revia Richard A. , Wang Kui , Kievit Forrest , Dayringer Chris , Jeon Mike , Ellenbogen Richard , Zhang Miqin
Published: March 2023

Abstract
Convection-enhanced delivery (CED) provides direct access of infusates to brain tumors; however, clinical translation of this technology has not been realized because of the inability to accurately visualize infusates in real-time and lack of targeting modalities against diffuse cancer cells. In this study, we use time-resolved MRI to reveal the kinetics of CED processes in a glioblastoma (GBM) model using iron oxide nanoparticles (NP) modified with a glioma-targeting ligand, chlorotoxin (CTX). Mice bearing orthotopic human GBM tumors were administered a single dose of targeted CTX-conjugated NP (NPCP-CTX) or nontargeted NP (NPCP) via CED. High-resolution T2-weighted, T2*-weighted, and quantitative T2 MRI were utilized to image NP delivery in real time and determined the volume of distribution (VD) of NPs at multiple time points over the first 48 hours post-CED. GBM-specific targeting was evaluated by flow cytometry and intracellular NP localization by histologic assessment. NPCP-CTX produced a VD of 121 ± 39 mm3 at 24 hours, a significant increase compared with NPCP, while exhibiting GBM specificity and localization to cell nuclei. Notably, CED of NPCP-CTX resulted in a sustained expansion of VD well after infusion, suggesting a possible active transport mechanism, which was further supported by the presence of NPs in endothelial and red blood cells. In summary, we show that time-resolved MRI is a suitable modality to study CED kinetics, and CTX-mediated CED facilitates extensive distribution of infusate and specific targeting of tumor cells.
Significance:
MRI is used to monitor convection-enhanced delivery in real time using a nanoparticle-based contrast agent, and glioma-specific targeting significantly improves the volume of distribution in tumors.
Data from Inhibition of Notch Signaling Enhances Chemosensitivity in B-cell Precursor Acute Lymphoblastic Leukemia
Authors: Takam Kamga Paul , Dal Collo Giada , Midolo Martina , Adamo Annalisa , Delfino Pietro , Mercuri Angela , Cesaro Simone , Mimiola Elda , Bonifacio Massimiliano , Andreini Angelo , Chilosi Marco , Krampera Mauro
Published: March 2023

Abstract
Notch3 and Notch4 support survival of primary B-cell acute lymphoblastic leukemia (B-ALL) cells, suggesting a role for Notch signaling in drug response. Here we used in vitro, in silico, and in vivo mouse xenograft model-based approaches to define the role of the Notch pathway in B-ALL chemosensitivity. We observed significant Notch receptor and ligand expression in B-ALL primary cells and cell lines. Primary leukemia cells from high-risk patients overexpressed Notch3, Notch4, and Jagged2 while displaying a reduction in expression levels of Notch1-4 following chemotherapy. We then analyzed in vitro cell survival of B-ALL cells treated with conventional chemotherapeutic agents alone or in combination with Notch signaling inhibitors. Gamma-secretase inhibitors (GSI) and anti-Notch4 were all capable of potentiating drug-induced cell death in B-ALL cells by upregulating intracellular levels of reactive oxygen species, which in turn modulated mTOR, NF-κB, and ERK expression. In NOG-mouse-based xenograft models of B-ALL, co-administration of the Notch inhibitor GSI-XII with the chemotherapeutic agent Ara-C lowered bone marrow leukemic burden compared with DMSO or Ara-C alone, thus prolonging mouse survival. Overall, our results support the potential effectiveness of Notch inhibitors in patients with B-ALL.

Significance: Inhibition of Notch signaling enhances the chemosensitivity of B-ALL cells, suggesting Notch inhibition as a potential therapeutic strategy to improve the outcome of patients with B-ALL.
Data from Prolactin Promotes Fibrosis and Pancreatic Cancer Progression
Authors: Tandon Manuj , Coudriet Gina M. , Criscimanna Angela , Socorro Mairobys , Eliliwi Mouhanned , Singhi Aatur D. , Cruz-Monserrate Zobeida , Bailey Peter , Lotze Michael T. , Zeh Herbert , Hu Jing , Goffin Vincent , Gittes George K. , Biankin Andrew V. , Esni Farzad
Published: March 2023

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is associated with significant fibrosis. Recent findings have highlighted the profibrotic activity of tissue-resident macrophages in the pancreatic cancer microenvironment. Here, we show that neoplastic pancreatic epithelium, as well as a subset of tissue-resident macrophages, expresses the prolactin-receptor (PRLR). High mobility group box 1–induced prolactin expression in the pancreas maintained FAK1 and STAT3 phosphorylation within the epithelium and stroma. Gain-of-function and loss-of-function experiments demonstrated the essential role of prolactin in promoting collagen deposition and fibrosis. Finally, the signaling cascade downstream of prolactin/PRLR activated STAT3 rather than STAT5 in PDAC. These findings suggest that targeting prolactin together with IL6, a known major activator of STAT3, could represent a novel therapeutic strategy for treating pancreatic cancer.
Significance:
Prolactin is a key factor in the cross-talk between the stroma and neoplastic epithelium, functioning to promote fibrosis and PDAC progression.
Data from EN1 Is a Transcriptional Dependency in Triple-Negative Breast Cancer Associated with Brain Metastasis
Authors: Peluffo Guillermo , Subedee Ashim , Harper Nicholas W. , Kingston Natalie , Jovanović Bojana , Flores Felipe , Stevens Laura E. , Beca Francisco , Trinh Anne , Chilamakuri Chandra Sekhar Reddy , Papachristou Evangelia K. , Murphy Katherine , Su Ying , Marusyk Andriy , D'Santos Clive S. , Rueda Oscar M. , Beck Andrew H. , Caldas Carlos , Carroll Jason S. , Polyak Kornelia
Published: March 2023

Abstract
To define transcriptional dependencies of triple-negative breast cancer (TNBC), we identified transcription factors highly and specifically expressed in primary TNBCs and tested their requirement for cell growth in a panel of breast cancer cell lines. We found that EN1 (engrailed 1) is overexpressed in TNBCs and its downregulation preferentially and significantly reduced viability and tumorigenicity in TNBC cell lines. By integrating gene expression changes after EN1 downregulation with EN1 chromatin binding patterns, we identified genes involved in WNT and Hedgehog signaling, neurogenesis, and axonal guidance as direct EN1 transcriptional targets. Quantitative proteomic analyses of EN1-bound chromatin complexes revealed association with transcriptional repressors and coactivators including TLE3, TRIM24, TRIM28, and TRIM33. High expression of EN1 correlated with short overall survival and increased risk of developing brain metastases in patients with TNBC. Thus, EN1 is a prognostic marker and a potential therapeutic target in TNBC.
Significance:
These findings show that the EN1 transcription factor regulates neurogenesis-related genes and is associated with brain metastasis in triple-negative breast cancer.
Data from MUC1-C Integrates Chromatin Remodeling and PARP1 Activity in the DNA Damage Response of Triple-Negative Breast Cancer Cells
Authors: Yamamoto Masaaki , Jin Caining , Hata Tsuyoshi , Yasumizu Yota , Zhang Yan , Hong Deli , Maeda Takahiro , Miyo Masaaki , Hiraki Masayuki , Suzuki Yozo , Hinohara Kunihiko , Rajabi Hasan , Kufe Donald
Published: March 2023

Abstract
The oncogenic MUC1-C protein is overexpressed in triple-negative breast cancer (TNBC) cells and contributes to their epigenetic reprogramming and chemoresistance. Here we show that targeting MUC1-C genetically or pharmacologically with the GO-203 inhibitor, which blocks MUC1-C nuclear localization, induced DNA double-strand breaks and potentiated cisplatin (CDDP)-induced DNA damage and death. MUC1-C regulated nuclear localization of the polycomb group proteins BMI1 and EZH2, which formed complexes with PARP1 during the DNA damage response. Targeting MUC1-C downregulated BMI1-induced H2A ubiquitylation, EZH2-driven H3K27 trimethylation, and activation of PARP1. As a result, treatment with GO-203 synergistically sensitized both mutant and wild-type BRCA1 TNBC cells to the PARP inhibitor olaparib. These findings uncover a role for MUC1-C in the regulation of PARP1 and identify a therapeutic strategy for enhancing the effectiveness of PARP inhibitors against TNBC.
Significance:
These findings demonstrate that targeting MUC1-C disrupts epigenetics of the PARP1 complex, inhibits PARP1 activity, and is synergistic with olaparib in TNBC cells.
Data from Targeting Glycolysis through Inhibition of Lactate Dehydrogenase Impairs Tumor Growth in Preclinical Models of Ewing Sarcoma
Authors: Yeung Choh , Gibson Anna E. , Issaq Sameer H. , Oshima Nobu , Baumgart Joshua T. , Edessa Leah D. , Rai Ganesha , Urban Daniel J. , Johnson Michelle S. , Benavides Gloria A. , Squadrito Giuseppe L. , Yohe Marielle E. , Lei Haiyan , Eldridge Sandy , Hamre John , Dowdy Tyrone , Ruiz-Rodado Victor , Lita Adrian , Mendoza Arnulfo , Shern Jack F. , Larion Mioara , Helman Lee J. , Stott Gordon M. , Krishna Murali C. , Hall Matthew D. , Darley-Usmar Victor , Neckers Leonard M. , Heske Christine M.
Published: March 2023

Abstract
Altered cellular metabolism, including an increased dependence on aerobic glycolysis, is a hallmark of cancer. Despite the fact that this observation was first made nearly a century ago, effective therapeutic targeting of glycolysis in cancer has remained elusive. One potentially promising approach involves targeting the glycolytic enzyme lactate dehydrogenase (LDH), which is overexpressed and plays a critical role in several cancers. Here, we used a novel class of LDH inhibitors to demonstrate, for the first time, that Ewing sarcoma cells are exquisitely sensitive to inhibition of LDH. EWS-FLI1, the oncogenic driver of Ewing sarcoma, regulated LDH A (LDHA) expression. Genetic depletion of LDHA inhibited proliferation of Ewing sarcoma cells and induced apoptosis, phenocopying pharmacologic inhibition of LDH. LDH inhibitors affected Ewing sarcoma cell viability both in vitro and in vivo by reducing glycolysis. Intravenous administration of LDH inhibitors resulted in the greatest intratumoral drug accumulation, inducing tumor cell death and reducing tumor growth. The major dose-limiting toxicity observed was hemolysis, indicating that a narrow therapeutic window exists for these compounds. Taken together, these data suggest that targeting glycolysis through inhibition of LDH should be further investigated as a potential therapeutic approach for cancers such as Ewing sarcoma that exhibit oncogene-dependent expression of LDH and increased glycolysis.
Significance:
LDHA is a pharmacologically tractable EWS-FLI1 transcriptional target that regulates the glycolytic dependence of Ewing sarcoma.
Data from Melanoma Extracellular Vesicles Generate Immunosuppressive Myeloid Cells by Upregulating PD-L1 via TLR4 Signaling
Authors: Fleming Viktor , Hu Xiaoying , Weller Céline , Weber Rebekka , Groth Christopher , Riester Zeno , Hüser Laura , Sun Qian , Nagibin Vasyl , Kirschning Carsten , Bronte Vincenzo , Utikal Jochen , Altevogt Peter , Umansky Viktor
Published: March 2023

Abstract
Tumor cell–derived extracellular vesicles (EV) convert normal myeloid cells into myeloid-derived suppressor cells (MDSC), inhibiting antitumor immune responses. Here, we show that EV from Ret mouse melanoma cells upregulate the expression of programmed cell death ligand 1 (PD-L1) on mouse immature myeloid cells (IMC), leading to suppression of T-cell activation. PD-L1 expression and the immunosuppressive potential of EV-generated MDSC were dependent on the expression of Toll-like receptors (TLR). IMC from Tlr4−/− mice failed to increase T-cell PD-L1 expression and immunosuppression with Ret-EV treatment, and this effect was dependent on heat-shock protein 86 (HSP86) as HSP86-deficient Ret cells could not stimulate PD-L1 expression on normal IMC; IMC from Tlr2−/− and Tlr7−/− mice demonstrated similar results, although to a lesser extent. HSP86-deficient Ret cells slowed tumor progression in vivo associated with decreased frequency of tumor-infiltrating PD-L1+CD11b+Gr1+ MDSC. EV from human melanoma cells upregulated PD-L1 and immunosuppression of normal monocytes dependent on HSP86. These findings highlight a novel EV-mediated mechanism of MDSC generation from normal myeloid cells, suggesting the importance of EV targeting for tumor therapy.
Significance:
These findings validate the importance of TLR4 signaling in reprogramming normal myeloid cells into functional myeloid-derived suppressor cells.
Data from Precise Spatiotemporal Interruption of Regulatory T-cell–Mediated CD8+ T-cell Suppression Leads to Tumor Immunity
Authors: Zhou Xiaoyu , Zhao Shushu , He Yue , Geng Shuang , Shi Yan , Wang Bin
Published: March 2023

Abstract
Tumors can develop despite the presence of competent host immunity via a complex system of immune evasion. One of the most studied factors originating from the host is immune suppression by regulatory T cells (Treg). Ample laboratory and clinical evidence suggests that Treg ablation leads to robust antitumor immune activation. However, how Tregs specifically achieve their suppression in the context of tumor progression is not entirely clear, particularly with regard to the timing and location where Treg inhibition takes place. In this work, we report that Tregs migrate to tumor-draining lymph nodes (TDLN) and block expression of sphingosine-1-phosphate receptor 1 (S1P1) on CD8+ T cells. This event trapped the CD8+ T cells in the TDLN and served as a facilitating factor for tumor growth. Intriguingly, minimalistic depletion of Tregs in TDLN in a short window following tumor inoculation was sufficient to restore CD8+ T-cell activities, which resulted in significant tumor reduction. Similar treatments outside this time frame had no such effect. Our work therefore reveals a subtle feature in tumor biology whereby Tregs appear to be driven by newly established tumors for a programmed encounter with newly activated CD8+ T cells in TDLN. Our results suggest the possibility that clinical interception of this step can be tested as a new strategy of cancer therapy, with expected high efficacy and low systemic side effects.
Significance:
These findings reveal a strong tumor suppressive effect invoked by minimal blockade of tumor draining lymph node regulatory T cells during early versus late tumorigenesis.
Data from Mesenchymal Stem Cell–Mediated Delivery of an Oncolytic Adenovirus Enhances Antitumor Efficacy in Hepatocellular Carcinoma
Authors: Yoon A-Rum , Hong JinWoo , Li Yan , Shin Ha Chul , Lee Hyunah , Kim Hyun Soo , Yun Chae-Ok
Published: March 2023

Abstract
Oncolytic virotherapy is a promising alternative to conventional treatment, yet systemic delivery of these viruses to tumors remains a major challenge. In this regard, mesenchymal stem cells (MSC) with well-established tumor-homing property could serve as a promising systemic delivery tool. We showed that MSCs could be effectively infected by hepatocellular carcinoma (HCC)-targeted oncolytic adenovirus (HCC-oAd) through modification of the virus' fiber domain and that the virus replicated efficiently in the cell carrier. HCC-targeting oAd loaded in MSCs (HCC-oAd/MSC) effectively lysed HCC cells in vitro under both normoxic and hypoxic conditions as a result of the hypoxia responsiveness of HCC-oAd. Importantly, systemically administered HCC-oAd/MSC, which were initially infected with a low viral dose, homed to HCC tumors and resulted in a high level of virion accumulation in the tumors, ultimately leading to potent tumor growth inhibition. Furthermore, viral dose reduction and tumor localization of HCC-oAd/MSC prevented the induction of hepatotoxicity by attenuating HCC-oAd hepatic accumulation. Taken together, these results demonstrate that MSC-mediated systemic delivery of oAd is a promising strategy for achieving synergistic antitumor efficacy with improved safety profiles.
Significance:
Mesenchymal stem cells enable delivery of an oncolytic adenovirus specifically to the tumor without posing any risk associated with systemic administration of naked virions to the host.
Data from EZH2 Inhibitor GSK126 Suppresses Antitumor Immunity by Driving Production of Myeloid-Derived Suppressor Cells
Authors: Huang Shuo , Wang Zhongyu , Zhou Jie , Huang Jiani , Zhou Li , Luo Jing , Wan Yisong Y. , Long Haixia , Zhu Bo
Published: March 2023

Abstract
Enhancer of zeste homolog (EZH2) is a key epigenetic regulator of gene expression and is frequently overexpressed in various cancer types, suggesting a role in oncogenesis. The therapeutic potential of EZH2 inhibitors is currently being explored, but their effect on antitumor immunity is largely unknown. Here we report that suppressing EZH2 activity using EZH2 inhibitor GSK126 resulted in increased numbers of myeloid-derived suppressor cells (MDSC) and fewer CD4+ and IFNγ+CD8+ T cells, which are involved in antitumor immunity. Addition of a neutralizing antibody against the myeloid differentiation antigen GR-1 or gemcitabine/5-fluorouracil–depleted MDSCs alleviated MDSC-mediated immunosuppression and increased CD4+ and CD8+ T-cell tumor infiltration and GSK126 therapeutic efficacy. Mechanistically, we identified a novel pathway of MDSC production in cancer in which EZH2 inhibition directs myeloid differentiation from primitive hematopoietic progenitor cells. These findings suggest that modulating the tumor immune microenvironment may improve the efficacy of EZH2 inhibitors.
Significance:
This study uncovers a potential mechanism behind disappointing results of a phase I clinical trial of EZH2 inhibitor GSK126 and identifies a translatable combinational strategy to overcome it.
Data from Collagen Remodeling in the Hypoxic Tumor-Mesothelial Niche Promotes Ovarian Cancer Metastasis
Authors: Natarajan Suchitra , Foreman Kaitlyn M. , Soriano Michaela I. , Rossen Ninna S. , Shehade Hussein , Fregoso Daniel R. , Eggold Joshua T. , Krishnan Venkatesh , Dorigo Oliver , Krieg Adam J. , Heilshorn Sarah C. , Sinha Subarna , Fuh Katherine C. , Rankin Erinn B.
Published: March 2023

Abstract
Peritoneal metastases are the leading cause of morbidity and mortality in high-grade serous ovarian cancer (HGSOC). Accumulating evidence suggests that mesothelial cells are an important component of the metastatic microenvironment in HGSOC. However, the mechanisms by which mesothelial cells promote metastasis are unclear. Here, we report that the HGSOC tumor-mesothelial niche was hypoxic, and hypoxic signaling enhanced collagen I deposition by mesothelial cells. Specifically, hypoxic signaling increased expression of lysyl oxidase (LOX) in mesothelial and ovarian cancer cells to promote collagen crosslinking and tumor cell invasion. The mesothelial niche was enriched with fibrillar collagen in human and murine omental metastases. Pharmacologic inhibition of LOX reduced tumor burden and collagen remodeling in murine omental metastases. These findings highlight an important role for hypoxia and mesothelial cells in the modification of the extracellular matrix and tumor invasion in HGSOC.
Significance:
This study identifies HIF/LOX signaling as a potential therapeutic target to inhibit collagen remodeling and tumor progression in HGSOC.
Data from A Genome-Wide Association Study Identifies Two Novel Susceptible Regions for Squamous Cell Carcinoma of the Head and Neck
Authors: Shete Sanjay , Liu Hongliang , Wang Jian , Yu Robert , Sturgis Erich M. , Li Guojun , Dahlstrom Kristina R. , Liu Zhensheng , Amos Christopher I. , Wei Qingyi
Published: March 2023

Abstract
To identify genetic variants for risk of squamous cell carcinoma of the head and neck (SCCHN), we conducted a two-phase genome-wide association study consisting of 7,858,089 SNPs in 2,171 cases and 4,493 controls of non-Hispanic white, of which, 434,839 typed and 7,423,250 imputed SNPs were used as the discovery. SNPs with P < 1 × 10−3 were further validated in the OncoArray study of oral and pharynx cancer (5,205 cases and 3,232 controls of European ancestry) from databases of Genotypes and Phenotypes. Meta-analysis of the discovery and replication studies identified one novel locus 6p22.1 (P = 2.96 × 10−9 for the leading rs259919) and two cancer susceptibility loci 6p21.32 (rs3135001, HLA-DQB1) and 6p21.33 (rs1265081, CCHCR1) associated with SCCHN risk. Further stratification by tumor site revealed four known cancer loci (5p15.33, 6p21.32, 6p21.33, and 2p23.1) associated with oral cavity cancer risk and oropharyngeal cancer risk, respectively. In addition, one novel locus 18q22.2 (P = 2.54 × 10−9 for the leading SNP rs142021700) was identified for hypopharynx and larynx cancer risk. For SNPs in those reported or novel loci, we also performed functional annotations by bioinformatics prediction and expression quantitative trait loci analysis. Collectively, our identification of four reported loci (2p23.1, 5p15.33, 6p21.32, and 6p21.33) and two novel loci (6p22.1 and 18q22.2) for SCCHN risk highlight the importance of human leukocyte antigen loci for oropharyngeal cancer risk, suggesting that immunologic mechanisms are implicated in the etiology of this subset of SCCHN.
Significance:
Two novel risk loci for SCCHN in non-Hispanic white individuals highlight the importance of immunologic mechanism in the disease etiology.
Data from A DNA Repair and Cell-Cycle Gene Expression Signature in Primary and Recurrent Glioblastoma: Prognostic Value and Clinical Implications
Authors: Gobin Matthieu , Nazarov Petr V. , Warta Rolf , Timmer Marco , Reifenberger Guido , Felsberg Joerg , Vallar Laurent , Chalmers Anthony J. , Herold-Mende Christel C. , Goldbrunner Roland , Niclou Simone P. , Van Dyck Eric
Published: March 2023

Abstract
Inevitable tumor recurrence and a poor median survival are frustrating reminders of the inefficacy of our current standard of care for patients with newly diagnosed glioblastoma (GBM), which includes surgery followed by radiotherapy and chemotherapy with the DNA alkylating agent temozolomide. Because resistance to genotoxic damage is achieved mainly through execution of the DNA damage response (DDR) and DNA repair pathways, knowledge of the changes in DNA repair and cell-cycle gene expression that occur during tumor development might help identify new targets and improve treatment. Here, we performed a gene expression analysis targeting components of the DNA repair and cell-cycle machineries in cohorts of paired tumor samples (i.e., biopsies from the same patient obtained at the time of primary tumor operation and at recurrence) from patients treated with radiotherapy or radiotherapy plus temozolomide. We identified and validated a 27-gene signature that resulted in the classification of GBM specimens into three groups, two of which displayed inverse expression profiles. Each group contained primary and recurrent samples, and the tumor at relapse frequently displayed a gene expression profile different from that of the matched primary biopsy. Within the groups that exhibited opposing gene expression profiles, the expression pattern of the gene signature at relapse was linked to progression-free survival. We provide experimental evidence that our signature exposes group-specific vulnerabilities against genotoxicants and inhibitors of the cell cycle and DDR, with the prospect of personalized therapeutic strategies.

Significance: These findings suggest that classification of GBM tumors based on a DNA repair and cell-cycle gene expression signature exposes vulnerabilities to standard-of-care therapies and offers the potential for personalized therapeutic strategies.
Data from HDAC10 Regulates Cancer Stem-Like Cell Properties in KRAS-Driven Lung Adenocarcinoma
Authors: Li Yixuan , Zhang Xiangyang , Zhu Shaoqi , Dejene Eden A. , Peng Weiqun , Sepulveda Antonia , Seto Edward
Published: March 2023

Abstract
Activation of oncogenic KRAS is the most common driving event in lung adenocarcinoma development. Despite the existing rationale for targeting activated KRAS and its downstream effectors, the failure of clinical trials to date indicates that the mechanism of KRAS-driven malignancy remains poorly understood. Here we report that histone deacetylase 10 (HDAC10) might function as a putative tumor suppressor in mice carrying a spontaneously activated oncogenic Kras allele. Hdac10 deletion accelerated KRAS-driven early-onset lung adenocarcinomas, increased macrophage infiltration in the tumor microenvironment, and shortened survival time in mice. Highly tumorigenic and stem-like lung adenocarcinoma cells were increased in Hdac10-deleted tumors compared with Hdac10 wild-type tumors. HDAC10 regulated the stem-like properties of KRAS-expressing tumor cells by targeting SOX9. Expression of SOX9 was significantly increased in Hdac10-deleted tumor cells and depletion of SOX9 in Hdac10 knockout (KO) lung adenocarcinoma cells inhibited growth of tumorspheres. The genes associated with TGFβ pathway were enriched in Hdac10 KO tumor cells, and activation of TGFβ signaling contributed to SOX9 induction in Hdac10 KO lung adenocarcinoma cells. Overall, our study evaluates the functions and mechanisms of action of HDAC10 in lung carcinogenesis that will inform the rationale for targeting its related regulatory signaling as an anticancer strategy.
Significance:
These findings linking HDAC10 and lung tumorigenesis identify potential novel strategies for targeting HDAC10 as a treatment for lung cancer.
Data from Inactivation of the Prolyl Isomerase Pin1 Sensitizes BRCA1-Proficient Breast Cancer to PARP Inhibition
Authors: Luo Man-Li , Zheng Fang , Chen Wenying , Liang Zhi-Mei , Chandramouly Gurushankar , Tan Jianan , Willis Nicholas A. , Chen Chun-Hau , Taveira Mateus de Oliveira , Zhou Xiao Zhen , Lu Kun Ping , Scully Ralph , Wulf Gerburg M. , Hu Hai
Published: March 2023

Abstract
PARP inhibitor monotherapies are effective to treat patients with breast, ovary, prostate, and pancreatic cancer with BRCA1 mutations, but not to the much more frequent BRCA wild-type cancers. Searching for strategies that would extend the use of PARP inhibitors to BRCA1-proficient tumors, we found that the stability of BRCA1 protein following ionizing radiation (IR) is maintained by postphosphorylational prolyl-isomerization adjacent to Ser1191 of BRCA1, catalyzed by prolyl-isomerase Pin1. Extinction of Pin1 decreased homologous recombination (HR) to the level of BRCA1-deficient cells. Pin1 stabilizes BRCA1 by preventing ubiquitination of Lys1037 of BRCA1. Loss of Pin1, or introduction of a BRCA1-mutant refractory to Pin1 binding, decreased the ability of BRCA1 to localize to repair foci and augmented IR-induced DNA damage. In vitro growth of HR-proficient breast, prostate, and pancreatic cancer cells were modestly repressed by olaparib or Pin1 inhibition using all-trans retinoic acid (ATRA), while combination treatment resulted in near-complete block of cell proliferation. In MDA-MB-231 xenografts and triple-negative breast cancer patient-derived xenografts, either loss of Pin1 or ATRA treatment reduced BRCA1 expression and sensitized breast tumors to olaparib. Together, our study reveals that Pin1 inhibition, with clinical widely used ATRA, acts as an effective HR disrupter that sensitizes BRCA1-proficient tumors to PARP inhibition.
Significance:
PARP inhibitors have been limited to treat homologous recombination–deficient tumors. All-trans retinoic acid, by inhibiting Pin1 and destabilizing BRCA1, extends benefit of PARP inhibitors to patients with homologous recombination–proficient tumors.

See related commentary by Cai, p. 2977
Data from Myeloid Cell–Derived TGFβ Signaling Regulates ECM Deposition in Mammary Carcinoma via Adenosine-Dependent Mechanisms
Authors: Vasiukov Georgii , Novitskaya Tatiana , Zijlstra Andries , Owens Philip , Ye Fei , Zhao Zhiguo , Moses Harold L. , Blackwell Timothy , Feoktistov Igor , Novitskiy Sergey V.
Published: March 2023

Abstract
TGFβ plays a crucial role in the tumor microenvironment by regulating cell–cell and cell–stroma interactions. We previously demonstrated that TGFβ signaling on myeloid cells regulates expression of CD73, a key enzyme for production of adenosine, a protumorigenic metabolite implicated in regulation of tumor cell behaviors, immune response, and angiogenesis. Here, using an MMTV-PyMT mouse mammary tumor model, we discovered that deletion of TGFβ signaling on myeloid cells (PyMT/TGFβRIILysM) affects extracellular matrix (ECM) formation in tumor tissue, specifically increasing collagen and decreasing fibronectin deposition. These changes were associated with mitigated tumor growth and reduced metastases. Reduced TGFβ signaling on fibroblasts was associated with their proximity to CD73+ myeloid cells in tumor tissue. Consistent with these findings, adenosine significantly downregulated TGFβ signaling on fibroblasts, an effect regulated by A2A and A2B adenosine receptors. METABRIC dataset analysis revealed that patients with triple-negative breast cancer and basal type harbored a similar signature of adenosine and ECM profiles; high expression of A2B adenosine receptors correlated with decreased expression of Col1 and was associated with poor outcome. Taken together, our studies reveal a new role for TGFβ signaling on myeloid cells in tumorigenesis. This discovered cross-talk between TGFβ/CD73 on myeloid cells and TGFβ signaling on fibroblasts can contribute to ECM remodeling and protumorigenic actions of cancer-associated fibroblasts.
Significance:
TGFβ signaling on fibroblasts is decreased in breast cancer, correlates with poor prognosis, and appears to be driven by adenosine that accelerates tumor progression and metastasis via ECM remodeling.
Data from A Protease-Activated Fluorescent Probe Allows Rapid Visualization of Keratinocyte Carcinoma during Excision
Authors: Walker Ethan , Liu Yiqiao , Kim InYoung , Biro Mark , Iyer Sukanya Raj , Ezaldein Harib , Scott Jeffrey , Merati Miesha , Mistur Rachel , Zhou Bo , Straight Brian , Yim Joshua J. , Bogyo Matthew , Mann Margaret , Wilson David L. , Basilion James P. , Popkin Daniel L.
Published: March 2023

Abstract
Keratinocyte carcinomas, including basal and squamous cell carcinomas, are the most common human cancers worldwide. While 75% of all keratinocyte carcinoma (4 million annual cases in the United States) are treated with conventional excision, this surgical modality has much lower cure rates than Mohs micrographic surgery, likely due to the bread-loaf histopathologic assessment that visualizes <1% of the tissue margins. A quenched protease-activated fluorescent probe 6qcNIR, which produces a signal only in the protease-rich tumor microenvironment, was topically applied to 90 specimens ex vivo immediately following excision. “Puzzle-fit” analysis was used to correlate the fluorescent images with histology. Probe-dependent fluorescent images correlated with cancer determined by conventional histology. Point-of-care fluorescent detection of skin cancer had a clinically relevant sensitivity of 0.73 and corresponding specificity of 0.88. Importantly, clinicians were effectively trained to read fluorescent images within 15 minutes with reliability and confidence, resulting in sensitivities of 62%–78% and specificities of 92%–97%. Fluorescent imaging using 6qcNIR allows 100% tumor margin assessment by generating en face images that correlate with histology and may be used to overcome the limitations of conventional bread-loaf histology. The utility of 6qcNIR was validated in a busy real-world clinical setting, and clinicians were trained to effectively read fluorescent margins with a short guided instruction, highlighting clinical adaptability. When used in conventional excision, this approach may result in higher cure rates at a lower cost by allowing same-day reexcision when needed, reducing patient anxiety and improving compliance by expediting postsurgical specimen assessment.
Significance:
A fluorescent-probe-tumor-visualization platform was developed and validated in human keratinocyte carcinoma excision specimens that may provide simple, rapid, and global assessment of margins during skin cancer excision, allowing same-day reexcision when needed.
Data from EIF3H Orchestrates Hippo Pathway–Mediated Oncogenesis via Catalytic Control of YAP Stability
Authors: Zhou Zhuan , Zhou Honghong , Ponzoni Luca , Luo Aiping , Zhu Rui , He Mingjing , Huang Yi , Guan Kun-Liang , Bahar Ivet , Liu Zhihua , Wan Yong
Published: March 2023

Abstract
EIF3H is presumed to be a critical translational initiation factor. Here, our unbiased screening for tumor invasion factors has identified an unexpected role for EIF3H as a deubiquitylating enzyme that dictates breast tumor invasion and metastasis by modulating the Hippo–YAP pathway. EIF3H catalyzed YAP for deubiquitylation, resulting in its stabilization. Structure-based molecular modeling and simulations coupled with biochemical characterization unveiled a unique catalytic mechanism for EIF3H in dissociating polyubiquitin chains from YAP through a catalytic triad consisting of Asp90, Asp91, and Gln121. Trp119 and Tyr 140 on EIF3H directly interacted with the N-terminal region of YAP1, facilitating complex formation of EIF3H and YAP1 for YAP1 deubiquitylation. Stabilization of YAP via elevated EIF3H promoted tumor invasion and metastasis. Interference of EIF3H-mediated YAP deubiquitylation blocked YAP-induced tumor progression and metastasis in breast cancer models. These findings point to a critical role for YAP regulation by EIF3H in tumor invasion and metastasis.
Significance:
This work demonstrates that EIF3H is a novel bona fide deubiquitinase that counteracts YAP ubiquitylation and proteolysis, and stabilization of YAP by EIF3H promotes tumor invasion and metastasis.
Data from Negative Regulation of p53-Induced Senescence by N-WASP Is Crucial for DMBA/TPA-Induced Skin Tumor Formation
Authors: Li Hui , Petersen Simon , Garcia Mariscal Alberto , Brakebusch Cord
Published: March 2023

Abstract
Mice with a keratinocyte-restricted deletion of the actin polymerization–promoting molecule, N-WASP, display cyclic hair loss and skin inflammation. Here, we showed that these mice were also resistant to 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)–induced skin tumor formation. This resistance correlated with decreased expression of the senescence regulator, DNMT1, and increased expression of the senescence marker, p16Ink4a, in N-WASP–deficient epidermis. Moreover, primary N-WASP–null keratinocytes displayed a premature senescence phenotype in vitro. Expression and activation of p53, a major inducer of senescence, was not significantly altered in N-WASP–null keratinocytes. However, impairment of p53 function effectively rescued the senescence phenotype, indicating that N-WASP was an inhibitor of p53-induced senescence. Mechanistically, N-WASP regulated senescence by preventing p53-dependent degradation of the H3K9 methyltransferases, G9a/GLP, and the DNA methyltransferase, DNMT1, which both control keratinocyte senescence. This pathway collaborated with other N-WASP–independent, senescence-promoting signaling downstream of p53 and allowed the fine tuning of p53-induced senescence by N-WASP. Collectively, these data reveal N-WASP as an inhibitor of p53-induced senescence, which might be of importance for skin tumor formation and cellular aging of keratinocytes.
Significance:
These findings demonstrate that N-WASP regulates p53-dependent senescence in keratinocytes in vitro and in vivo.
Data from MYC Drives Group 3 Medulloblastoma through Transformation of Sox2+ Astrocyte Progenitor Cells
Authors: Tao Ran , Murad Najiba , Xu Zhenhua , Zhang Peng , Okonechnikov Konstantin , Kool Marcel , Rivero-Hinojosa Samuel , Lazarski Christopher , Zheng Pan , Liu Yang , Eberhart Charles G. , Rood Brian R. , Packer Roger , Pei Yanxin
Published: March 2023

Abstract
A subset of group 3 medulloblastoma frequently harbors amplification or overexpression of MYC lacking additional focal aberrations, yet it remains unclear whether MYC overexpression alone can induce tumorigenesis and which cells give rise to these tumors. Here, we showed that astrocyte progenitors in the early postnatal cerebellum were susceptible to transformation by MYC. The resulting tumors specifically resembled human group 3 medulloblastoma based on histology and gene-expression profiling. Gene-expression analysis of MYC-driven medulloblastoma cells revealed altered glucose metabolic pathways with marked overexpression of lactate dehydrogenase A (LDHA). LDHA abundance correlated positively with MYC expression and was associated with poor prognosis in human group 3 medulloblastoma. Inhibition of LDHA significantly reduced growth of both mouse and human MYC-driven tumors but had little effect on normal cerebellar cells or SHH-associated medulloblastoma. By generating a new mouse model, we demonstrated for the first time that astrocyte progenitors can be transformed by MYC and serve as the cells of origin for group 3 medulloblastoma. Moreover, we identified LDHA as a novel, specific therapeutic target for this devastating disease.
Significance:
Insights from a new model identified LDHA as a novel target for group 3 medulloblastoma, paving the way for the development of effective therapies against this disease.
Data from Enhanced Fatty Acid Scavenging and Glycerophospholipid Metabolism Accompany Melanocyte Neoplasia Progression in Zebrafish
Authors: Henderson Fiona , Johnston Hannah R. , Badrock Andrew P. , Jones Emrys A. , Forster Duncan , Nagaraju Raghavendar T. , Evangelou Christos , Kamarashev Jivko , Green Michael , Fairclough Michael , Ramirez Irene Barinaga-Rementeria , He Shuning , Snaar-Jagalska B. Ewa , Hollywood Katherine , Dunn Warwick B. , Spaink Herman P. , Smith Michael P. , Lorigan Paul , Claude Emmanuelle , Williams Kaye J. , McMahon Adam W. , Hurlstone Adam
Published: March 2023

Abstract
Alterations in lipid metabolism in cancer cells impact cell structure, signaling, and energy metabolism, making lipid metabolism a potential diagnostic marker and therapeutic target. In this study, we combined PET, desorption electrospray ionization-mass spectrometry (DESI-MS), nonimaging MS, and transcriptomic analyses to interrogate changes in lipid metabolism in a transgenic zebrafish model of oncogenic RAS-driven melanocyte neoplasia progression. Exogenous fatty acid uptake was detected in melanoma tumor nodules by PET using the palmitic acid surrogate tracer 14(R,S)-18F-fluoro-6-thia-heptadecanoic acid ([18F]-FTHA), consistent with upregulation of genes associated with fatty acid uptake found through microarray analysis. DESI-MS imaging revealed that FTHA uptake in tumors was heterogeneous. Transcriptome and lipidome analyses further highlighted dysregulation of glycerophospholipid pathways in melanoma tumor nodules, including increased abundance of phosphatidyl ethanolamine and phosphatidyl choline species, corroborated by DESI-MS, which again revealed heterogeneous phospholipid composition in tumors. Overexpression of the gene encoding lipoprotein lipase (LPL), which was upregulated in zebrafish melanocyte tumor nodules and expressed in the majority of human melanomas, accelerated progression of oncogenic RAS-driven melanocyte neoplasia in zebrafish. Depletion or antagonism of LPL suppressed human melanoma cell growth; this required simultaneous fatty acid synthase (FASN) inhibition when FASN expression was also elevated. Collectively, our findings implicate fatty acid acquisition as a possible therapeutic target in melanoma, and the methods we developed for monitoring fatty acid uptake have potential for diagnosis, patient stratification, and monitoring pharmacologic response.
Significance:
These findings demonstrate the translational potential of monitoring fatty acid uptake and identify lipoprotein lipase as a potential therapeutic target in melanoma.
Data from Tumor Cell–Derived Angiopoietin-2 Promotes Metastasis in Melanoma
Authors: Abdul Pari Ashik Ahmed , Singhal Mahak , Hübers Corinne , Mogler Carolin , Schieb Benjamin , Gampp Anja , Gengenbacher Nicolas , Reynolds Louise E. , Terhardt Dorothee , Géraud Cyrill , Utikal Jochen , Thomas Markus , Goerdt Sergij , Hodivala-Dilke Kairbaan M. , Augustin Hellmut G. , Felcht Moritz
Published: March 2023

Abstract
The angiopoietin (Angpt)–TIE signaling pathway controls vascular maturation and maintains the quiescent phenotype of resting vasculature. The contextual agonistic and antagonistic Tie2 ligand ANGPT2 is believed to be exclusively produced by endothelial cells, disrupting constitutive ANGPT1–TIE2 signaling to destabilize the microvasculature during pathologic disorders like inflammation and cancer. However, scattered reports have also portrayed tumor cells as a source of ANGPT2. Employing ISH-based detection of ANGPT2, we found strong tumor cell expression of ANGPT2 in a subset of patients with melanoma. Comparative analysis of biopsies revealed a higher fraction of ANGPT2-expressing tumor cells in metastatic versus primary sites. Tumor cell–expressed Angpt2 was dispensable for primary tumor growth, yet in-depth analysis of primary tumors revealed enhanced intratumoral necrosis upon silencing of tumor cell Angpt2 expression in the absence of significant immune and vascular alterations. Global transcriptional profiling of Angpt2-deficient tumor cells identified perturbations in redox homeostasis and an increased response to cellular oxidative stress. Ultrastructural analyses illustrated a significant increase of dysfunctional mitochondria in Angpt2-silenced tumor cells, thereby resulting in enhanced reactive oxygen species (ROS) production and downstream MAPK stress signaling. Functionally, enhanced ROS in Angpt2-silenced tumor cells reduced colonization potential in vitro and in vivo. Taken together, these findings uncover the hitherto unappreciated role of tumor cell–expressed ANGPT2 as an autocrine-positive regulator of metastatic colonization and validate ANGPT2 as a therapeutic target for a well-defined subset of patients with melanoma.
Significance:
This study reveals that tumor cells can be a source of ANGPT2 in the tumor microenvironment and that tumor cell-derived ANGPT2 augments metastatic colonization by protecting tumor cells from oxidative stress.
Data from Transcriptome-Wide Association Study Identifies New Candidate Susceptibility Genes for Glioma
Authors: Atkins Isabelle , Kinnersley Ben , Ostrom Quinn T. , Labreche Karim , Il'yasova Dora , Armstrong Georgina N. , Eckel-Passow Jeanette E. , Schoemaker Minouk J. , Nöthen Markus M. , Barnholtz-Sloan Jill S. , Swerdlow Anthony J. , Simon Matthias , Rajaraman Preetha , Chanock Stephen J. , Shildkraut Joellen , Bernstein Jonine L. , Hoffmann Per , Jöckel Karl-Heinz , Lai Rose K. , Claus Elizabeth B. , Olson Sara H. , Johansen Christoffer , Wrensch Margaret R. , Melin Beatrice , Jenkins Robert B. , Sanson Marc , Bondy Melissa L. , Houlston Richard S.
Published: March 2023

Abstract
Genome-wide association studies (GWAS) have so far identified 25 loci associated with glioma risk, with most showing specificity for either glioblastoma (GBM) or non-GBM tumors. The majority of these GWAS susceptibility variants reside in noncoding regions and the causal genes underlying the associations are largely unknown. Here we performed a transcriptome-wide association study to search for novel risk loci and candidate causal genes at known GWAS loci using Genotype-Tissue Expression Project (GTEx) data to predict cis-predicted gene expression in relation to GBM and non-GBM risk in conjunction with GWAS summary statistics on 12,488 glioma cases (6,183 GBM and 5,820 non-GBM) and 18,169 controls. Imposing a Bonferroni-corrected significance level of P < 5.69 × 10−6, we identified 31 genes, including GALNT6 at 12q13.33, as a candidate novel risk locus for GBM (mean Z = 4.43; P = 5.68 × 10−6). GALNT6 resides at least 55 Mb away from any previously identified glioma risk variant, while all other 30 significantly associated genes were located within 1 Mb of known GWAS-identified loci and were not significant after conditioning on the known GWAS-identified variants. These data identify a novel locus (GALNT6 at 12q13.33) and 30 genes at 12 known glioma risk loci associated with glioma risk, providing further insights into glioma tumorigenesis.
Significance:
This study identifies new genes associated with glioma risk, increasing understanding of how these tumors develop.
Data from ICOS Is an Indicator of T-cell–Mediated Response to Cancer Immunotherapy
Authors: Xiao Zunyu , Mayer Aaron T. , Nobashi Tomomi W. , Gambhir Sanjiv S.
Published: March 2023

Abstract
Immunotherapy is innovating clinical cancer management. Nevertheless, only a small fraction of patient's benefit from current immunotherapies. To improve clinical management of cancer immunotherapy, it is critical to develop strategies for response monitoring and prediction. In this study, we describe inducible T-cell costimulator (ICOS) as a conserved mediator of immune response across multiple therapy strategies. ICOS expression was evaluated by flow cytometry, 89Zr-DFO-ICOS mAb PET/CT imaging was performed on Lewis lung cancer models treated with different immunotherapy strategies, and the change in tumor volume was used as a read-out for therapeutic response. ImmunoPET imaging of ICOS enabled sensitive and specific detection of activated T cells and early benchmarking of immune response. A STING (stimulator of interferon genes) agonist was identified as a promising therapeutic approach in this manner. The STING agonist generated significantly stronger immune responses as measured by ICOS ImmunoPET and delayed tumor growth compared with programmed death-1 checkpoint blockade. More importantly, ICOS ImmunoPET enabled early and robust prediction of therapeutic response across multiple treatment regimens. These data show that ICOS is an indicator of T-cell–mediated immune response and suggests ICOS ImmunoPET as a promising strategy for monitoring, comparing, and predicting immunotherapy success in cancer.
Significance:
ICOS ImmunoPET is a promising strategy to noninvasively predict and monitor immunotherapy response.

See related commentary by Choyke, p. 2975