bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Selective Targeting of Myoblast Fusogenic Signaling and Differentiation-Arrest Antagonizes Rhabdomyosarcoma Cells
Authors: Granados Valerie A. , Avirneni-Vadlamudi Usha , Dalal Pooja , Scarborough Samuel R. , Galindo Kathleen A. , Mahajan Priya , Galindo Rene L.
Published: March 2024

Abstract
Rhabdomyosarcoma (RMS) is an aggressive soft tissue malignancy comprised histologically of skeletal muscle lineage precursors that fail to exit the cell cycle and fuse into differentiated syncytial muscle—for which the underlying pathogenetic mechanisms remain unclear. In contrast to myogenic transcription factor signaling, the molecular machinery that orchestrates the discrete process of myoblast fusion in mammals is poorly understood and unexplored in RMS. The fusogenic machinery in Drosophila, however, is understood in much greater detail, where myoblasts are divided into two distinct pools, founder cells (FC) and fusion competent myoblasts (fcm). Fusion is heterotypic and only occurs between FCs and fcms. Here, we interrogated a comprehensive RNA-sequencing database and found that human RMS diffusely demonstrates an FC lineage gene signature, revealing that RMS is a disease of FC lineage rhabdomyoblasts. We next exploited our Drosophila RMS-related model to isolate druggable FC-specific fusogenic elements underlying RMS, which uncovered the EGFR pathway. Using RMS cells, we showed that EGFR inhibitors successfully antagonized RMS RD cells, whereas other cell lines were resistant. EGFR inhibitor–sensitive cells exhibited decreased activation of the EGFR intracellular effector Akt, whereas Akt activity remained unchanged in inhibitor-resistant cells. We then demonstrated that Akt inhibition antagonizes RMS—including RMS resistant to EGFR inhibition—and that sustained activity of the Akt1 isoform preferentially blocks rhabdomyoblast differentiation potential in cell culture and in vivo. These findings point towards selective targeting of fusion- and differentiation-arrest via Akt as a broad RMS therapeutic vulnerability.
Significance:
EGFR and its downstream signaling mediator AKT1 play a role in the fusion and differentiation processes of rhabdomyosarcoma cells, representing a therapeutic vulnerability of rhabdomyosarcoma.
Data from Oncogenic MYC Induces the Impaired Ribosome Biogenesis Checkpoint and Stabilizes p53 Independent of Increased Ribosome Content
Authors: Morcelle Carmen , Menoyo Sandra , Morón-Duran Francisco D. , Tauler Albert , Kozma Sara C. , Thomas George , Gentilella Antonio
Published: March 2024

Abstract
The role of MYC in regulating p53 stability as a function of increased ribosome biogenesis is controversial. On the one hand, it was suggested that MYC drives the overexpression of ribosomal proteins (RP)L5 and RPL11, which bind and inhibit HDM2, stabilizing p53. On the other, it has been proposed that increased ribosome biogenesis leads the consumption of RPL5/RPL11 into nascent ribosomes, reducing p53 levels and enhancing tumorigenesis. Here, we show that the components that make up the recently described impaired ribosome biogenesis checkpoint (IRBC) complex, RPL5, RPL11, and 5S rRNA, are reduced following MYC silencing. This leads to a rapid reduction in p53 protein half-life in an HDM2-dependent manner. In contrast, MYC induction leads to increased ribosome biogenesis and p53 protein stabilization. Unexpectedly, there is no change in free RPL5/RPL11 levels, but there is a striking increase in IRBC complex bound to HDM2. Our data support a cell-intrinsic tumor-suppressor response to MYC expression, which is presently being exploited to treat cancer.
Significance:
Oncogenic MYC induces the impaired ribosome biogenesis checkpoint, which could be potentially targeted for cancer treatment.
Data from Toward Personalized Computer Simulation of Breast Cancer Treatment: A Multiscale Pharmacokinetic and Pharmacodynamic Model Informed by Multitype Patient Data
Authors: Lai Xiaoran , Geier Oliver M. , Fleischer Thomas , Garred Øystein , Borgen Elin , Funke Simon W. , Kumar Surendra , Rognes Marie E. , Seierstad Therese , Børresen-Dale Anne-Lise , Kristensen Vessela N. , Engebraaten Olav , Köhn-Luque Alvaro , Frigessi Arnoldo
Published: March 2024

Abstract
The usefulness of mechanistic models to disentangle complex multiscale cancer processes, such as treatment response, has been widely acknowledged. However, a major barrier for multiscale models to predict treatment outcomes in individual patients lies in their initialization and parametrization, which needs to reflect individual cancer characteristics accurately. In this study, we use multitype measurements acquired routinely on a single breast tumor, including histopathology, MRI, and molecular profiling, to personalize parts of a complex multiscale model of breast cancer treated with chemotherapeutic and antiangiogenic agents. The model accounts for drug pharmacokinetics and pharmacodynamics. We developed an open-source computer program that simulates cross-sections of tumors under 12-week therapy regimens and used it to individually reproduce and elucidate treatment outcomes of 4 patients. Two of the tumors did not respond to therapy, and model simulations were used to suggest alternative regimens with improved outcomes dependent on the tumor's individual characteristics. It was determined that more frequent and lower doses of chemotherapy reduce tumor burden in a low proliferative tumor while lower doses of antiangiogenic agents improve drug penetration in a poorly perfused tumor. Furthermore, using this model, we were able to correctly predict the outcome in another patient after 12 weeks of treatment. In summary, our model bridges multitype clinical data to shed light on individual treatment outcomes.
Significance:
Mathematical modeling is used to validate possible mechanisms of tumor growth, resistance, and treatment outcome.
Data from An ERG Enhancer–Based Reporter Identifies Leukemia Cells with Elevated Leukemogenic Potential Driven by ERG-USP9X Feed-Forward Regulation
Authors: Aqaqe Nasma , Yassin Muhammad , Yassin Abed Alkader , Ershaid Nour , Katz-Even Chen , Zipin-Roitman Adi , Kugler Eitan , Lechman Eric R. , Gan Olga I. , Mitchell Amanda , Dick John E. , Izraeli Shai , Milyavsky Michael
Published: March 2024

Abstract
Acute leukemia is a rapidly progressing blood cancer with low survival rates. Unfavorable prognosis is attributed to insufficiently characterized subpopulations of leukemia stem cells (LSC) that drive chemoresistance and leukemia relapse. Here we utilized a genetic reporter that assesses stemness to enrich and functionally characterize LSCs. We observed heterogeneous activity of the ERG+85 enhancer–based fluorescent reporter in human leukemias. Cells with high reporter activity (tagBFPHigh) exhibited elevated expression of stemness and chemoresistance genes and demonstrated increased clonogenicity and resistance to chemo- and radiotherapy as compared with their tagBFPNeg counterparts. The tagBFPHigh fraction was capable of regenerating the original cellular heterogeneity and demonstrated increased invasive ability. Moreover, the tagBFPHigh fraction was enriched for leukemia-initiating cells in a xenograft assay. We identified the ubiquitin hydrolase USP9X as a novel ERG transcriptional target that sustains ERG+85–positive cells by controlling ERG ubiquitination. Therapeutic targeting of USP9X led to preferential inhibition of the ERG-dependent leukemias. Collectively, these results characterize human leukemia cell functional heterogeneity and suggest that targeting ERG via USP9X inhibition may be a potential treatment strategy in patients with leukemia.
Significance:
This study couples a novel experimental tool with state-of-the-art approaches to delineate molecular mechanisms underlying stem cell-related characteristics in leukemia cells.
Data from DNA Methylation Controls Metastasis-Suppressive 14q32-Encoded miRNAs
Authors: Oshima Go , Poli Elizabeth C. , Bolt Michael J. , Chlenski Alexandre , Forde Martin , Jutzy Jessica M.S. , Biyani Neha , Posner Mitchell C. , Pitroda Sean P. , Weichselbaum Ralph R. , Khodarev Nikolai N.
Published: March 2024

Abstract
Expression of 14q32-encoded miRNAs is a favorable prognostic factor in patients with metastatic cancer. In this study, we used genomic inhibition of DNA methylation through disruption of DNA methyltransferases DNMT1 and DNMT3B and pharmacologic inhibition with 5-Aza-2′-deoxycytidine (5-Aza-dC, decitabine) to demonstrate that DNA methylation predominantly regulates expression of metastasis-suppressive miRNAs in the 14q32 cluster. DNA demethylation facilitated CCCTC-binding factor (CTCF) recruitment to the maternally expressed gene 3 differentially methylated region (MEG3-DMR), which acts as a cis-regulatory element for 14q32 miRNA expression. 5-Aza-dC activated demethylation of the MEG3-DMR and expression of 14q32 miRNAs, which suppressed adhesion, invasion, and migration (AIM) properties of metastatic tumor cells. Cancer cells with MEG3-DMR hypomethylation exhibited constitutive expression of 14q32 miRNAs and resistance to 5-Aza-dC–induced suppression of AIM. Expression of methylation-dependent 14q32 miRNAs suppressed metastatic colonization in preclinical models of lung and liver metastasis and correlated with improved clinical outcomes in patients with metastatic cancer. These findings implicate epigenetic modification via DNA methylation in the regulation of metastatic propensity through miRNA networks and identify a previously unrecognized action of decitabine on the activation of metastasis-suppressive miRNAs.
Significance:
This study investigates epigenetic regulation of metastasis-suppressive miRNAs and the effect on metastasis.
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 2024

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 Hepatic Endothelial Notch Activation Protects against Liver Metastasis by Regulating Endothelial-Tumor Cell Adhesion Independent of Angiocrine Signaling
Authors: Wohlfeil Sebastian A. , Häfele Verena , Dietsch Bianca , Schledzewski Kai , Winkler Manuel , Zierow Johanna , Leibing Thomas , Mohammadi Mona Malek , Heineke Joerg , Sticht Carsten , Olsavszky Victor , Koch Philipp-Sebastian , Géraud Cyrill , Goerdt Sergij
Published: March 2024

Abstract
The interaction of tumor cells with organ-specific endothelial cells (EC) is an important step during metastatic progression. Notch signaling in organ-specific niches has been implicated in mediating opposing effects on organotropic metastasis to the lungs and the liver, respectively. In this study, we scrutinized the role of endothelial Notch activation during liver metastasis. To target hepatic EC (HEC), a novel EC subtype-specific Cre driver mouse was generated. Clec4g-Cretg/wt mice were crossed to Rosa26N1ICD-IRES-GFP to enhance Notch signaling in HEC (NICDOE-HEC). In NICDOE-HEC mice, hepatic metastasis of malignant melanoma and colorectal carcinoma was significantly reduced. These mice revealed reduced liver growth and impaired metabolic zonation due to suppression of hepatic angiocrine Wnt signaling. Hepatic metastasis, however, was not controlled by angiocrine Wnt signaling, as deficiency of the Wnt cargo receptor Wls in HEC of WlsHEC-KO mice did not affect hepatic metastasis. In contrast, the hepatic microvasculature in NICDOE-HEC mice revealed a special form of sinusoidal capillarization, with effacement of endothelial zonation functionally paralleled by reduced tumor cell adhesion in vivo. Notably, expression of endothelial adhesion molecule ICAM1 by HEC was significantly reduced. Treatment with an anti-ICAM1 antibody significantly inhibited tumor cell adhesion to HEC in wild-type mice confirming that Notch controls hepatic metastasis via modulation of HEC adhesion molecules. As endothelial Notch activation in the lung has been shown to promote lung metastasis, tumor therapy will require approaches that target Notch in an organ-, cell type-, and context-specific manner.
Significance:
Manipulation of Notch signaling in the endothelium has opposing, organ-specific effects on metastasis to the lung and the liver, demonstrating that this pathway should be targeted in a cell- and context-specific fashion.
Data from Pathogenic Epigenetic Consequences of Genetic Alterations in IDH-Wild-Type Diffuse Astrocytic Gliomas
Authors: Ohka Fumiharu , Shinjo Keiko , Deguchi Shoichi , Matsui Yusuke , Okuno Yusuke , Katsushima Keisuke , Suzuki Miho , Kato Akira , Ogiso Noboru , Yamamichi Akane , Aoki Kosuke , Suzuki Hiromichi , Sato Shinya , Arul Rayan Nirmala , Prabhakar Shyam , Göke Jonathan , Shimamura Teppei , Maruyama Reo , Takahashi Satoru , Suzumura Akio , Kimura Hiroshi , Wakabayashi Toshihiko , Zong Hui , Natsume Atsushi , Kondo Yutaka
Published: March 2024

Abstract
Gliomas are classified by combining histopathologic and molecular features, including isocitrate dehydrogenase (IDH) status. Although IDH-wild-type diffuse astrocytic glioma (DAG) shows a more aggressive phenotype than IDH-mutant type, lack of knowledge regarding relevant molecular drivers for this type of tumor has hindered the development of therapeutic agents. Here, we examined human IDH-wild-type DAGs and a glioma mouse model with a mosaic analysis with double markers (MADM) system, which concurrently lacks p53 and NF1 and spontaneously develops tumors highly comparable with human IDH-wild-type DAG without characteristic molecular features of glioblastoma (DAG-nonMF). During tumor formation, enhancer of zeste homolog (EZH2) and the other polycomb repressive complex 2 (PRC2) components were upregulated even at an early stage of tumorigenesis, together with an increased number of genes with H3K27me3 or H3K27me3 and H3K4me3 bivalent modifications. Among the epigenetically dysregulated genes, frizzled-8 (Fzd8), which is known to be a cancer- and stem cell reprogramming–related gene, was gradually silenced during tumorigenesis. Genetic and pharmacologic inhibition of EZH2 in MADM mice showed reactivation of aberrant H3K27me3 target genes, including Fzd8, together with significant reduction of tumor size. Our study clarifies a pathogenic molecular pathway of IDH-wild-type DAG-nonMF that depends on EZH2 activity and provides a strong rationale for targeting EZH2 as a promising therapeutic approach for this type of glioma.
Significance:
EZH2 is involved in the generation of IDH-wild-type diffuse astrocytic gliomas and is a potential therapeutic target for this type of glioma.
Data from IDO1 and Kynurenine Pathway Metabolites Activate PI3K-Akt Signaling in the Neoplastic Colon Epithelium to Promote Cancer Cell Proliferation and Inhibit Apoptosis
Authors: Bishnupuri Kumar S. , Alvarado David M. , Khouri Alexander N. , Shabsovich Mark , Chen Baosheng , Dieckgraefe Brian K. , Ciorba Matthew A.
Published: March 2024

Abstract
The tryptophan-metabolizing enzyme indoleamine 2,3 dioxygenase 1 (IDO1) is frequently overexpressed in epithelial-derived malignancies, where it plays a recognized role in promoting tumor immune tolerance. We previously demonstrated that the IDO1–kynurenine pathway (KP) also directly supports colorectal cancer growth by promoting activation of β-catenin and driving neoplastic growth in mice lacking intact adaptive immunity. In this study, we sought to delineate the specific role of epithelial IDO1 in colon tumorigenesis and define how IDO1 and KP metabolites interact with pivotal neoplastic signaling pathways of the colon epithelium. We generated a novel intestinal epithelial–specific IDO1 knockout mouse and utilized established colorectal cancer cell lines containing β-catenin–stabilizing mutations, human colorectal cancer samples, and human-derived epithelial organoids (colonoids and tumoroids). Mice with intestinal epithelial–specific knockout of IDO1 developed fewer and smaller tumors than wild-type littermates in a model of inflammation-driven colon tumorigenesis. Moreover, their tumors exhibited reduced nuclear β-catenin and neoplastic proliferation but increased apoptosis. Mechanistically, KP metabolites (except kynurenic acid) rapidly activated PI3K-Akt signaling in the neoplastic epithelium to promote nuclear translocation of β-catenin, cellular proliferation, and resistance to apoptosis. Together, these data define a novel cell-autonomous function and mechanism by which IDO1 activity promotes colorectal cancer progression. These findings may have implications for the rational design of new clinical trials that exploit a synergy of IDO1 inhibitors with conventional cancer therapies for which Akt activation provides resistance such as radiation.

Significance: This study identifies a new mechanistic link between IDO1 activity and PI3K/AKT signaling, both of which are important pathways involved in cancer growth and resistance to cancer therapy.
Data from Bicyclic Peptides as a New Modality for Imaging and Targeting of Proteins Overexpressed by Tumors
Authors: Eder Matthias , Pavan Silvia , Bauder-Wüst Ulrike , van Rietschoten Katerine , Baranski Ann-Christin , Harrison Helen , Campbell Spencer , Stace Catherine L. , Walker Edward H. , Chen Liuhong , Bennett Gavin , Mudd Gemma , Schierbaum Ursula , Leotta Karin , Haberkorn Uwe , Kopka Klaus , Teufel Daniel P.
Published: March 2024

Abstract
Molecular imaging of cancers using probes specific for tumor-associated target proteins offers a powerful solution for providing information regarding selection of targeted therapy, patient stratification, and response to therapy. Here we demonstrate the power of bicyclic peptides as targeting probes, exemplified with the tumor-overexpressed matrix metalloproteinase MT1-MMP as a target. A bicyclic peptide with subnanomolar affinity towards MT1-MMP was identified, and its radioconjugate showed selective tumor uptake in an HT1080 xenograft mouse model. Proteolytic stabilization of the peptide by chemical modification significantly enhanced the in vivo tumor signal [from 2.5%ID/g to 12%ID/g at 1 hour post injection (p.i.)]. Studies using mouse xenograft models with different cell lines show a robust correlation between tumor signals and in vivo MT1-MMP expression levels. Fatty acid modification of the bicyclic peptide extended its circulating half-life, resulting in increased tumor signals (36%ID/g at 6 hours p.i.). Comparative work with an equipotent radiolabeled MT1-MMP targeting antibody demonstrated starkly differential biodistribution and tumor accumulation properties, with the tumor signal slowly increasing to 6.2%ID/g within 48 hours. The rapid tumor penetration characteristics of bicyclic peptides, coupled with high potency and chemical versatility, thus offer high-contrast imaging probes for clinical diagnostics with compelling additional potential in targeted therapy.

Significance: This work demonstrates the potential of bicyclic peptides as a platform for the development of high-contrast imaging probes for potential use in clinical cancer diagnostics and molecularly targeted therapeutics.
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 2024

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 Targeting Hippo-Dependent and Hippo-Independent YAP1 Signaling for the Treatment of Childhood Rhabdomyosarcoma
Authors: Slemmons Katherine K. , Yeung Choh , Baumgart Joshua T. , Juarez Jhazeel O. Martinez , McCalla Amy , Helman Lee J.
Published: March 2024

Abstract
Rhabdomyosarcoma is the most common childhood soft-tissue sarcoma, yet patients with metastatic or recurrent disease continue to do poorly, indicating a need for new treatments. The SRC family tyrosine kinase YES1 is upregulated in rhabdomyosarcoma and is necessary for growth, but clinical trials using single agent dasatinib, a SRC family kinase inhibitor, have failed in sarcomas. YAP1 (YES-associated protein) is highly expressed in rhabdomyosarcoma, driving growth and survival when the upstream Hippo tumor suppressor pathway is silenced, but efforts to pharmacologically inhibit YAP1 have been unsuccessful. Here we demonstrate that treatment of rhabdomyosarcoma with DNA methyltransferase inhibitor (DNMTi) upregulates Hippo activators RASSF1 and RASSF5 by promoter demethylation, activating canonical Hippo signaling and increasing inactivation of YAP1 by phosphorylation. Treatment with DNMTi decreased rhabdomyosarcoma cell growth and increased apoptosis and differentiation, an effect partially rescued by expression of constitutively active YAP (S127A), suggesting the effects of DNMTi treatment are, in part, due to Hippo-dependent inhibition of YAP1. In addition, YES1 and YAP1 interacted in the nucleus of rhabdomyosarcoma cells, and genetic or pharmacologic suppression of YES1 resulted in cytoplasmic retention of YAP1 and decreased YAP1 target gene expression, suggesting YES1 regulates YAP1 in a Hippo-independent manner. Combined treatment with DNMTi and dasatinib targeted both Hippo-dependent and Hippo-independent regulation of YAP1, ablating rhabdomyosarcoma cell growth in vitro and trending toward decreased tumor growth in vivo. These results show that the mechanisms regulating YAP1 in rhabdomyosarcoma can be inhibited by combinatorial therapy of DNMTi and dasatinib, laying the groundwork for future clinical investigations.
Significance:
This study elucidates the signaling pathways that regulate the oncogenic protein YAP1 and identifies a combination therapy to target these pathways in the childhood tumor rhabdomyosarcoma.
Data from HACE1 Prevents Lung Carcinogenesis via Inhibition of RAC-Family GTPases
Authors: Kogler Melanie , Tortola Luigi , Negri Gian Luca , Leopoldi Alexandra , El-Naggar Amal M. , Mereiter Stefan , Gomez-Diaz Carlos , Nitsch Roberto , Tortora Davide , Kavirayani Anoop M. , Gapp Bianca V. , Rao Shuan , Uribesalgo Iris , Hoffmann David , Cikes Domagoj , Novatchkova Maria , Williams David A. , Trent Jeffrey M. , Ikeda Fumiyo , Daugaard Mads , Hagelkruys Astrid , Sorensen Poul H. , Penninger Josef M.
Published: March 2024

Abstract
HACE1 is an E3 ubiquitin ligase with important roles in tumor biology and tissue homeostasis. Loss or mutation of HACE1 has been associated with the occurrence of a variety of neoplasms, but the underlying mechanisms have not been defined yet. Here, we report that HACE1 is frequently mutated in human lung cancer. In mice, loss of Hace1 led to enhanced progression of KRasG12D-driven lung tumors. Additional ablation of the oncogenic GTPase Rac1 partially reduced progression of Hace1−/− lung tumors. RAC2, a novel ubiquitylation target of HACE1, could compensate for the absence of its homolog RAC1 in Hace1-deficient, but not in HACE1-sufficient tumors. Accordingly, ablation of both Rac1 and Rac2 fully averted the increased progression of KRasG12D-driven lung tumors in Hace1−/− mice. In patients with lung cancer, increased expression of HACE1 correlated with reduced levels of RAC1 and RAC2 and prolonged survival, whereas elevated expression of RAC1 and RAC2 was associated with poor prognosis. This work defines HACE1 as a crucial regulator of the oncogenic activity of RAC-family GTPases in lung cancer development.
Significance:
These findings reveal that mutation of the tumor suppressor HACE1 disrupts its role as a regulator of the oncogenic activity of RAC-family GTPases in human and murine lung cancer.
Data from Spatiotemporal Regulation of ΔNp63 by TGFβ-Regulated miRNAs Is Essential for Cancer Metastasis
Authors: Bui Ngoc H.B. , Napoli Marco , Davis Andrew John , Abbas Hussein A. , Rajapakshe Kimal , Coarfa Cristian , Flores Elsa R.
Published: March 2024

Abstract
ΔNp63 is a transcription factor of the p53 family and has crucial functions in normal development and disease. The expression pattern of ΔNp63 in human cancer suggests dynamic regulation of this isoform during cancer progression and metastasis. Many primary and metastatic tumors express high levels of ΔNp63, while ΔNp63 loss is crucial for tumor dissemination, indicating an oscillatory expression of ΔNp63 during cancer progression. Here, we use genetically engineered orthotopic mouse models of breast cancer to show that while depletion of ΔNp63 inhibits primary mammary adenocarcinoma development, oscillatory expression of ΔNp63 in established tumors is crucial for metastatic dissemination in breast cancer. A TGFβ-regulated miRNA network acted as upstream regulators of this oscillatory expression of ΔNp63 during cancer progression. This work sheds light on the pleiotropic roles of ΔNp63 in cancer and unveils critical functions of TGFβ in the metastatic process.
Significance:
This study unveils TGFβ signaling and a network of four miRNAs as upstream regulators of ΔNp63, providing key information for the development of therapeutic strategies to treat cancers that commonly overexpress ΔNp63.
Data from Label-Free Raman Spectroscopy Reveals Signatures of Radiation Resistance in the Tumor Microenvironment
Authors: Paidi Santosh K. , Diaz Paola Monterroso , Dadgar Sina , Jenkins Samir V. , Quick Charles M. , Griffin Robert J. , Dings Ruud P.M. , Rajaram Narasimhan , Barman Ishan
Published: March 2024

Abstract
Delay in the assessment of tumor response to radiotherapy continues to pose a major challenge to quality of life for patients with nonresponsive tumors. Here, we exploited label-free Raman spectroscopic mapping to elucidate radiation-induced biomolecular changes in tumors and uncovered latent microenvironmental differences between treatment-resistant and -sensitive tumors. We used isogenic radiation-resistant and -sensitive A549 human lung cancer cells and human head and neck squamous cell carcinoma (HNSCC) cell lines (UM-SCC-47 and UM-SCC-22B, respectively) to grow tumor xenografts in athymic nude mice and demonstrated the molecular specificity and quantitative nature of Raman spectroscopic tissue assessments. Raman spectra obtained from untreated and treated tumors were subjected to chemometric analysis using multivariate curve resolution-alternating least squares (MCR-ALS) and support vector machine (SVM) to quantify biomolecular differences in the tumor microenvironment. The Raman measurements revealed significant and reliable differences in lipid and collagen content postradiation in the tumor microenvironment, with consistently greater changes observed in the radiation-sensitive tumors. In addition to accurately evaluating tumor response to therapy, the combination of Raman spectral markers potentially offers a route to predicting response in untreated tumors prior to commencing treatment. Combined with its noninvasive nature, our findings provide a rationale for in vivo studies using Raman spectroscopy, with the ultimate goal of clinical translation for patient stratification and guiding adaptation of radiotherapy during the course of treatment.
Significance:
These findings highlight the sensitivity of label-free Raman spectroscopy to changes induced by radiotherapy and indicate the potential to predict radiation resistance prior to commencing therapy.
Data from An Interactive Resource to Probe Genetic Diversity and Estimated Ancestry in Cancer Cell Lines
Authors: Dutil Julie , Chen Zhihua , Monteiro Alvaro N. , Teer Jamie K. , Eschrich Steven A.
Published: March 2024

Abstract
Recent work points to a lack of diversity in genomics studies from genome-wide association studies to somatic (tumor) genome analyses. Yet, population-specific genetic variation has been shown to contribute to health disparities in cancer risk and outcomes. Immortalized cancer cell lines are widely used in cancer research, from mechanistic studies to drug screening. Larger collections of cancer cell lines better represent the genomic heterogeneity found in primary tumors. Yet, the genetic ancestral origin of cancer cell lines is rarely acknowledged and often unknown. Using genome-wide genotyping data from 1,393 cancer cell lines from the Catalogue of Somatic Mutations in Cancer (COSMIC) and Cancer Cell Line Encyclopedia (CCLE), we estimated the genetic ancestral origin for each cell line. Our data indicate that cancer cell line collections are not representative of the diverse ancestry and admixture characterizing human populations. We discuss the implications of genetic ancestry and diversity of cellular models for cancer research and present an interactive tool, Estimated Cell Line Ancestry (ECLA), where ancestry can be visualized with reference populations of the 1000 Genomes Project. Cancer researchers can use this resource to identify cell line models for their studies by taking ancestral origins into consideration.
Data from The Frequency of Ras Mutations in Cancer
Authors: Prior Ian A. , Hood Fiona E. , Hartley James L.
Published: March 2024

Abstract
Ras is frequently mutated in cancer, however, there is a lack of consensus in the literature regarding the cancer mutation frequency of Ras, with quoted values varying from 10%–30%. This variability is at least in part due to the selective aggregation of data from different databases and the dominant influence of particular cancer types and particular Ras isoforms within these datasets. To provide a more definitive figure for Ras mutation frequency in cancer, we cross-referenced the data in all major publicly accessible cancer mutation databases to determine reliable mutation frequency values for each Ras isoform in all major cancer types. These percentages were then applied to current U.S. cancer incidence statistics to estimate the number of new patients each year that have Ras-mutant cancers. We find that approximately 19% of patients with cancer harbor Ras mutations, equivalent to approximately 3.4 million new cases per year worldwide. We discuss the Ras isoform and mutation-specific trends evident within the datasets that are relevant to current Ras-targeted therapies.
Data from PET Reporter Gene Imaging and Ganciclovir-Mediated Ablation of Chimeric Antigen Receptor T Cells in Solid Tumors
Authors: Murty Surya , Labanieh Louai , Murty Tara , Gowrishankar Gayatri , Haywood Tom , Alam Israt S. , Beinat Corinne , Robinson Elise , Aalipour Amin , Klysz Dorota D. , Cochran Jennifer R. , Majzner Robbie G. , Mackall Crystal L. , Gambhir Sanjiv S.
Published: March 2024

Abstract
Imaging strategies to monitor chimeric antigen receptor (CAR) T-cell biodistribution and proliferation harbor the potential to facilitate clinical translation for the treatment of both liquid and solid tumors. In addition, the potential adverse effects of CAR T cells highlight the need for mechanisms to modulate CAR T-cell activity. The herpes simplex virus type 1 thymidine kinase (HSV1-tk) gene has previously been translated as a PET reporter gene for imaging of T-cell trafficking in patients with brain tumor. The HSV1-TK enzyme can act as a suicide gene of transduced cells through treatment with the prodrug ganciclovir. Here we report the molecular engineering, imaging, and ganciclovir-mediated destruction of B7H3 CAR T cells incorporating a mutated version of the HSV1-tk gene (sr39tk) with improved enzymatic activity for ganciclovir. The sr39tk gene did not affect B7H3 CAR T-cell functionality and in vitro and in vivo studies in osteosarcoma models showed no significant effect on B7H3 CAR T-cell antitumor activity. PET/CT imaging with 9-(4-[18F]-fluoro-3-[hydroxymethyl]butyl)guanine ([18F]FHBG) of B7H3-sr39tk CAR T cells in an orthotopic model of osteosarcoma revealed tumor homing and systemic immune expansion. Bioluminescence and PET imaging of B7H3-sr39tk CAR T cells confirmed complete tumor ablation with intraperitoneal ganciclovir administration. This imaging and suicide ablation system can provide insight into CAR T-cell migration and proliferation during clinical trials while serving as a suicide switch to limit potential toxicities.
Significance:
This study showcases the only genetically engineered system capable of serving the dual role both as an effective PET imaging reporter and as a suicide switch for CAR T cells.
Data from Suppression of ABCE1-Mediated mRNA Translation Limits N-MYC–Driven Cancer Progression
Authors: Gao Jixuan , Jung MoonSun , Mayoh Chelsea , Venkat Pooja , Hannan Katherine M. , Fletcher Jamie I. , Kamili Alvin , Gifford Andrew J. , Kusnadi Eric P. , Pearson Richard B. , Hannan Ross D. , Haber Michelle , Norris Murray D. , Somers Klaartje , Henderson Michelle J.
Published: March 2024

Abstract
The ability of the N-MYC transcription factor to drive cancer progression is well demonstrated in neuroblastoma, the most common extracranial pediatric solid tumor, where MYCN amplification heralds a poor prognosis, with only 11% of high-risk patients surviving past 5 years. However, decades of attempts of direct inhibition of N-MYC or its paralogues has led to the conclusion that this protein is “undruggable.” Therefore, targeting pathways upregulated by N-MYC signaling presents an alternative therapeutic approach. Here, we show that MYCN-amplified neuroblastomas are characterized by elevated rates of protein synthesis and that high expression of ABCE1, a translation factor directly upregulated by N-MYC, is itself a strong predictor of poor clinical outcome. Despite the potent ability of N-MYC in heightening protein synthesis and malignant characteristics in cancer cells, suppression of ABCE1 alone selectively negated this effect, returning the rate of translation to baseline levels and significantly reducing the growth, motility, and invasiveness of MYCN-amplified neuroblastoma cells and patient-derived xenograft tumors in vivo. The growth of nonmalignant cells or MYCN-nonamplified neuroblastoma cells remained unaffected by reduced ABCE1, supporting a therapeutic window associated with targeting ABCE1. Neuroblastoma cells with c-MYC overexpression also required ABCE1 to maintain cell proliferation and translation. Taken together, ABCE1-mediated translation constitutes a critical process in the progression of N-MYC–driven and c-MYC–driven cancers that warrants investigations into methods of its therapeutic inhibition.
Significance:
These findings demonstrate that N-MYC–driven cancers are reliant on elevated rates of protein synthesis driven by heightened expression of ABCE1, a vulnerability that can be exploited through suppression of ABCE1.
Data from Decitabine Induces Gene Derepression on Monosomic Chromosomes: In Vitro and In Vivo Effects in Adverse-Risk Cytogenetics AML
Authors: Greve Gabriele , Schüler Julia , Grüning Björn A. , Berberich Bettina , Stomper Julia , Zimmer Dennis , Gutenkunst Lea , Bönisch Ulrike , Meier Ruth , Blagitko-Dorfs Nadja , Grishina Olga , Pfeifer Dietmar , Weichenhan Dieter , Plass Christoph , Lübbert Michael
Published: March 2024

Abstract
Hypomethylating agents (HMA) have become the backbone of nonintensive acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) treatment, also by virtue of their activity in patients with adverse genetics, for example, monosomal karyotypes, often with losses on chromosome 7, 5, or 17. No comparable activity is observed with cytarabine, a cytidine analogue without DNA-hypomethylating properties. As evidence exists for compounding hypermethylation and gene silencing of hemizygous tumor suppressor genes (TSG), we thus hypothesized that this effect may preferentially be reversed by the HMAs decitabine and azacitidine. An unbiased RNA-sequencing approach was developed to interrogate decitabine-induced transcriptome changes in AML cell lines with or without a deletion of chromosomes 7q, 5q or 17p. HMA treatment preferentially upregulated several hemizygous TSG in this genomic region, significantly derepressing endogenous retrovirus (ERV)3–1, with promoter demethylation, enhanced chromatin accessibility, and increased H3K4me3 levels. Decitabine globally reactivated multiple transposable elements, with activation of the dsRNA sensor RIG-I and interferon regulatory factor (IRF)7. Induction of ERV3–1 and RIG-I mRNA was also observed during decitabine treatment in vivo in serially sorted peripheral blood AML blasts. In patient-derived monosomal karyotype AML murine xenografts, decitabine treatment resulted in superior survival rates compared with cytarabine. Collectively, these data demonstrate preferential gene derepression and ERV reactivation in AML with chromosomal deletions, providing a mechanistic explanation that supports the clinical observation of superiority of HMA over cytarabine in this difficult-to-treat patient group.
Significance:
These findings unravel the molecular mechanism underlying the intriguing clinical activity of HMAs in AML/MDS patients with chromosome 7 deletions and other monosomal karyotypes.

See related commentary by O'Hagan et al., p. 813
Data from Nanoengineered Disruption of Heat Shock Protein 90 Targets Drug-Induced Resistance and Relieves Natural Killer Cell Suppression in Breast Cancer
Authors: Smalley Munisha , Natarajan Siva Kumar , Mondal Jayanta , Best Douglas , Goldman David , Shanthappa Basavaraja , Pellowe Moriah , Dash Chinmayee , Saha Tanmoy , Khiste Sachin , Ramadurai Nithya , Eton Elliot O. , Smalley Joshua L. , Brown Andrew , Thayakumar Allen , Rahman Mamunur , Arai Kazuya , Kohandel Mohammad , Sengupta Shiladitya , Goldman Aaron
Published: March 2024

Abstract
Drug-induced resistance, or tolerance, is an emerging yet poorly understood failure of anticancer therapy. The interplay between drug-tolerant cancer cells and innate immunity within the tumor, the consequence on tumor growth, and therapeutic strategies to address these challenges remain undescribed. Here, we elucidate the role of taxane-induced resistance on natural killer (NK) cell tumor immunity in triple-negative breast cancer (TNBC) and the design of spatiotemporally controlled nanomedicines, which boost therapeutic efficacy and invigorate “disabled” NK cells. Drug tolerance limited NK cell immune surveillance via drug-induced depletion of the NK-activating ligand receptor axis, NK group 2 member D, and MHC class I polypeptide-related sequence A, B. Systems biology supported by empirical evidence revealed the heat shock protein 90 (Hsp90) simultaneously controls immune surveillance and persistence of drug-treated tumor cells. On the basis of this evidence, we engineered a “chimeric” nanotherapeutic tool comprising taxanes and a cholesterol-tethered Hsp90 inhibitor, radicicol, which targets the tumor, reduces tolerance, and optimally reprimes NK cells via prolonged induction of NK-activating ligand receptors via temporal control of drug release in vitro and in vivo. A human ex vivo TNBC model confirmed the importance of NK cells in drug-induced death under pressure of clinically approved agents. These findings highlight a convergence between drug-induced resistance, the tumor immune contexture, and engineered approaches that consider the tumor and microenvironment to improve the success of combinatorial therapy.
Significance:
This study uncovers a molecular mechanism linking drug-induced resistance and tumor immunity and provides novel engineered solutions that target these mechanisms in the tumor and improve immunity, thus mitigating off-target effects.
Data from “3G” Trial: An RNA Editing Signature to Guide Gastric Cancer Chemotherapy
Authors: An Omer , Song Yangyang , Ke Xinyu , So Jimmy Bok-Yan , Sundar Raghav , Yang Henry , Rha Sun Young , Lee Ming Hui , Tay Su Ting , Ong Xuewen , Tan Angie Lay Keng , Ng Matthew Chau Hsien , Tantoso Erwin , Chen Leilei , Tan Patrick , Yong Wei Peng
Published: March 2024

Abstract
Gastric cancer cases are often diagnosed at an advanced stage with poor prognosis. Platinum-based chemotherapy has been internationally accepted as first-line therapy for inoperable or metastatic gastric cancer. To achieve greater benefits, selection of patients eligible for this treatment is critical. Although gene expression profiling has been widely used as a genomic classifier to identify molecular subtypes of gastric cancer and to stratify patients for different chemotherapy regimens, its prediction accuracy can be improved. Adenosine-to-inosine (A-to-I) RNA editing has emerged as a new player contributing to gastric cancer development and progression, offering potential clinical utility for diagnosis and treatment. Using a systematic computational approach followed by both in vitro validations and in silico validations in The Cancer Genome Atlas (TCGA), we conducted a transcriptome-wide RNA editing analysis of a cohort of 104 patients with advanced gastric cancer and identified an RNA editing (GCRE) signature to guide gastric cancer chemotherapy. RNA editing events stood as a prognostic and predictive biomarker in advanced gastric cancer. A GCRE score based on the GCRE signature consisted of 50 editing sites associated with 29 genes, predicting response to chemotherapy with a high accuracy (84%). Of note, patients demonstrating higher editing levels of this panel of sites presented a better overall response. Consistently, gastric cancer cell lines with higher editing levels showed higher chemosensitivity. Applying the GCRE score on TCGA dataset confirmed that responders had significantly higher levels of editing in advanced gastric cancer. Overall, this newly defined GCRE signature reliably stratifies patients with advanced gastric cancer and predicts response from chemotherapy.
Significance:
This study describes a novel A-to-I RNA editing signature as a prognostic and predictive biomarker in advanced gastric cancer, providing a new tool to improve patient stratification and response to therapy.
Data from Altered Mitochondria Functionality Defines a Metastatic Cell State in Lung Cancer and Creates an Exploitable Vulnerability
Authors: Chuang Chen-Hua , Dorsch Madeleine , Dujardin Philip , Silas Sukrit , Ueffing Kristina , Hölken Johanna M. , Yang Dian , Winslow Monte M. , Grüner Barbara M.
Published: March 2024

Abstract
Lung cancer is a prevalent and lethal cancer type that leads to more deaths than the next four major cancer types combined. Metastatic cancer spread is responsible for most cancer-related deaths but the cellular changes that enable cancer cells to leave the primary tumor and establish inoperable and lethal metastases remain poorly understood. To uncover genes that are specifically required to sustain metastasis survival or growth, we performed a genome-scale pooled lentiviral-shRNA library screen in cells that represent nonmetastatic and metastatic states of lung adenocarcinoma. Mitochondrial ribosome and mitochondria-associated genes were identified as top gene sets associated with metastasis-specific lethality. Metastasis-derived cell lines in vitro and metastases analyzed ex vivo from an autochthonous lung cancer mouse model had lower mitochondrial membrane potential and reduced mitochondrial functionality than nonmetastatic primary tumors. Electron microscopy of metastases uncovered irregular mitochondria with bridging and loss of normal membrane structure. Consistent with these findings, compounds that inhibit mitochondrial translation or replication had a greater effect on the growth of metastasis-derived cells. Finally, mice with established tumors developed fewer metastases upon treatment with phenformin in vivo. These results suggest that the metastatic cell state in lung adenocarcinoma is associated with a specifically altered mitochondrial functionality that can be therapeutically exploited.
Significance:
This study characterizes altered mitochondria functionality of the metastatic cell state in lung cancer and opens new avenues for metastasis-specific therapeutic targeting.