bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from The Interaction of SWI/SNF with the Ribosome Regulates Translation and Confers Sensitivity to Translation Pathway Inhibitors in Cancers with Complex Perturbations
Authors: Ulicna Livia , Kimmey Samuel C. , Weber Christopher M. , Allard Grace M. , Wang Aihui , Bui Nam Q. , Bendall Sean C. , Crabtree Gerald R. , Bean Gregory R. , Van Rechem Capucine
Published: March 2024

Abstract
Subunits from the chromatin remodelers mammalian SWItch/Sucrose Non-Fermentable (mSWI/SNF) are mutated, deleted, or amplified in more than 40% of cancers. Understanding their functions in normal cells and the consequences of cancerous alterations will provide insight into developing new targeted therapies. Here we examined whether mSWI/SNF mutations increase cellular sensitivity to specific drugs. Taking advantage of the DepMap studies, we demonstrate that cancer cells harboring mutations of specific mSWI/SNF subunits exhibit a genetic dependency on translation factors and are sensitive to translation pathway inhibitors. Furthermore, mSWI/SNF subunits were present in the cytoplasm and interacted with the translation initiation machinery, and short-term inhibition and depletion of specific subunits decreased global translation, implicating a direct role for these factors in translation. Depletion of specific mSWI/SNF subunits also increased sensitivity to mTOR-PI3K inhibitors. In patient-derived breast cancer samples, mSWI/SNF subunits expression in both the nucleus and the cytoplasm was substantially altered. In conclusion, an unexpected cytoplasmic role for mSWI/SNF complexes in translation suggests potential new therapeutic opportunities for patients afflicted by cancers demonstrating alterations in their subunits.
Significance:
This work establishes direct functions for mSWI/SNF in translation and demonstrates that alterations in mSWI/SNF confer a therapeutic vulnerability to translation pathway inhibitors in cancer cells.
Data from Inhibition of EGFR Overcomes Acquired Lenvatinib Resistance Driven by STAT3–ABCB1 Signaling in Hepatocellular Carcinoma
Authors: Hu Beiyuan , Zou Tiantian , Qin Wei , Shen Xiaotian , Su Yinghan , Li Jianhua , Chen Yang , Zhang Ze , Sun Haoting , Zheng Yan , Wang Chao-Qun , Wang Zhengxin , Li Tian-En , Wang Shun , Zhu Le , Wang Xufeng , Fu Yan , Ren Xudong , Dong Qiongzhu , Qin Lun-Xiu
Published: March 2024

Abstract
Lenvatinib is an inhibitor of multiple receptor tyrosine kinases that was recently authorized for first-line treatment of hepatocellular carcinoma (HCC). However, the clinical benefits derived from lenvatinib are limited, highlighting the urgent need to understand mechanisms of resistance. We report here that HCC cells develop resistance to lenvatinib by activating EGFR and stimulating the EGFR–STAT3–ABCB1 axis. Lenvatinib resistance was accompanied by aberrant cholesterol metabolism and lipid raft activation. ABCB1 was activated by EGFR in a lipid raft–dependent manner, which significantly enhanced the exocytosis of lenvatinib to mediate resistance. Furthermore, clinical specimens of HCC showed a correlation between the activation of the EGFR–STAT3–ABCB1 pathway and lenvatinib response. Erlotinib, an EGFR inhibitor that has also been shown to inhibit ABCB1, suppressed lenvatinib exocytosis, and combined treatment with lenvatinib and erlotinib demonstrated a significant synergistic effect on HCC both in vitro and in vivo. Taken together, these findings characterize a mechanism of resistance to a first-line treatment for HCC and offer a practical means to circumvent resistance and treat the disease.
Significance:
HCC cells acquire resistance to lenvatinib by activating the EGFR–STAT3–ABCB1 pathway, identifying combined treatment with erlotinib as a strategy to overcome acquired resistance and improve the clinical benefit of lenvatinib.
Data from Genomic Profiling of Bronchoalveolar Lavage Fluid in Lung Cancer
Authors: Nair Viswam S. , Hui Angela Bik-Yu , Chabon Jacob J. , Esfahani Mohammad S. , Stehr Henning , Nabet Barzin Y. , Zhou Li , Chaudhuri Aadel A. , Benson Jalen , Ayers Kelsey , Bedi Harmeet , Ramsey Meghan , Van Wert Ryan , Antic Sanja , Lui Natalie , Backhus Leah , Berry Mark , Sung Arthur W. , Massion Pierre P. , Shrager Joseph B. , Alizadeh Ash A. , Diehn Maximilian
Published: March 2024

Abstract
Genomic profiling of bronchoalveolar lavage (BAL) samples may be useful for tumor profiling and diagnosis in the clinic. Here, we compared tumor-derived mutations detected in BAL samples from subjects with non–small cell lung cancer (NSCLC) to those detected in matched plasma samples. Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq) was used to genotype DNA purified from BAL, plasma, and tumor samples from patients with NSCLC. The characteristics of cell-free DNA (cfDNA) isolated from BAL fluid were first characterized to optimize the technical approach. Somatic mutations identified in tumor were then compared with those identified in BAL and plasma, and the potential of BAL cfDNA analysis to distinguish lung cancer patients from risk-matched controls was explored. In total, 200 biofluid and tumor samples from 38 cases and 21 controls undergoing BAL for lung cancer evaluation were profiled. More tumor variants were identified in BAL cfDNA than plasma cfDNA in all stages (P < 0.001) and in stage I to II disease only. Four of 21 controls harbored low levels of cancer-associated driver mutations in BAL cfDNA [mean variant allele frequency (VAF) = 0.5%], suggesting the presence of somatic mutations in nonmalignant airway cells. Finally, using a Random Forest model with leave-one-out cross-validation, an exploratory BAL genomic classifier identified lung cancer with 69% sensitivity and 100% specificity in this cohort and detected more cancers than BAL cytology. Detecting tumor-derived mutations by targeted sequencing of BAL cfDNA is technically feasible and appears to be more sensitive than plasma profiling. Further studies are required to define optimal diagnostic applications and clinical utility.
Significance:
Hybrid-capture, targeted deep sequencing of lung cancer mutational burden in cell-free BAL fluid identifies more tumor-derived mutations with increased allele frequencies compared with plasma cell-free DNA.

See related commentary by Rolfo et al., p. 2826
Data from Cell–Cell Interactions Drive Metastasis of Circulating Tumor Microemboli
Authors: Tao Jianxin , Zhu Lei , Yakoub Mina , Reißfelder Christoph , Loges Sonja , Schölch Sebastian
Published: March 2024

Abstract
Circulating tumor cells are the cellular mediators of distant metastasis in solid malignancies. Their metastatic potential can be augmented by clustering with other tumor cells or nonmalignant cells, forming circulating tumor microemboli (CTM). Cell–cell interactions are key regulators within CTM that convey enhanced metastatic properties, including improved cell survival, immune evasion, and effective extravasation into distant organs. However, the cellular and molecular mechanism of CTM formation, as well as the biology of interactions between tumor cells and immune cells, platelets, and stromal cells in the circulation, remains to be determined. Here, we review the current literature on cell–cell interactions in homotypic and heterotypic CTM and provide perspectives on therapeutic strategies to attenuate CTM-mediated metastasis by targeting cell–cell interactions.
Data from Imaging Glioblastoma Response to Radiotherapy Using 2H Magnetic Resonance Spectroscopy Measurements of Fumarate Metabolism
Authors: Hesse Friederike , Wright Alan J. , Somai Vencel , Bulat Flaviu , Kreis Felix , Brindle Kevin M.
Published: March 2024

Abstract
Early detection of tumor cell death in glioblastoma following treatment with chemoradiation has the potential to distinguish between true disease progression and pseudoprogression. Tumor cell death can be detected noninvasively in vivo by imaging the production of [2,3-2H2]malate from [2,3-2H2]fumarate using 2H magnetic resonance (MR) spectroscopic imaging. We show here that 2H MR spectroscopy and spectroscopic imaging measurements of [2,3-2H2]fumarate metabolism can detect tumor cell death in orthotopically implanted glioblastoma models within 48 hours following the completion of chemoradiation. Following the injection of [2,3-2H2]fumarate into tumor-bearing mice, production of [2,3-2H2]malate was measured in a human cell line–derived model and in radiosensitive and radioresistant patient-derived models of glioblastoma that were treated with temozolomide followed by targeted fractionated irradiation. The increase in the [2,3-2H2]malate/[2,3-2H2]fumarate signal ratio posttreatment, which correlated with histologic assessment of cell death, was a more sensitive indicator of treatment response than diffusion-weighted and contrast agent–enhanced 1H MRI measurements, which have been used clinically to detect responses of glioblastoma to chemoradiation. Overall, early detection of glioblastoma cell death using 2H MRI of malate production from fumarate could help improve the clinical evaluation of response to chemoradiation.
Significance:
2H magnetic resonance imaging of labeled fumarate metabolism can detect early evidence of tumor cell death following chemoradiation, meeting a clinical need to reliably detect treatment response in glioblastoma.
Data from A Distinct Chromatin State Drives Therapeutic Resistance in Invasive Lobular Breast Cancer
Authors: Nardone Agostina , Qiu Xintao , Spisak Sandor , Nagy Zsuzsanna , Feiglin Ariel , Feit Avery , Cohen Feit Gabriela , Xie Yingtian , Font-Tello Alba , Guarducci Cristina , Hermida-Prado Francisco , Syamala Sudeepa , Lim Klothilda , Munoz Gomez Miguel , Pun Matthew , Cornwell MacIntosh , Liu Weihan , Ors Aysegul , Mohammed Hisham , Cejas Paloma , Brock Jane B. , Freedman Matthew L. , Winer Eric P. , Fu Xiaoyong , Schiff Rachel , Long Henry W. , Metzger Filho Otto , Jeselsohn Rinath
Published: March 2024

Abstract
Most invasive lobular breast cancers (ILC) are of the luminal A subtype and are strongly hormone receptor–positive. Yet, ILC is relatively resistant to tamoxifen and associated with inferior long-term outcomes compared with invasive ductal cancers (IDC). In this study, we sought to gain mechanistic insights into these clinical findings that are not explained by the genetic landscape of ILC and to identify strategies to improve patient outcomes. A comprehensive analysis of the epigenome of ILC in preclinical models and clinical samples showed that, compared with IDC, ILC harbored a distinct chromatin state linked to gained recruitment of FOXA1, a lineage-defining pioneer transcription factor. This resulted in an ILC-unique FOXA1–estrogen receptor (ER) axis that promoted the transcription of genes associated with tumor progression and poor outcomes. The ILC-unique FOXA1–ER axis led to retained ER chromatin binding after tamoxifen treatment, which facilitated tamoxifen resistance while remaining strongly dependent on ER signaling. Mechanistically, gained FOXA1 binding was associated with the autoinduction of FOXA1 in ILC through an ILC-unique FOXA1 binding site. Targeted silencing of this regulatory site resulted in the disruption of the feed-forward loop and growth inhibition in ILC. In summary, ILC is characterized by a unique chromatin state and FOXA1–ER axis that is associated with tumor progression, offering a novel mechanism of tamoxifen resistance. These results underscore the importance of conducting clinical trials dedicated to patients with ILC in order to optimize treatments in this breast cancer subtype.
Significance:
A unique FOXA1–ER axis in invasive lobular breast cancer promotes disease progression and tamoxifen resistance, highlighting a potential therapeutic avenue for clinical investigations dedicated to this disease.

See related commentary by Blawski and Toska, p. 3668
Data from The Prostate Cancer Androgen Receptor Cistrome in African American Men Associates with Upregulation of Lipid Metabolism and Immune Response
Authors: Berchuck Jacob E. , Adib Elio , Abou Alaiwi Sarah , Dash Amit K. , Shin Jin Na , Lowder Dallin , McColl Collin , Castro Patricia , Carelli Ryan , Benedetti Elisa , Deng Jenny , Robertson Matthew , Baca Sylvan C. , Bell Connor , McClure Heather M. , El Zarif Talal , Davidsohn Matthew P. , Lakshminarayanan Gitanjali , Rizwan Kinza , Skapura Darlene G. , Grimm Sandra L. , Davis Christel M. , Ehli Erik A. , Kelleher Kaitlin M. , Seo Ji-Heui , Mitsiades Nicholas , Coarfa Cristian , Pomerantz Mark M. , Loda Massimo , Ittmann Michael , Freedman Matthew L. , Kaochar Salma
Published: March 2024

Abstract
African-American (AA) men are more likely to be diagnosed with and die from prostate cancer than European American (EA) men. Despite the central role of the androgen receptor (AR) transcription factor in prostate cancer, little is known about the contribution of epigenetics to observed racial disparities. We performed AR chromatin immunoprecipitation sequencing on primary prostate tumors from AA and EA men, finding that sites with greater AR binding intensity in AA relative to EA prostate cancer are enriched for lipid metabolism and immune response genes. Integration with transcriptomic and metabolomic data demonstrated coinciding upregulation of lipid metabolism gene expression and increased lipid levels in AA prostate cancer. In a metastatic prostate cancer cohort, upregulated lipid metabolism associated with poor prognosis. These findings offer the first insights into ancestry-specific differences in the prostate cancer AR cistrome. The data suggest a model whereby increased androgen signaling may contribute to higher levels of lipid metabolism, immune response, and cytokine signaling in AA prostate tumors. Given the association of upregulated lipogenesis with prostate cancer progression, our study provides a plausible biological explanation for the higher incidence and aggressiveness of prostate cancer observed in AA men.
Significance:
With immunotherapies and inhibitors of metabolic enzymes in clinical development, the altered lipid metabolism and immune response in African-American men provides potential therapeutic opportunities to attenuate racial disparities in prostate cancer.
Data from A Genomically and Clinically Annotated Patient-Derived Xenograft Resource for Preclinical Research in Non–Small Cell Lung Cancer
Authors: Woo Xing Yi , Srivastava Anuj , Mack Philip C. , Graber Joel H. , Sanderson Brian J. , Lloyd Michael W. , Chen Mandy , Domanskyi Sergii , Gandour-Edwards Regina , Tsai Rebekah A. , Keck James , Cheng Mingshan , Bundy Margaret , Jocoy Emily L. , Riess Jonathan W. , Holland William , Grubb Stephen C. , Peterson James G. , Stafford Grace A. , Paisie Carolyn , Neuhauser Steven B. , Karuturi R. Krishna Murthy , George Joshy , Simons Allen K. , Chavaree Margaret , Tepper Clifford G. , Goodwin Neal , Airhart Susan D. , Lara Primo N. , Openshaw Thomas H. , Liu Edison T. , Gandara David R. , Bult Carol J.
Published: March 2024

Abstract
Patient-derived xenograft (PDX) models are an effective preclinical in vivo platform for testing the efficacy of novel drugs and drug combinations for cancer therapeutics. Here we describe a repository of 79 genomically and clinically annotated lung cancer PDXs available from The Jackson Laboratory that have been extensively characterized for histopathologic features, mutational profiles, gene expression, and copy-number aberrations. Most of the PDXs are models of non–small cell lung cancer (NSCLC), including 37 lung adenocarcinoma (LUAD) and 33 lung squamous cell carcinoma (LUSC) models. Other lung cancer models in the repository include four small cell carcinomas, two large cell neuroendocrine carcinomas, two adenosquamous carcinomas, and one pleomorphic carcinoma. Models with both de novo and acquired resistance to targeted therapies with tyrosine kinase inhibitors are available in the collection. The genomic profiles of the LUAD and LUSC PDX models are consistent with those observed in patient tumors from The Cancer Genome Atlas and previously characterized gene expression-based molecular subtypes. Clinically relevant mutations identified in the original patient tumors were confirmed in engrafted PDX tumors. Treatment studies performed in a subset of the models recapitulated the responses expected on the basis of the observed genomic profiles. These models therefore serve as a valuable preclinical platform for translational cancer research.
Significance:
Patient-derived xenografts of lung cancer retain key features observed in the originating patient tumors and show expected responses to treatment with standard-of-care agents, providing experimentally tractable and reproducible models for preclinical investigations.
Data from Loss of LOXL2 Promotes Uterine Hypertrophy and Tumor Progression by Enhancing H3K36ac-Dependent Gene Expression
Authors: Lu Xufeng , Xin Dazhuan E. , Du Juanjuan K. , Zou Quanli C. , Wu Qian , Zhang Yanan S. , Deng Wenhai , Yue Jicheng , Fan Xing S. , Zeng Yuanyuan , Cheng Xiaju , Li Xue , Hou Zhaoyuan , Mohan Man , Zhao Ting C. , Lu Xiaomei , Chang Zhijie , Xu Liyan , Sun Yu , Zu Xiongbing , Zhang Yu , Chinn Y. Eugene
Published: March 2024

Abstract
Lysyl oxidase-like 2 (LOXL2) is a member of the scavenger receptor cysteine-rich (SRCR) repeat carrying LOX family. Although LOXL2 is suspected to be involved in histone association and chromatin modification, the role of LOXL2 in epigenetic regulation during tumorigenesis and cancer progression remains unclear. Here, we report that nuclear LOXL2 associates with histone H3 and catalyzes H3K36ac deacetylation and deacetylimination. Both the N-terminal SRCR repeats and the C-terminal catalytic domain of LOXL2 carry redundant deacetylase catalytic activity. Overexpression of LOXL2 markedly reduced H3K36 acetylation and blocked H3K36ac-dependent transcription of genes, including c-MYC, CCND1, HIF1A, and CD44. Consequently, LOXL2 overexpression reduced cancer cell proliferation in vitro and inhibited xenograft tumor growth in vivo. In contrast, LOXL2 deficiency resulted in increased H3K36 acetylation and aberrant expression of H3K36ac-dependent genes involved in multiple oncogenic signaling pathways. Female LOXL2-deficient mice spontaneously developed uterine hypertrophy and uterine carcinoma. Moreover, silencing LOXL2 in cancer cells enhanced tumor progression and reduced the efficacy of cisplatin and anti-programmed cell death 1 (PD-1) combination therapy. Clinically, low nuclear LOXL2 expression and high H3K36ac levels corresponded to poor prognosis in uterine endometrial carcinoma patients. These results suggest that nuclear LOXL2 restricts cancer development in the female reproductive system via the regulation of H3K36ac deacetylation.
Significance:
LOXL2 loss reprograms the epigenetic landscape to promote uterine cancer initiation and progression and repress the efficacy of anti–PD-1 immunotherapy, indicating that LOXL2 is a tumor suppressor.
Data from VRK1 Is a Synthetic–Lethal Target in VRK2-Deficient Glioblastoma
Authors: Shields Julie A. , Meier Samuel R. , Bandi Madhavi , Mulkearns-Hubert Erin E. , Hajdari Nicole , Ferdinez Maria Dam , Engel Justin L. , Silver Daniel J. , Shen Binzhang , Zhang Wenhai , Hubert Christopher G. , Mitchell Kelly , Shakya Sajina , Zhao Shan-Chuan , Bejnood Alborz , Zhang Minjie , Tjin Tham Sjin Robert , Wilker Erik , Lathia Justin D. , Andersen Jannik N. , Chen Yingnan , Li Fang , Weber Barbara , Huang Alan , Emmanuel Natasha
Published: March 2024

Abstract
Synthetic lethality is a genetic interaction that results in cell death when two genetic deficiencies co-occur but not when either deficiency occurs alone, which can be co-opted for cancer therapeutics. Pairs of paralog genes are among the most straightforward potential synthetic–lethal interactions by virtue of their redundant functions. Here, we demonstrate a paralog-based synthetic lethality by targeting vaccinia-related kinase 1 (VRK1) in glioblastoma (GBM) deficient of VRK2, which is silenced by promoter methylation in approximately two thirds of GBM. Genetic knockdown of VRK1 in VRK2-null or VRK2-methylated cells resulted in decreased activity of the downstream substrate barrier to autointegration factor (BAF), a regulator of post-mitotic nuclear envelope formation. Reduced BAF activity following VRK1 knockdown caused nuclear lobulation, blebbing, and micronucleation, which subsequently resulted in G2–M arrest and DNA damage. The VRK1–VRK2 synthetic–lethal interaction was dependent on VRK1 kinase activity and was rescued by ectopic expression of VRK2. In VRK2-methylated GBM cell line–derived xenograft and patient-derived xenograft models, knockdown of VRK1 led to robust tumor growth inhibition. These results indicate that inhibiting VRK1 kinase activity could be a viable therapeutic strategy in VRK2-methylated GBM.
Significance:
A paralog synthetic–lethal interaction between VRK1 and VRK2 sensitizes VRK2-methylated glioblastoma to perturbation of VRK1 kinase activity, supporting VRK1 as a drug discovery target in this disease.
Data from β-Catenin Up-Regulates the Expression of the Urokinase Plasminogen Activator in Human Colorectal Tumors
Authors: Hiendlmeyer Elke , Regus Susanne , Wassermann Stella , Hlubek Falk , Haynl Angela , Dimmler Arno , Koch Claudia , Knoll Claudia , van Beest Moniek , Reuning Ute , Brabletz Thomas , Kirchner Thomas , Jung Andreas
Published: March 2024

Abstract
Expression of the urokinase plasminogen activator (uPA) increases during the progression of colorectal tumors from adenomas to carcinomas. The highest amounts of uPA are found at the invasion front of carcinomas, which also displays a strong expression of nuclear β-catenin and is therefore a region expressing β-catenin target genes at high levels. Here we show that β-catenin contributes to the transactivation of uPA. Therefore, β-catenin might have an impact on the capacity of colorectal tumors for invasion and metastasis, as well as dormancy, which are hallmarks of cancer.
Data from Genomic Landscapes and Hallmarks of Mutant RAS in Human Cancers
Authors: Scharpf Robert B. , Balan Archana , Ricciuti Biagio , Fiksel Jacob , Cherry Christopher , Wang Chenguang , Lenoue-Newton Michele L. , Rizvi Hira A. , White James R. , Baras Alexander S. , Anaya Jordan , Landon Blair V. , Majcherska-Agrawal Marta , Ghanem Paola , Lee Jocelyn , Raskin Leon , Park Andrew S. , Tu Huakang , Hsu Hil , Arbour Kathryn C. , Awad Mark M. , Riely Gregory J. , Lovly Christine M. , Anagnostou Valsamo
Published: March 2024

Abstract
The RAS family of small GTPases represents the most commonly activated oncogenes in human cancers. To better understand the prevalence of somatic RAS mutations and the compendium of genes that are coaltered in RAS-mutant tumors, we analyzed targeted next-generation sequencing data of 607,863 mutations from 66,372 tumors in 51 cancer types in the AACR Project GENIE Registry. Bayesian hierarchical models were implemented to estimate the cancer-specific prevalence of RAS and non-RAS somatic mutations, to evaluate co-occurrence and mutual exclusivity, and to model the effects of tumor mutation burden and mutational signatures on comutation patterns. These analyses revealed differential RAS prevalence and comutations with non-RAS genes in a cancer lineage-dependent and context-dependent manner, with differences across age, sex, and ethnic groups. Allele-specific RAS co-mutational patterns included an enrichment in NTRK3 and chromatin-regulating gene mutations in KRAS G12C-mutant non–small cell lung cancer. Integrated multiomic analyses of 10,217 tumors from The Cancer Genome Atlas (TCGA) revealed distinct genotype-driven gene expression programs pointing to differential recruitment of cancer hallmarks as well as phenotypic differences and immune surveillance states in the tumor microenvironment of RAS-mutant tumors. The distinct genomic tracks discovered in RAS-mutant tumors reflected differential clinical outcomes in TCGA cohort and in an independent cohort of patients with KRAS G12C-mutant non–small cell lung cancer that received immunotherapy-containing regimens. The RAS genetic architecture points to cancer lineage–specific therapeutic vulnerabilities that can be leveraged for rationally combining RAS-mutant allele-directed therapies with targeted therapies and immunotherapy.
Significance:
The complex genomic landscape of RAS-mutant tumors is reflective of selection processes in a cancer lineage–specific and context-dependent manner, highlighting differential therapeutic vulnerabilities that can be clinically translated.
Data from An Exercise-Induced Metabolic Shield in Distant Organs Blocks Cancer Progression and Metastatic Dissemination
Authors: Sheinboim Danna , Parikh Shivang , Manich Paulee , Markus Irit , Dahan Sapir , Parikh Roma , Stubbs Elisa , Cohen Gali , Zemser-Werner Valentina , Bell Rachel E. , Ruiz Sara Arciniegas , Percik Ruth , Brenner Ronen , Leibou Stav , Vaknine Hananya , Arad Gali , Gerber Yariv , Keinan-Boker Lital , Shimony Tal , Bikovski Lior , Goldstein Nir , Constantini Keren , Labes Sapir , Mordechai Shimonov , Doron Hila , Lonescu Ariel , Ziv Tamar , Nizri Eran , Choshen Guy , Eldar-Finkelman Hagit , Tabach Yuval , Helman Aharon , Ben-Eliyahu Shamgar , Erez Neta , Perlson Eran , Geiger Tamar , Ben-Zvi Danny , Khaled Mehdi , Gepner Yftach , Levy Carmit
Published: March 2024

Abstract
Exercise prevents cancer incidence and recurrence, yet the underlying mechanism behind this relationship remains mostly unknown. Here we report that exercise induces the metabolic reprogramming of internal organs that increases nutrient demand and protects against metastatic colonization by limiting nutrient availability to the tumor, generating an exercise-induced metabolic shield. Proteomic and ex vivo metabolic capacity analyses of murine internal organs revealed that exercise induces catabolic processes, glucose uptake, mitochondrial activity, and GLUT expression. Proteomic analysis of routinely active human subject plasma demonstrated increased carbohydrate utilization following exercise. Epidemiologic data from a 20-year prospective study of a large human cohort of initially cancer-free participants revealed that exercise prior to cancer initiation had a modest impact on cancer incidence in low metastatic stages but significantly reduced the likelihood of highly metastatic cancer. In three models of melanoma in mice, exercise prior to cancer injection significantly protected against metastases in distant organs. The protective effects of exercise were dependent on mTOR activity, and inhibition of the mTOR pathway with rapamycin treatment ex vivo reversed the exercise-induced metabolic shield. Under limited glucose conditions, active stroma consumed significantly more glucose at the expense of the tumor. Collectively, these data suggest a clash between the metabolic plasticity of cancer and exercise-induced metabolic reprogramming of the stroma, raising an opportunity to block metastasis by challenging the metabolic needs of the tumor.
Significance:
Exercise protects against cancer progression and metastasis by inducing a high nutrient demand in internal organs, indicating that reducing nutrient availability to tumor cells represents a potential strategy to prevent metastasis.

See related commentary by Zerhouni and Piskounova, p. 4124
Data from FILIP1L Loss Is a Driver of Aggressive Mucinous Colorectal Adenocarcinoma and Mediates Cytokinesis Defects through PFDN1
Authors: Kwon Mijung , Rubio Genesaret , Nolan Nicholas , Auteri Peter , Volmar Jean Arly , Adem Asha , Javidian Parisa , Zhou Zhongren , Verzi Michael P. , Pine Sharon R. , Libutti Steven K.
Published: March 2024

Abstract
Aneuploid mucinous colorectal adenocarcinoma (MAC) is an aggressive subtype of colorectal cancer with poor prognosis. The tumorigenic mechanisms in aneuploid MAC are currently unknown. Here we show that downregulation of Filamin A–interacting protein 1-like (FILIP1L) is a driver of MAC. Loss of FILIP1L increased xenograft growth, and, in colon-specific knockout mice, induced colonic epithelial hyperplasia and mucin secretion. The molecular chaperone prefoldin 1 (PFDN1) was identified as a novel binding partner of FILIP1L at the centrosomes throughout mitosis. FILIP1L was required for proper centrosomal localization of PFDN1 and regulated proteasome-dependent degradation of PFDN1. Importantly, increased PFDN1, caused by downregulation of FILIP1L, drove multinucleation and cytokinesis defects in vitro and in vivo, which were confirmed by time-lapse imaging and 3D cultures of normal epithelial cells. Overall, these findings suggest that downregulation of FILIP1L and subsequent upregulation of PFDN1 is a driver of the unique neoplastic characteristics in aggressive aneuploid MAC.
Significance:
This study identifies FILIP1L as a tumor suppressor in mucinous colon cancer and demonstrates that FILIP1L loss results in aberrant stabilization of a centrosome-associated chaperone protein to drive aneuploidy and disease progression.
Data from Development of Gene Expression–Based Score to Predict Sensitivity of Multiple Myeloma Cells to DNA Methylation Inhibitors
Authors: Moreaux Jérôme , Rème Thierry , Leonard Wim , Veyrune Jean-Luc , Requirand Guilhem , Goldschmidt Hartmut , Hose Dirk , Klein Bernard
Published: March 2024

Abstract
Multiple myeloma is a plasma cell cancer with poor survival, characterized by the clonal expansion of multiple myeloma cells (MMC), primarily in the bone marrow. Novel compounds are currently tested in this disease, but partial or minor patients' responses are observed for most compounds used as a single agent. The design of predictors for drug efficacy could be most useful to better understand basic mechanisms targeted by these drugs and design clinical trials. In the current study, we report the building of a DNA methylation score (DM score) predicting the efficacy of decitabine, an inhibitor of DNA methyltransferase (DNMT), targeting methylation-regulated gene expression. DM score was built by identifying 47 genes regulated by decitabine in human myeloma cell lines and the expression of which in primary MMCs of previously untreated patients is predictive for overall survival. A high DM score predicts patients' poor survival, and, of major interest, high sensitivity of primary MMCs or human myeloma cell lines to decitabine in vitro. Thus, DM score could be useful to design novel treatments with DMNT inhibitor in multiple myeloma and has highlighted 47 genes, the gene products of which could be important for multiple myeloma disease development. Mol Cancer Ther; 11(12); 2685–92. ©2012 AACR.
Data from hTERT Promotes Imatinib Resistance in Chronic Myeloid Leukemia Cells: Therapeutic Implications
Authors: Deville Laure , Hillion Josette , Pendino Frédéric , Samy Mona , Nguyen Eric , Ségal-Bendirdjian Evelyne
Published: March 2024

Abstract
Imatinib mesylate has shown remarkable efficacy in the treatment of patients in the chronic phase of chronic myeloid leukemia. However, despite an overall significant hematological and cytogenetic response, imatinib therapy may favor the emergence of drug-resistant clones, ultimately leading to relapse. Some imatinib resistance mechanisms had not been fully elucidated yet. In this study we used sensitive and resistant sublines from a Bcr-Abl positive cell line to investigate the putative involvement of telomerase in the promotion of imatinib resistance. We showed that sensitivity to imatinib can be partly restored in imatinib-resistant cells by targeting telomerase expression, either by the introduction of a dominant-negative form of the catalytic protein subunit of the telomerase (hTERT) or by the treatment with all-trans-retinoic acid, a clinically used drug. Furthermore, we showed that hTERT overexpression favors the development of imatinib resistance through both its antiapoptotic and telomere maintenance functions. Therefore, combining antitelomerase strategies to imatinib treatment at the beginning of the treatment should be promoted to reduce the risk of imatinib resistance development and increase the probability of eradicating the disease. Mol Cancer Ther; 10(5); 711–19. ©2011 AACR.
Data from FcRL5 as a Target of Antibody–Drug Conjugates for the Treatment of Multiple Myeloma
Authors: Elkins Kristi , Zheng Bing , Go MaryAnn , Slaga Dionysos , Du Changchun , Scales Suzie J. , Yu Shang-Fan , McBride Jacqueline , de Tute Ruth , Rawstron Andy , Jack Andrew S. , Ebens Allen , Polson Andrew G.
Published: March 2024

Abstract
Fc receptor-like 5 (FcRL5/FcRH5/IRTA2/CD307) is a surface protein expressed selectively on B cells and plasma cells. We found that FcRL5 was expressed at elevated levels on the surface of plasma cells from the bone marrow of patients diagnosed with multiple myeloma. This prevalence in multiple myeloma and narrow pattern of normal expression indicate that FcRL5 could be a target for antibody-based therapies for multiple myeloma, particularly antibody–drug conjugates (ADC), potent cytotoxic drugs linked to antibodies via specialized chemical linkers, where limited expression on normal tissues is a key component to their safety. We found that FcRL5 is internalized upon antibody binding, indicating that ADCs to FcRL5 could be effective. Indeed, we found that FcRL5 ADCs were efficacious in vitro and in vivo but the unconjugated antibody was not. The two most effective consisted of our anti-FcRL5 antibody conjugated through cysteines to monomethylauristatin E (MMAE) by a maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (MC-vcPAB) linker (anti-FcRL5-MC-vcPAB-MMAE) or conjugated via lysines to the maytansinoid DM4 through a disulfide linker (anti-FcRL5-SPDB-DM4). These two ADCs were highly effective in vivo in combination with bortezomib or lenalidomide, drugs in use for the treatment of multiple myeloma. These data show that the FcRL5 ADCs described herein show promise as an effective treatment for multiple myeloma. Mol Cancer Ther; 11(10); 2222–32. ©2012 AACR.
Data from Digitoxin-Induced Cytotoxicity in Cancer Cells Is Mediated through Distinct Kinase and Interferon Signaling Networks
Authors: Prassas Ioannis , Karagiannis George S. , Batruch Ihor , Dimitromanolakis Apostolos , Datti Alessandro , Diamandis Eleftherios P.
Published: March 2024

Abstract
Cardiac glycosides (e.g., digoxin, digitoxin) constitute a diverse family of plant-derived sodium pump inhibitors that have been in clinical use for the treatment of heart-related diseases (congestive heart failure, atrial arrhythmia) for many years. Recently though, accumulating in vitro and in vivo evidence highlight potential anticancer properties of these compounds. Despite the fact that members of this family have advanced to clinical trial testing in cancer therapeutics, their cytotoxic mechanism is not yet elucidated. In this study, we investigated the cytotoxic properties of cardiac glycosides against a panel of pancreatic cancer cell lines, explored their apoptotic mechanism, and characterized the kinetics of cell death induced by these drugs. Furthermore, we deployed a high-throughput kinome screening approach and identified several kinases of the Na-K-ATPase-mediated signal transduction circuitry (epidermal growth factor receptor, Src, pkC, and mitogen-activated protein kinases) as important mediators downstream of cardiac glycoside cytotoxic action. To further extend our knowledge on their mode of action, we used mass-spectrometry–based quantitative proteomics (stable isotope labeling of amino acids in cell culture) coupled with bioinformatics to capture large-scale protein perturbations induced by a physiological dose of digitoxin in BxPC-3 pancreatic cancer cells and identified members of the interferon family as key regulators of the main protein/protein interactions downstream of digitoxin action. Hence, our findings provide more in-depth information regarding the molecular mechanisms underlying cardiac glycoside-induced cytotoxicity. Mol Cancer Ther; 10(11); 2083–93. ©2011 AACR.
Data from Navitoclax (ABT-263) Reduces Bcl-xL–Mediated Chemoresistance in Ovarian Cancer Models
Authors: Wong Maureen , Tan Nguyen , Zha Jiping , Peale Franklin V. , Yue Peng , Fairbrother Wayne J. , Belmont Lisa D.
Published: March 2024

Abstract
To examine the potential of combining Bcl-2 family inhibitors with chemotherapy in ovarian cancer, we evaluated a panel of 27 ovarian cancer cell lines for response to the combination of navitoclax (formerly ABT-263) and paclitaxel or gemcitabine. The majority of cell lines exhibited a greater than additive response to either combination, as determined by the Bliss independence model, and more than 50% of the ovarian cell lines exhibited strong synergy for the navitoclax/paclitaxel combination. To identify biomarkers for tumors likely to respond to this combination, we evaluated the protein levels of intrinsic apoptosis pathway components. Bcl-xL seems necessary, but not sufficient, for navitoclax/paclitaxel synergy in vitro, suggesting that exclusion of patients whose tumors have low or undetectable Bcl-xL would enrich for patients responsive to the combination. We evaluated Bcl-xL levels in ovarian cancer tumor tissue from 40 patients (20 taxane responsive and 20 with poor response to taxane) and found that patients with high Bcl-xL were less sensitive to taxane treatment (10 of 12) Bcl-xL positive patients, P = 0.014). These data support the use of navitoclax in combination with taxane-based therapy in ovarian cancer patients with high levels of Bcl-xL. Mol Cancer Ther; 11(4); 1026–35. ©2012 AACR.
Data from Lipoprotein Lipase Links Dietary Fat to Solid Tumor Cell Proliferation
Authors: Kuemmerle Nancy B. , Rysman Evelien , Lombardo Portia S. , Flanagan Alison J. , Lipe Brea C. , Wells Wendy A. , Pettus Jason R. , Froehlich Heather M. , Memoli Vincent A. , Morganelli Peter M. , Swinnen Johannes V. , Timmerman Luika A. , Chaychi Leila , Fricano Catherine J. , Eisenberg Burton L. , Coleman William B. , Kinlaw William B.
Published: March 2024

Abstract
Many types of cancer cells require a supply of fatty acids (FA) for growth and survival, and interrupting de novo FA synthesis in model systems causes potent anticancer effects. We hypothesized that, in addition to synthesis, cancer cells may obtain preformed, diet-derived FA by uptake from the bloodstream. This would require hydrolytic release of FA from triglyceride in circulating lipoprotein particles by the secreted enzyme lipoprotein lipase (LPL), and the expression of CD36, the channel for cellular FA uptake. We find that selected breast cancer and sarcoma cells express and secrete active LPL, and all express CD36. We further show that LPL, in the presence of triglyceride-rich lipoproteins, accelerates the growth of these cells. Providing LPL to prostate cancer cells, which express low levels of the enzyme, did not augment growth, but did prevent the cytotoxic effect of FA synthesis inhibition. Moreover, LPL knockdown inhibited HeLa cell growth. In contrast to the cell lines, immunohistochemical analysis confirmed the presence of LPL and CD36 in the majority of breast, liposarcoma, and prostate tumor tissues examined (n = 181). These findings suggest that, in addition to de novo lipogenesis, cancer cells can use LPL and CD36 to acquire FA from the circulation by lipolysis, and this can fuel their growth. Interfering with dietary fat intake, lipolysis, and/or FA uptake will be necessary to target the requirement of cancer cells for FA. Mol Cancer Ther; 10(3); 427–36. ©2011 AACR.
Data from 2-Methoxy-5-Amino-N-Hydroxybenzamide Sensitizes Colon Cancer Cells to TRAIL-Induced Apoptosis by Regulating Death Receptor 5 and Survivin Expression
Authors: Stolfi Carmine , Caruso Roberta , Franzè Eleonora , Rizzo Angelamaria , Rotondi Angela , Monteleone Ivan , Fantini Massimo Claudio , Pallone Francesco , Monteleone Giovanni
Published: March 2024

Abstract
TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis is a crucial event in the control of tumor growth. However, many cancer cells, including colon cancer cells, are resistant to TRAIL-driven cell death. We have recently shown that 2-methoxy-5-amino-N-hydroxybenzamide (herein termed 2-14), a novel derivative of mesalamine, induces endoplasmic reticulum stress in colon cancer cells. Because endoplasmic reticulum stress-induced signals regulate the expression of molecules involved in TRAIL-driven apoptosis, we examined whether 2-14 makes colon cancer cells sensitive to TRAIL. Colon cancer cells were cultured with 2-14 and/or TRAIL. Death receptor (DR) 4/DR5 were analyzed by real-time PCR and flow cytometry. TRAIL pathway–associated proteins and extracellular signal–regulated kinase (ERK) were assessed by Western blotting. The in vivo capability of 2-14 to sensitize colon cancer cells to TRAIL-induced apoptosis was evaluated in a syngenic colon cancer model in which CT26-derived grafts were induced in mice. 2-14 promoted ERK-dependent induction of DR5, thereby enhancing TRAIL-mediated caspase-8 activation and apoptosis. Analysis of TRAIL-related pro- and antiapoptotic factors and functional studies revealed that survivin is involved in the protection of colon cancer cells against TRAIL-driven apoptosis. Notably, 2-14 enhanced ubiquitination and proteasome-mediated degradation of survivin. These data were confirmed in a murine model of TRAIL-resistant colon cancer in which 2-14 upregulated DR5, reduced survivin expression, and synergized with TRAIL in inhibiting tumor growth. Similarly, intraperitoneal administration of 2-14 to mice upregulated DR5 and downregulated survivin in a model of colitis-associated colon cancer. These findings indicate that 2-14 acts as a sensitizer for TRAIL-induced apoptosis and suggest that 2-14 can be useful in the therapy for TRAIL-resistant colon cancer. Mol Cancer Ther; 10(10); 1969–81. ©2011 AACR.
Data from Pharmacodynamic Evaluation of the Target Efficacy of SB939, an Oral HDAC Inhibitor with Selectivity for Tumor Tissue
Authors: Novotny-Diermayr Veronica , Sausgruber Nina , Loh Yung Kiang , Pasha Mohammed Khalid , Jayaraman Ramesh , Hentze Hannes , Yong Wei-Peng , Goh Boon-Cher , Toh Han-Chong , Ethirajulu Kantharaj , Zhu Joy , Wood Jeanette Marjorie
Published: March 2024

Abstract
SB939 is an oral histone deacetylase (HDAC) inhibitor currently in phase II clinical trials potently inhibiting class I, II, and IV HDACs with favorable pharmacokinetic properties, resulting in tumor tissue accumulation. To show target efficacy, a Western blot assay measuring histone H3 acetylation (acH3) relative to a loading control was developed, validated on cancer cell lines, peripheral blood mononuclear cells (PBMC), and in animal tumor models. Exposure of cells to 60 nmol/L (22 ng/mL) SB939 for 24 hours was sufficient to detect an acH3 signal in 25 μg of protein lysate. AcH3 levels of liver, spleen, PBMCs, bone marrow and tumor were measured in BALB/c mice, HCT-116 xenografted BALB/c nude mice, or in SCID mice orthotopically engrafted with AML (HL-60) after oral treatment with SB939. AcH3 could only be detected after treatment. In all tissues, the highest signal detected was at the 3-hour time point on day 1. On day 15, the signal decreased in normal tissues but increased in cancerous tissues and became detectable in the bone marrow of leukemic mice. In all tissues, acH3 correlated with SB939 dose levels (r2 = 0.76–0.94). When applied to PBMCs from 30 patients with advanced solid malignancies in a phase I clinical trial, a dose-dependent (10–80 mg) increase in relative acH3 was observed 3-hour postdose on day 1, correlating with Cmax and AUC of SB939 concentrations in plasma (r = 0.97, P = 0.014). Our data show that the favorable pharmacokinetic and pharmacodynamic properties of SB939 are translated from preclinical models to patients. Mol Cancer Ther; 10(7); 1207–17. ©2011 AACR.
Data from Therapeutic Potential and Molecular Mechanism of a Novel, Potent, Nonpeptide, Smac Mimetic SM-164 in Combination with TRAIL for Cancer Treatment
Authors: Lu Jianfeng , McEachern Donna , Sun Haiying , Bai Longchuan , Peng Yuefeng , Qiu Su , Miller Rebecca , Liao Jinhui , Yi Han , Liu Meilan , Bellail Anita , Hao Chunhai , Sun Shi-Yong , Ting Adrian T. , Wang Shaomeng
Published: March 2024

Abstract
Smac mimetics are being developed as a new class of anticancer therapies. Because the single-agent activity of Smac mimetics is very limited, rational combinations represent a viable strategy for their clinical development. The combination of Smac mimetics with TNF-related apoptosis inducing ligand (TRAIL) may be particularly attractive because of the low toxicity of TRAIL to normal cells and the synergistic antitumor activity observed for the combination. In this study, we have investigated the combination synergy between TRAIL and a potent Smac mimetic, SM-164, in vitro and in vivo and the underlying molecular mechanism of action for the synergy. Our study shows that SM-164 is highly synergistic with TRAIL in vitro in both TRAIL-sensitive and TRAIL-resistant cancer cell lines of breast, prostate, and colon cancer. Furthermore, the combination of SM-164 with TRAIL induces rapid tumor regression in vivo in a breast cancer xenograft model in which either agent is ineffective. Our data show that X-linked IAP (XIAP) and cellular IAP 1 (cIAP1), but not cIAP2, work in concert to attenuate the activity of TRAIL; SM-164 strongly enhances TRAIL activity by concurrently targeting XIAP and cIAP1. Moreover, although RIP1 plays a minimal role in the activity of TRAIL as a single agent, it is required for the synergistic interaction between TRAIL and SM-164. This study provides a strong rationale to develop the combination of SM-164 and TRAIL as a new therapeutic strategy for the treatment of human cancer. Mol Cancer Ther; 10(5); 902–14. ©2011 AACR.
Data from Low-Dose Fractionated Radiation Potentiates the Effects of Cisplatin Independent of the Hyper-Radiation Sensitivity in Human Lung Cancer Cells
Authors: Gupta Seema , Koru-Sengul Tulay , Arnold Susanne M. , Devi Gayathri R. , Mohiuddin Mohammed , Ahmed Mansoor M.
Published: March 2024

Abstract
In this study, the role of hyper-radiation sensitivity (HRS) in potentiating the effects of cisplatin by low-dose fractionated radiation (LDFRT) was evaluated in four human non–small cell lung cancer cell lines. Presence of HRS and cisplatin enhancement ratio (CER) by LDFRT/2 Gy was assessed using colony-forming and apoptotic assays. Cell-cycle disturbances were studied by flow cytometry. Expression of genes involved in apoptosis was assessed using real-time reverse transcriptase PCR arrays. H-157 cells showed a distinct HRS region, followed by UKY-29 and A549 cells, whereas it was absent in H460 cells, which when lack HRS showed maximum CER with LDFRT (4 × 0.5 Gy) both by clonogenic inhibition and by apoptosis compared with single fraction of 2 Gy whereas the most radioresistant A549 cells had the least CER, with no significant differences between LDFRT or 2 Gy. Interestingly, in H-157 cells, a more pronounced CER was observed with LDFRT when assessed by apoptosis but clonogenic inhibition-CER was higher with 2 Gy than with LDFRT. Excluding H-157 cells, the CER by LDFRT was inversely proportional to radioresistance [(determined by D0, the dose to reduce survival by 67% from any point on the linear portion of the survival curve or surviving fraction (SF) at 2 Gy (SF2)] of the cells. LDFRT alone or in combination with cisplatin induced larger number of proapoptotic genes than 2 Gy or cisplatin + 2 Gy in cells showing HRS when compared to H460 cells that lack HRS. These findings indicate that chemopotentiation by LDFRT is correlated more with the intrinsic radiation sensitivity of the non–small lung cancer cells than the HRS phenomenon whereas the mode of cell killing is both through apoptosis and clonogenic inhibition. Mol Cancer Ther; 10(2); 292–302. ©2011 AACR.