bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from MYC Drives Group 3 Medulloblastoma through Transformation of Sox2+ Astrocyte Progenitor Cells
Authors: Tao Ran , Murad Najiba , Xu Zhenhua , Zhang Peng , Okonechnikov Konstantin , Kool Marcel , Rivero-Hinojosa Samuel , Lazarski Christopher , Zheng Pan , Liu Yang , Eberhart Charles G. , Rood Brian R. , Packer Roger , Pei Yanxin
Published: March 2024

Abstract
A subset of group 3 medulloblastoma frequently harbors amplification or overexpression of MYC lacking additional focal aberrations, yet it remains unclear whether MYC overexpression alone can induce tumorigenesis and which cells give rise to these tumors. Here, we showed that astrocyte progenitors in the early postnatal cerebellum were susceptible to transformation by MYC. The resulting tumors specifically resembled human group 3 medulloblastoma based on histology and gene-expression profiling. Gene-expression analysis of MYC-driven medulloblastoma cells revealed altered glucose metabolic pathways with marked overexpression of lactate dehydrogenase A (LDHA). LDHA abundance correlated positively with MYC expression and was associated with poor prognosis in human group 3 medulloblastoma. Inhibition of LDHA significantly reduced growth of both mouse and human MYC-driven tumors but had little effect on normal cerebellar cells or SHH-associated medulloblastoma. By generating a new mouse model, we demonstrated for the first time that astrocyte progenitors can be transformed by MYC and serve as the cells of origin for group 3 medulloblastoma. Moreover, we identified LDHA as a novel, specific therapeutic target for this devastating disease.
Significance:
Insights from a new model identified LDHA as a novel target for group 3 medulloblastoma, paving the way for the development of effective therapies against this disease.
Data from AQP4 Aggregation State Is a Determinant for Glioma Cell Fate
Authors: Simone Laura , Pisani Francesco , Mola Maria G. , De Bellis Manuela , Merla Giuseppe , Micale Lucia , Frigeri Antonio , Vescovi Angelo L. , Svelto Maria , Nicchia Grazia P.
Published: March 2024

Abstract
The glial water channel protein aquaporin-4 (AQP4) forms heterotetramers in the plasma membrane made of the M23-AQP4 and M1-AQP4 isoforms. The isoform ratio controls AQP4 aggregation into supramolecular structures called orthogonal arrays of particles (AQP4-OAP). The role of AQP4 aggregation into OAP in malignant gliomas is still unclear. In this study, we demonstrate that AQP4 aggregation/disaggregation into OAP influences the biology of glioma cells. Selective expression of the OAP-forming isoform M23-AQP4 (AQP4-OAP) triggered cell shape changes in glioma cells associated with alterations to the F-actin cytoskeleton that affected apoptosis. By contrast, expression of M1-AQP4 (AQP4-tetramers), which is unable to aggregate into OAP, ameliorated glioma cell invasiveness, improved cell migration, and increased methalloproteinase-9 activity. Two prolines (254 and 296) at the C-terminus tail were shown to be important in mediating the relationship between the actin cytoskeleton and AQP4-OAP and AQP4-tetramers. In conclusion, this study demonstrates that AQP4 aggregation state might be an important determinant in orienting glioma cells to persist or perish. AQP4 disaggregation may potentiate invasiveness potential, whereas AQP4 aggregation may activate the apoptotic path. This study shows a new perspective on the role of AQP4 in brain tumors not necessarily associated with edema formation but with AQP4 aggregation/disaggregation dynamics and their link with the actin cytoskeleton.
Significance:
This study demonstrates how AQP4 aggregation influences plasma membrane dynamics to alter cell proliferation, invasiveness, migration, and apoptotic potential in glioma cells.
Data from Enhanced Fatty Acid Scavenging and Glycerophospholipid Metabolism Accompany Melanocyte Neoplasia Progression in Zebrafish
Authors: Henderson Fiona , Johnston Hannah R. , Badrock Andrew P. , Jones Emrys A. , Forster Duncan , Nagaraju Raghavendar T. , Evangelou Christos , Kamarashev Jivko , Green Michael , Fairclough Michael , Ramirez Irene Barinaga-Rementeria , He Shuning , Snaar-Jagalska B. Ewa , Hollywood Katherine , Dunn Warwick B. , Spaink Herman P. , Smith Michael P. , Lorigan Paul , Claude Emmanuelle , Williams Kaye J. , McMahon Adam W. , Hurlstone Adam
Published: March 2024

Abstract
Alterations in lipid metabolism in cancer cells impact cell structure, signaling, and energy metabolism, making lipid metabolism a potential diagnostic marker and therapeutic target. In this study, we combined PET, desorption electrospray ionization-mass spectrometry (DESI-MS), nonimaging MS, and transcriptomic analyses to interrogate changes in lipid metabolism in a transgenic zebrafish model of oncogenic RAS-driven melanocyte neoplasia progression. Exogenous fatty acid uptake was detected in melanoma tumor nodules by PET using the palmitic acid surrogate tracer 14(R,S)-18F-fluoro-6-thia-heptadecanoic acid ([18F]-FTHA), consistent with upregulation of genes associated with fatty acid uptake found through microarray analysis. DESI-MS imaging revealed that FTHA uptake in tumors was heterogeneous. Transcriptome and lipidome analyses further highlighted dysregulation of glycerophospholipid pathways in melanoma tumor nodules, including increased abundance of phosphatidyl ethanolamine and phosphatidyl choline species, corroborated by DESI-MS, which again revealed heterogeneous phospholipid composition in tumors. Overexpression of the gene encoding lipoprotein lipase (LPL), which was upregulated in zebrafish melanocyte tumor nodules and expressed in the majority of human melanomas, accelerated progression of oncogenic RAS-driven melanocyte neoplasia in zebrafish. Depletion or antagonism of LPL suppressed human melanoma cell growth; this required simultaneous fatty acid synthase (FASN) inhibition when FASN expression was also elevated. Collectively, our findings implicate fatty acid acquisition as a possible therapeutic target in melanoma, and the methods we developed for monitoring fatty acid uptake have potential for diagnosis, patient stratification, and monitoring pharmacologic response.
Significance:
These findings demonstrate the translational potential of monitoring fatty acid uptake and identify lipoprotein lipase as a potential therapeutic target in melanoma.
Data from Engineering the Human Fc Region Enables Direct Cell Killing by Cancer Glycan–Targeting Antibodies without the Need for Immune Effector Cells or Complement
Authors: Vankemmelbeke Mireille , McIntosh Richard S. , Chua Jia Xin , Kirk Thomas , Daniels Ian , Patsalidou Marilena , Moss Robert , Parsons Tina , Scott David , Harris Gemma , Ramage Judith M. , Spendlove Ian , Durrant Lindy G.
Published: March 2024

Abstract
Murine IgG3 glycan-targeting mAb often induces direct cell killing in the absence of immune effector cells or complement via a proinflammatory mechanism resembling oncotic necrosis. This cancer cell killing is due to noncovalent association between Fc regions of neighboring antibodies, resulting in enhanced avidity. Human isotypes do not contain the residues underlying this cooperative binding mode; consequently, the direct cell killing of mouse IgG3 mAb is lost upon chimerization or humanization. Using the Lewisa/c/x -targeting 88mAb, we identified the murine IgG3 residues underlying the direct cell killing and increased avidity via a series of constant region shuffling and subdomain swapping approaches to create improved (“i”) chimeric mAb with enhanced tumor killing in vitro and in vivo. Constant region shuffling identified a major CH3 and a minor CH2 contribution, which was further mapped to discontinuous regions among residues 286–306 and 339–378 that, when introduced in 88hIgG1, recapitulated the direct cell killing and avidity of 88mIgG3. Of greater interest was the creation of a sialyl-di-Lewisa–targeting i129G1 mAb via introduction of these selected residues into 129hIgG1, converting it into a direct cell killing mAb with enhanced avidity and significant in vivo tumor control. The human iG1 mAb, termed Avidimabs, retained effector functions, paving the way for the proinflammatory direct cell killing to promote antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity through relief of immunosuppression. Ultimately, Fc engineering of human glycan-targeting IgG1 mAb confers proinflammatory direct cell killing and enhanced avidity, an approach that could be used to improve the avidity of other mAb with therapeutic potential.
Significance:
Fc engineering enhances avidity and direct cell killing of cancer-targeting anti-glycan antibodies to create superior clinical candidates for cancer immunotherapy.
Data from HIF2-Induced Long Noncoding RNA RAB11B-AS1 Promotes Hypoxia-Mediated Angiogenesis and Breast Cancer Metastasis
Authors: Niu Yanling , Bao Lei , Chen Yan , Wang Chenliang , Luo Maowu , Zhang Bo , Zhou Mi , Wang Jennifer E. , Fang Yisheng V. , Kumar Ashwani , Xing Chao , Wang Yingfei , Luo Weibo
Published: March 2024

Abstract
Hypoxia induces a vast array of long noncoding RNAs (lncRNA) in breast cancer cells, but their biological functions remain largely unknown. Here, we identified a hitherto uncharacterized hypoxia-induced lncRNA RAB11B-AS1 in breast cancer cells. RAB11B-AS1 is a natural lncRNA upregulated in human breast cancer and its expression is induced by hypoxia-inducible factor 2 (HIF2), but not HIF1, in response to hypoxia. RAB11B-AS1 enhanced the expression of angiogenic factors including VEGFA and ANGPTL4 in hypoxic breast cancer cells by increasing recruitment of RNA polymerase II. In line with increased angiogenic factors, conditioned media from RAB11B-AS1-overexpressing breast cancer cells promoted tube formation of human umbilical vein endothelial cells in vitro. Gain- and loss-of-function studies revealed that RAB11B-AS1 increased breast cancer cell migration and invasion in vitro and promoted tumor angiogenesis and breast cancer distant metastasis without affecting primary tumor growth in mice. Taken together, these findings uncover a fundamental mechanism of hypoxia-induced tumor angiogenesis and breast cancer metastasis.
Significance:
This study reveals the molecular mechanism by which the lncRNA RAB11B-AS1 regulates hypoxia-induced angiogenesis and breast cancer metastasis, and provides new insights into the functional interaction between a lncRNA and tumor microenvironment.
Data from Tumor Mutational Burden Is Polygenic and Genetically Associated with Complex Traits and Diseases
Authors: Sun Xiwei , Xue Angli , Qi Ting , Chen Dan , Shi Dandan , Wu Yang , Zheng Zhili , Zeng Jian , Yang Jian
Published: March 2024

Abstract
Tumor mutational burden (TMB) is an emerging biomarker of response to immunotherapy in solid tumors. However, the extent to which variation in TMB between patients is attributable to germline genetic variation remains elusive. Here, using 7,004 unrelated patients of European descent across 33 cancer types from The Cancer Genome Atlas, we show that pan-cancer TMB is polygenic with approximately 13% of its variation explained by approximately 1.1 million common variants altogether. We identify germline variants that affect TMB in stomach adenocarcinoma through altering the expression levels of BAG5 and KLC1. Further analyses provide evidence that TMB is genetically associated with complex traits and diseases, such as smoking, rheumatoid arthritis, height, and cancers, and some of the associations are likely causal. Overall, these results provide new insights into the genetic basis of somatic mutations in tumors and may inform future efforts to use genetic variants to stratify patients for immunotherapy.
Significance:
This study provides evidence for a polygenic architecture of tumor mutational burden and opens an avenue for the use of whole-genome germline genetic variations to stratify patients with cancer for immunotherapy.
Data from Lymphatic PD-L1 Expression Restricts Tumor-Specific CD8+ T-cell Responses
Authors: Cousin Nikola , Cap Stefan , Dihr Manuel , Tacconi Carlotta , Detmar Michael , Dieterich Lothar C.
Published: March 2024

Abstract
Lymph node (LN)–resident lymphatic endothelial cells (LEC) mediate peripheral tolerance by self-antigen presentation on MHC-I and constitutive expression of T-cell inhibitory molecules, including PD-L1 (CD274). Tumor-associated LECs also upregulate PD-L1, but the specific role of lymphatic PD-L1 in tumor immunity is not well understood. In this study, we generated a mouse model lacking lymphatic PD-L1 expression and challenged these mice with two orthotopic tumor models, B16F10 melanoma and MC38 colorectal carcinoma. Lymphatic PD-L1 deficiency resulted in consistent expansion of tumor-specific CD8+ T cells in tumor-draining LNs in both tumor models, reduced primary tumor growth in the MC38 model, and increased efficacy of adoptive T-cell therapy in the B16F10 model. Strikingly, lymphatic PD-L1 acted primarily by inducing apoptosis in tumor-specific CD8+ central memory T cells. Overall, these findings demonstrate that LECs restrain tumor-specific immunity via PD-L1, which may explain why some patients with cancer without PD-L1 expression in the tumor microenvironment still respond to PD-L1/PD-1–targeted immunotherapy.
Significance:
A new lymphatic-specific PD-L1 knockout mouse model reveals that lymphatic endothelial PD-L1 expression reduces tumor immunity, inducing apoptosis in tumor-specific CD8+ central memory cells in tumor-draining lymph nodes.
Data from Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma Determine Response to SLC7A11 Inhibition
Authors: Sharbeen George , McCarroll Joshua A. , Akerman Anouschka , Kopecky Chantal , Youkhana Janet , Kokkinos John , Holst Jeff , Boyer Cyrille , Erkan Mert , Goldstein David , Timpson Paul , Cox Thomas R. , Pereira Brooke A. , Chitty Jessica L. , Fey Sigrid K. , Najumudeen Arafath K. , Campbell Andrew D. , Sansom Owen J. , Ignacio Rosa Mistica C. , Naim Stephanie , Liu Jie , Russia Nelson , Lee Julia , Chou Angela , Johns Amber , Gill Anthony J. , Gonzales-Aloy Estrella , Gebski Val , Guan Yi Fang , Pajic Marina , Turner Nigel , Apte Minoti V. , Davis Thomas P. , Morton Jennifer P. , Haghighi Koroush S. , Kasparian Jorjina , McLean Benjamin J. , Setargew Yordanos F. , Phillips Phoebe A.
Published: March 2024

Abstract
Cancer-associated fibroblasts (CAF) are major contributors to pancreatic ductal adenocarcinoma (PDAC) progression through protumor signaling and the generation of fibrosis, the latter of which creates a physical barrier to drugs. CAF inhibition is thus an ideal component of any therapeutic approach for PDAC. SLC7A11 is a cystine transporter that has been identified as a potential therapeutic target in PDAC cells. However, no prior study has evaluated the role of SLC7A11 in PDAC tumor stroma and its prognostic significance. Here we show that high expression of SLC7A11 in human PDAC tumor stroma, but not tumor cells, is independently prognostic of poorer overall survival. Orthogonal approaches showed that PDAC-derived CAFs are highly dependent on SLC7A11 for cystine uptake and glutathione synthesis and that SLC7A11 inhibition significantly decreases CAF proliferation, reduces their resistance to oxidative stress, and inhibits their ability to remodel collagen and support PDAC cell growth. Importantly, specific ablation of SLC7A11 from the tumor compartment of transgenic mouse PDAC tumors did not affect tumor growth, suggesting the stroma can substantially influence PDAC tumor response to SLC7A11 inhibition. In a mouse orthotopic PDAC model utilizing human PDAC cells and CAFs, stable knockdown of SLC7A11 was required in both cell types to reduce tumor growth, metastatic spread, and intratumoral fibrosis, demonstrating the importance of targeting SLC7A11 in both compartments. Finally, treatment with a nanoparticle gene-silencing drug against SLC7A11, developed by our laboratory, reduced PDAC tumor growth, incidence of metastases, CAF activation, and fibrosis in orthotopic PDAC tumors. Overall, these findings identify an important role of SLC7A11 in PDAC-derived CAFs in supporting tumor growth.
Significance:
This study demonstrates that SLC7A11 in PDAC stromal cells is important for the tumor-promoting activity of CAFs and validates a clinically translatable nanomedicine for therapeutic SLC7A11 inhibition in PDAC.
Data from YTHDF1 Promotes Gastric Carcinogenesis by Controlling Translation of FZD7
Authors: Pi Jingnan , Wang Wen , Ji Ming , Wang Xiaoshuang , Wei Xueju , Jin Jing , Liu Tao , Qiang Jiaqi , Qi Zhihong , Li Feng , Liu Yue , Ma Yanni , Si Yanmin , Huo Yue , Gao Yufeng , Chen Yiying , Dong Lei , Su Rui , Chen Jianjun , Rao Shuan , Yi Ping , Yu Shuyang , Wang Fang , Yu Jia
Published: March 2024

Abstract
N6-methyladenosine (m6A) is the most prevalent internal RNA modification in mammals that regulates homeostasis and function of modified RNA transcripts. Here, we aimed to investigate the role of YTH m6A RNA-binding protein 1 (YTHDF1), a key regulator of m6A methylation in gastric cancer tumorigenesis. Multiple bioinformatic analyses of different human cancer databases identified key m6A-associated genetic mutations that regulated gastric tumorigenesis. YTHDF1 was mutated in about 7% of patients with gastric cancer, and high expression of YTHDF1 was associated with more aggressive tumor progression and poor overall survival. Inhibition of YTHDF1 attenuated gastric cancer cell proliferation and tumorigenesis in vitro and in vivo. Mechanistically, YTHDF1 promoted the translation of a key Wnt receptor frizzled7 (FZD7) in an m6A-dependent manner, and mutated YTHDF1 enhanced expression of FZD7, leading to hyperactivation of the Wnt/β-catenin pathway and promotion of gastric carcinogenesis. Our results demonstrate the oncogenic role of YTHDF1 and its m6A-mediated regulation of Wnt/β-catenin signaling in gastric cancer, providing a novel approach of targeting such epigenetic regulators in this disease.
Significance:
This study provides a rationale for controlling translation of key oncogenic drivers in cancer by manipulating epigenetic regulators, representing a novel and efficient strategy for anticancer treatment.
Data from Transient Competitive Inhibition Bypasses the Binding Site Barrier to Improve Tumor Penetration of Trastuzumab and Enhance T-DM1 Efficacy
Authors: Bordeau Brandon M. , Yang Yujie , Balthasar Joseph P.
Published: March 2024

Abstract
Poor penetration of mAbs in solid tumors is explained, in part, by the binding site barrier hypothesis. Following extravasation, mAbs rapidly bind cellular antigens, leading to the observation that, at subsaturating doses, therapeutic antibody in solid tumors localizes around tumor vasculature. Here we report a unique strategy to overcome the binding site barrier through transient competitive inhibition of antibody–antigen binding. The anti-trastuzumab single domain antibody 1HE was identified through in vitro binding assays as a model inhibitor. Coadministration of 1HE did not alter the plasma pharmacokinetics of trastuzumab or ado-trastuzumab emtansine (T-DM1) in vivo. Administration of 1HE alone was rapidly eliminated with a terminal plasma half-life of 1.2 hours, while coadministrations of 1HE with trastuzumab had a terminal half-life of 56 hours. In mice harboring SKOV3 xenografts, coadministration of 1HE with trastuzumab led to significant increases in both penetration of trastuzumab from vasculature and the percentage of tumor area that stained positive for trastuzumab. 1HE coadministered with a single dose of T-DM1 to NCI-N87 xenograft–bearing mice significantly enhanced T-DM1 efficacy, increasing median survival. These results support the hypothesis that transient competitive inhibition can improve therapeutic antibody distribution in solid tumors and enhance antibody efficacy.
Significance:
This study describes the development of a transient competitive inhibition strategy that enhances the tumor penetration and efficacy of anticancer antibodies.

See related commentary by van Dongen, p. 3956
Data from RNA Splicing Factors SRRM3 and SRRM4 Distinguish Molecular Phenotypes of Castration-Resistant Neuroendocrine Prostate Cancer
Authors: Labrecque Mark P. , Brown Lisha G. , Coleman Ilsa M. , Lakely Bryce , Brady Nicholas J. , Lee John K. , Nguyen Holly M. , Li Dapei , Hanratty Brian , Haffner Michael C. , Rickman David S. , True Lawrence D. , Lin Daniel W. , Lam Hung-Ming , Alumkal Joshi J. , Corey Eva , Nelson Peter S. , Morrissey Colm
Published: March 2024

Abstract
Neuroendocrine (NE) differentiation in metastatic castration-resistant prostate cancer (mCRPC) is an increasingly common clinical feature arising from cellular plasticity. We recently characterized two mCRPC phenotypes with NE features: androgen receptor (AR)-positive NE-positive amphicrine prostate cancer (AMPC) and AR-negative small cell or neuroendocrine prostate cancer (SCNPC). Here, we interrogated the regulation of RE1-silencing transcription factor (REST), a transcriptional repressor of neuronal genes, and elucidated molecular programs driving AMPC and SCNPC biology. Analysis of prostate cancer cell lines, mCRPC specimens, and LuCaP patient-derived xenograft models detected alternative splicing of REST to REST4 and attenuated REST repressor activity in AMPC and SCNPC. The REST locus was also hypermethylated and REST expression was reduced in SCNPC. While serine/arginine repetitive matrix protein 4 (SRRM4) was previously implicated in alternative splicing of REST in mCRPC, we detected SRRM3 expression in REST4-positive, SRRM4-negative AMPC, and SCNPC. In CRPC cell lines, SRRM3 induced alternative splicing of REST to REST4 and exacerbated the expression of REST-repressed genes. Furthermore, SRRM3 and SRRM4 expression defined molecular subsets of AMPC and SCNPC across species and tumor types. Two AMPC phenotypes and three SCNPC phenotypes were characterized, denoted either by REST attenuation and ASCL1 activity or by progressive activation of neuronal transcription factor programs, respectively. These results nominate SRRM3 as the principal REST splicing factor expressed in early NE differentiation and provide a framework to molecularly classify diverse NE phenotypes in mCRPC.
Significance:
This study identifies SRRM3 as a key inducer of cellular plasticity in prostate cancer with neuroendocrine features and delineates distinct neuroendocrine phenotypes to inform therapeutic development and precision medicine applications.
Data from STK11/LKB1 Loss of Function Is Associated with Global DNA Hypomethylation and S-Adenosyl-Methionine Depletion in Human Lung Adenocarcinoma
Authors: Koenig Michael J. , Agana Bernice A. , Kaufman Jacob M. , Sharpnack Michael F. , Wang Walter Z. , Weigel Christoph , Navarro Fabio C.P. , Amann Joseph M. , Cacciato Nicole , Arasada Rajeswara Rao , Gerstein Mark B. , Wysocki Vicki H. , Oakes Christopher , Carbone David P.
Published: March 2024

Abstract
STK11 (liver kinase B1, LKB1) is the fourth most frequently mutated gene in lung adenocarcinoma, with loss of function observed in up to 30% of all cases. Our previous work identified a 16-gene signature for LKB1 loss of function through mutational and nonmutational mechanisms. In this study, we applied this genetic signature to The Cancer Genome Atlas (TCGA) lung adenocarcinoma samples and discovered a novel association between LKB1 loss and widespread DNA demethylation. LKB1-deficient tumors showed depletion of S-adenosyl-methionine (SAM-e), which is the primary substrate for DNMT1 activity. Lower methylation following LKB1 loss involved repetitive elements (RE) and altered RE transcription, as well as decreased sensitivity to azacytidine. Demethylated CpGs were enriched for FOXA family consensus binding sites, and nuclear expression, localization, and turnover of FOXA was dependent upon LKB1. Overall, these findings demonstrate that a large number of lung adenocarcinomas exhibit global hypomethylation driven by LKB1 loss, which has implications for both epigenetic therapy and immunotherapy in these cancers.
Significance:
Lung adenocarcinomas with LKB1 loss demonstrate global genomic hypomethylation associated with depletion of SAM-e, reduced expression of DNMT1, and increased transcription of repetitive elements.
Data from Stress-Mediated Reprogramming of Prostate Cancer One-Carbon Cycle Drives Disease Progression
Authors: Pällmann Nora , Deng Ke , Livgård Marte , Tesikova Martina , Jin Yixin , Frengen Nicolai Sebastian , Kahraman Nermin , Mokhlis Hamada M. , Ozpolat Bulent , Kildal Wanja , Danielsen Havard Emil , Fazli Ladan , Rennie Paul S. , Banerjee Partha P. , Üren Aykut , Jin Yang , Kuzu Omer F. , Saatcioglu Fahri
Published: March 2024

Abstract
One-carbon (1C) metabolism has a key role in metabolic programming with both mitochondrial (m1C) and cytoplasmic (c1C) components. Here we show that activating transcription factor 4 (ATF4) exclusively activates gene expression involved in m1C, but not the c1C cycle in prostate cancer cells. This includes activation of methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) expression, the central player in the m1C cycle. Consistent with the key role of m1C cycle in prostate cancer, MTHFD2 knockdown inhibited prostate cancer cell growth, prostatosphere formation, and growth of patient-derived xenograft organoids. In addition, therapeutic silencing of MTHFD2 by systemically administered nanoliposomal siRNA profoundly inhibited tumor growth in preclinical prostate cancer mouse models. Consistently, MTHFD2 expression is significantly increased in human prostate cancer, and a gene expression signature based on the m1C cycle has significant prognostic value. Furthermore, MTHFD2 expression is coordinately regulated by ATF4 and the oncoprotein c-MYC, which has been implicated in prostate cancer. These data suggest that the m1C cycle is essential for prostate cancer progression and may serve as a novel biomarker and therapeutic target.
Significance:
These findings demonstrate that the mitochondrial, but not cytoplasmic, one-carbon cycle has a key role in prostate cancer cell growth and survival and may serve as a biomarker and/or therapeutic target.
Data from Phenotypic Heterogeneity and Metastasis of Breast Cancer Cells
Authors: Hapach Lauren A. , Carey Shawn P. , Schwager Samantha C. , Taufalele Paul V. , Wang Wenjun , Mosier Jenna A. , Ortiz-Otero Nerymar , McArdle Tanner J. , Goldblatt Zachary E. , Lampi Marsha C. , Bordeleau Francois , Marshall Jocelyn R. , Richardson Isaac M. , Li Jiahe , King Michael R. , Reinhart-King Cynthia A.
Published: March 2024

Abstract
Although intratumoral genomic heterogeneity can impede cancer research and treatment, less is known about the effects of phenotypic heterogeneities. To investigate the role of cell migration heterogeneities in metastasis, we phenotypically sorted metastatic breast cancer cells into two subpopulations based on migration ability. Although migration is typically considered to be associated with metastasis, when injected orthotopically in vivo, the weakly migratory subpopulation metastasized significantly more than the highly migratory subpopulation. To investigate the mechanism behind this observation, both subpopulations were assessed at each stage of the metastatic cascade, including dissemination from the primary tumor, survival in the circulation, extravasation, and colonization. Although both subpopulations performed each step successfully, weakly migratory cells presented as circulating tumor cell (CTC) clusters in the circulation, suggesting clustering as one potential mechanism behind the increased metastasis of weakly migratory cells. RNA sequencing revealed weakly migratory subpopulations to be more epithelial and highly migratory subpopulations to be more mesenchymal. Depletion of E-cadherin expression from weakly migratory cells abrogated metastasis. Conversely, induction of E-cadherin expression in highly migratory cells increased metastasis. Clinical patient data and blood samples showed that CTC clustering and E-cadherin expression are both associated with worsened patient outcome. This study demonstrates that deconvolving phenotypic heterogeneities can reveal fundamental insights into metastatic progression. More specifically, these results indicate that migratory ability does not necessarily correlate with metastatic potential and that E-cadherin promotes metastasis in phenotypically sorted breast cancer cell subpopulations by enabling CTC clustering.
Significance:
This study employs phenotypic cell sorting for migration to reveal a weakly migratory, highly metastatic breast cancer cell subpopulation regulated by E-cadherin, highlighting the dichotomy between cancer cell migration and metastasis.
Data from Radiation-Induced Phosphorylation of a Prion-Like Domain Regulates Transformation by FUS-CHOP
Authors: Chen Mark , Foster Joseph P. , Lock Ian C. , Leisenring Nathan H. , Daniel Andrea R. , Floyd Warren , Xu Eric , Davis Ian J. , Kirsch David G.
Published: March 2024

Abstract
Chromosomal translocations generate oncogenic fusion proteins in approximately one-third of sarcomas, but how these proteins promote tumorigenesis is not well understood. Interestingly, some translocation-driven cancers exhibit dramatic clinical responses to therapy, such as radiotherapy, although the precise mechanism has not been elucidated. Here we reveal a molecular mechanism by which the fusion oncoprotein FUS-CHOP promotes tumor maintenance that also explains the remarkable sensitivity of myxoid liposarcomas to radiation therapy. FUS-CHOP interacted with chromatin remodeling complexes to regulate sarcoma cell proliferation. One of these chromatin remodelers, SNF2H, colocalized with FUS-CHOP genome-wide at active enhancers. Following ionizing radiation, DNA damage response kinases phosphorylated the prion-like domain of FUS-CHOP to impede these protein–protein interactions, which are required for transformation. Therefore, the DNA damage response after irradiation disrupted oncogenic targeting of chromatin remodelers required for FUS-CHOP–driven sarcomagenesis. This mechanism of disruption links phosphorylation of the prion-like domain of an oncogenic fusion protein to DNA damage after ionizing radiation and reveals that a dependence on oncogenic chromatin remodeling underlies sensitivity to radiation therapy in myxoid liposarcoma.
Significance:
Prion-like domains, which are frequently translocated in cancers as oncogenic fusion proteins that drive global epigenetic changes, confer sensitivity to radiation via disruption of oncogenic interactions.
Data from Nicotinamide Mononucleotide Prevents Cisplatin-Induced Cognitive Impairments
Authors: Yoo Ki Hyun , Tang Jason J. , Rashid Mohammad Abdur , Cho Chang Hoon , Corujo-Ramirez Ana , Choi Jonghoon , Bae Mun Gyeong , Brogren Danielle , Hawse John R. , Hou Xiaonan , Weroha S. John , Oliveros Alfredo , Kirkeby Lindsey A. , Baur Joseph A. , Jang Mi-Hyeon
Published: March 2024

Abstract
Chemotherapy-induced cognitive impairment (CICI) is often reported as a neurotoxic side effect of chemotherapy. Although CICI has emerged as a significant medical problem, meaningful treatments are not currently available due to a lack of mechanistic understanding underlying CICI pathophysiology. Using the platinum-based chemotherapy cisplatin as a model for CICI, we show here that cisplatin suppresses nicotinamide adenine dinucleotide (NAD+) levels in the adult female mouse brain in vivo and in human cortical neurons derived from induced pluripotent stem cells in vitro. Increasing NAD+ levels through nicotinamide mononucleotide (NMN) administration prevented cisplatin-induced abnormalities in neural progenitor proliferation, neuronal morphogenesis, and cognitive function without affecting tumor growth and antitumor efficacy of cisplatin. Mechanistically, cisplatin inhibited expression of the NAD+ biosynthesis rate-limiting enzyme nicotinamide phosphoribosyl transferase (Nampt). Selective restoration of Nampt expression in adult-born neurons was sufficient to prevent cisplatin-induced defects in dendrite morphogenesis and memory function. Taken together, our findings suggest that aberrant Nampt-mediated NAD+ metabolic pathways may be a key contributor in cisplatin-induced neurogenic impairments, thus causally leading to memory dysfunction. Therefore, increasing NAD+ levels could represent a promising and safe therapeutic strategy for cisplatin-related neurotoxicity.
Significance:
Increasing NAD+ through NMN supplementation offers a potential therapeutic strategy to safely prevent cisplatin-induced cognitive impairments, thus providing hope for improved quality of life in cancer survivors.
Data from ELOVL5 Is a Critical and Targetable Fatty Acid Elongase in Prostate Cancer
Authors: Centenera Margaret M. , Scott Julia S. , Machiels Jelle , Nassar Zeyad D. , Miller Deanna C. , Zinonos Irene , Dehairs Jonas , Burvenich Ingrid J.G. , Zadra Giorgia , Chetta Paolo M. , Bango Clyde , Evergren Emma , Ryan Natalie K. , Gillis Joanna L. , Mah Chui Yan , Tieu Terence , Hanson Adrienne R. , Carelli Ryan , Bloch Katarzyna , Panagopoulos Vasilios , Waelkens Etienne , Derua Rita , Williams Elizabeth D. , Evdokiou Andreas , Cifuentes-Rius Anna , Voelcker Nicolas H. , Mills Ian G. , Tilley Wayne D. , Scott Andrew M. , Loda Massimo , Selth Luke A. , Swinnen Johannes V. , Butler Lisa M.
Published: March 2024

Abstract
The androgen receptor (AR) is the key oncogenic driver of prostate cancer, and despite implementation of novel AR targeting therapies, outcomes for metastatic disease remain dismal. There is an urgent need to better understand androgen-regulated cellular processes to more effectively target the AR dependence of prostate cancer cells through new therapeutic vulnerabilities. Transcriptomic studies have consistently identified lipid metabolism as a hallmark of enhanced AR signaling in prostate cancer, yet the relationship between AR and the lipidome remains undefined. Using mass spectrometry–based lipidomics, this study reveals increased fatty acyl chain length in phospholipids from prostate cancer cells and patient-derived explants as one of the most striking androgen-regulated changes to lipid metabolism. Potent and direct AR-mediated induction of ELOVL fatty acid elongase 5 (ELOVL5), an enzyme that catalyzes fatty acid elongation, was demonstrated in prostate cancer cells, xenografts, and clinical tumors. Assessment of mRNA and protein in large-scale data sets revealed ELOVL5 as the predominant ELOVL expressed and upregulated in prostate cancer compared with nonmalignant prostate. ELOVL5 depletion markedly altered mitochondrial morphology and function, leading to excess generation of reactive oxygen species and resulting in suppression of prostate cancer cell proliferation, 3D growth, and in vivo tumor growth and metastasis. Supplementation with the monounsaturated fatty acid cis-vaccenic acid, a direct product of ELOVL5 elongation, reversed the oxidative stress and associated cell proliferation and migration effects of ELOVL5 knockdown. Collectively, these results identify lipid elongation as a protumorigenic metabolic pathway in prostate cancer that is androgen-regulated, critical for metastasis, and targetable via ELOVL5.
Significance:
This study identifies phospholipid elongation as a new metabolic target of androgen action that is critical for prostate tumor metastasis.
Data from Association between Smoking History and Tumor Mutation Burden in Advanced Non–Small Cell Lung Cancer
Authors: Wang Xinan , Ricciuti Biagio , Nguyen Tom , Li Xihao , Rabin Michael S. , Awad Mark M. , Lin Xihong , Johnson Bruce E. , Christiani David C.
Published: March 2024

Abstract
Lung carcinogenesis is a complex and stepwise process involving accumulation of genetic mutations in signaling and oncogenic pathways via interactions with environmental factors and host susceptibility. Tobacco exposure is the leading cause of lung cancer, but its relationship to clinically relevant mutations and the composite tumor mutation burden (TMB) has not been fully elucidated. In this study, we investigated the dose–response relationship in a retrospective observational study of 931 patients treated for advanced-stage non–small cell lung cancer (NSCLC) between April 2013 and February 2020 at the Dana Farber Cancer Institute and Brigham and Women’s Hospital. Doubling smoking pack-years was associated with increased KRASG12C and less frequent EGFRdel19 and EGFRL858R mutations, whereas doubling smoking-free months was associated with more frequent EGFRL858R. In advanced lung adenocarcinoma, doubling smoking pack-years was associated with an increase in TMB, whereas doubling smoking-free months was associated with a decrease in TMB, after controlling for age, gender, and stage. There is a significant dose–response association of smoking history with genetic alterations in cancer-related pathways and TMB in advanced lung adenocarcinoma.
Significance:
This study clarifies the relationship between smoking history and clinically relevant mutations in non–small cell lung cancer, revealing the potential of smoking history as a surrogate for tumor mutation burden.
Data from Ferroptosis Inducers Are a Novel Therapeutic Approach for Advanced Prostate Cancer
Authors: Ghoochani Ali , Hsu En-Chi , Aslan Merve , Rice Meghan A. , Nguyen Holly M. , Brooks James D. , Corey Eva , Paulmurugan Ramasamy , Stoyanova Tanya
Published: March 2024

Abstract
Ferroptosis is a type of programmed cell death induced by the accumulation of lipid peroxidation and lipid reactive oxygen species in cells. It has been recently demonstrated that cancer cells are vulnerable to ferroptosis inducers (FIN). However, the therapeutic potential of FINs in prostate cancer in preclinical settings has not been explored. In this study, we demonstrate that mediators of ferroptosis, solute carrier family 7 member 11, SLC3A2, and glutathione peroxidase, are expressed in treatment-resistant prostate cancer. We further demonstrate that treatment-resistant prostate cancer cells are sensitive to two FINs, erastin and RSL3. Treatment with erastin and RSL3 led to a significant decrease in prostate cancer cell growth and migration in vitro and significantly delayed the tumor growth of treatment-resistant prostate cancer in vivo, with no measurable side effects. Combination of erastin or RSL3 with standard-of-care second-generation antiandrogens for advanced prostate cancer halted prostate cancer cell growth and migration in vitro and tumor growth in vivo. These results demonstrate the potential of erastin or RSL3 independently and in combination with standard-of-care second-generation antiandrogens as novel therapeutic strategies for advanced prostate cancer.
Significance:
These findings reveal that induction of ferroptosis is a new therapeutic strategy for advanced prostate cancer as a monotherapy and in combination with second-generation antiandrogens.
Data from Serine-Threonine Kinase TAO3-Mediated Trafficking of Endosomes Containing the Invadopodia Scaffold TKS5α Promotes Cancer Invasion and Tumor Growth
Authors: Iizuka Shinji , Quintavalle Manuela , Navarro Jose C. , Gribbin Kyle P. , Ardecky Robert J. , Abelman Matthew M. , Ma Chen-Ting , Sergienko Eduard , Zeng Fu-Yue , Pass Ian , Thomas George V. , McWeeney Shannon K. , Hassig Christian A. , Pinkerton Anthony B. , Courtneidge Sara A.
Published: March 2024

Abstract
Invadopodia are actin-based proteolytic membrane protrusions required for invasive behavior and tumor growth. In this study, we used our high-content screening assay to identify kinases whose activity affects invadopodia formation. Among the top hits selected for further analysis was TAO3, an STE20-like kinase of the GCK subfamily. TAO3 was overexpressed in many human cancers and regulated invadopodia formation in melanoma, breast, and bladder cancers. Furthermore, TAO3 catalytic activity facilitated melanoma growth in three-dimensional matrices and in vivo. A novel, potent catalytic inhibitor of TAO3 was developed that inhibited invadopodia formation and function as well as tumor cell extravasation and growth. Treatment with this inhibitor demonstrated that TAO3 activity is required for endosomal trafficking of TKS5α, an obligate invadopodia scaffold protein. A phosphoproteomics screen for TAO3 substrates revealed the dynein subunit protein LIC2 as a relevant substrate. Knockdown of LIC2 or expression of a phosphomimetic form promoted invadopodia formation. Thus, TAO3 is a new therapeutic target with a distinct mechanism of action.
Significance:
An unbiased screening approach identifies TAO3 as a regulator of invadopodia formation and function, supporting clinical development of this class of target.
Data from α1-Acid Glycoprotein Enhances the Immunosuppressive and Protumor Functions of Tumor-Associated Macrophages
Authors: Matsusaka Kotaro , Fujiwara Yukio , Pan Cheng , Esumi Shigeyuki , Saito Yoichi , Bi Jing , Nakamura Yuka , Mukunoki Ayumi , Takeo Toru , Nakagata Naomi , Yoshii Daiki , Fukuda Ryo , Nagasaki Taisei , Tanaka Ryusei , Komori Hisakazu , Maeda Hitoshi , Watanabe Hiroshi , Tamada Koji , Komohara Yoshihiro , Maruyama Toru
Published: March 2024

Abstract
Blood levels of acute-phase protein α1-acid glycoprotein (AGP, orosmucoid) increase in patients with cancer. Although AGP is produced from hepatocytes following stimulation by immune cell–derived cytokines under conditions of inflammation and tumorigenesis, the functions of AGP in tumorigenesis and tumor progression remain unknown. In the present study, we revealed that AGP contributes directly to tumor development by induction of programmed death ligand 1 (PD-L1) expression and IL6 production in macrophages. Stimulation of AGP induced PD-L1 expression in both human monocyte–derived macrophages through STAT1 activation, whereas AGP had no direct effect on PD-L1 expression in tumor cells. AGP also induced IL6 production from macrophages, which stimulated proliferation in tumor cells by IL6R-mediated activation of STAT3. Furthermore, administration of AGP to AGP KO mice phenocopied effects of tumor-associated macrophages (TAM) on tumor progression. AGP decreased IFNγ secretion from T cells and enhanced STAT3 activation in subcutaneous tumor tissues. In addition, AGP regulated PD-L1 expression and IL6 production in macrophages by binding with CD14, a coreceptor for Toll-like receptor 4 (TLR4), and inducing TLR4 signaling. These results provide the first evidence that AGP is directly involved in tumorigenesis by interacting with TAMs and that AGP might be a target molecule for anticancer therapy.
Significance:
AGP-mediated suppression of antitumor immunity contributes to tumor progression by inducing PD-L1 expression and IL6 production in TAMs.
Data from mTOR Activation Initiates Renal Cell Carcinoma Development by Coordinating ERK and p38MAPK
Authors: Wu Hongguang , He Dan , Biswas Soma , Shafiquzzaman Md , Zhou Xin , Charron Jean , Wang Yibin , Nayak Bijaya K. , Habib Samy L. , Liu Huijuan , Li Baojie
Published: March 2024

Abstract
Renal cell carcinoma (RCC) mainly originates from renal proximal tubules. Intriguingly, disruption of genes frequently mutated in human RCC samples thus far has only generated RCC originated from other renal tubule parts in mouse models. This hampers our understanding of the pathogenesis of RCC. Here we show that mTOR signaling, often activated in RCC samples, initiates RCC development from renal proximal tubules. Ablation of Tsc1, encoding an mTOR suppressor, in proximal tubule cells led to multiple precancerous renal cysts. mTOR activation increased MEK1 expression and ERK activation, and Mek1 ablation or inhibition diminished cyst formation in Tsc1-deficient mice. mTOR activation also increased MKK6 expression and p38MAPK activation, and ablation of the p38α-encoding gene further enhanced cyst formation and led to RCC with clear cell RCC features. Mechanistically, Tsc1 deletion induced p53 and p16 expression in a p38MAPK-dependent manner, and deleting Tsc1 and Trp53 or Cdkn2a (encoding p16) enhanced renal cell carcinogenesis. Thus, mTOR activation in combination with inactivation of the p38MAPK–p53/p16 pathway drives RCC development from renal proximal tubules. Moreover, this study uncovers previously unidentified mechanisms by which mTOR controls cell proliferation and suggests the MEK–ERK axis to be a potential target for treatment of RCC.
Significance:
Mouse modeling studies show that mTOR activation in combination with inactivation of the p38MAPK–p53/p16 axis initiates renal cell carcinoma that mimics human disease, identifying potential therapeutic targets for RCC treatment.
Data from Oxidized Low-Density Lipoprotein Links Hypercholesterolemia and Bladder Cancer Aggressiveness by Promoting Cancer Stemness
Authors: Yang Lin , Sun Jingya , Li Meiqian , Long Yiming , Zhang Dianzheng , Guo Hongqian , Huang Ruimin , Yan Jun
Published: March 2024

Abstract
Hypercholesterolemia is a prevalent metabolic disorder that has been implicated in the development of steroid-targeted cancers. However, the link between hypercholesterolemia and urinary bladder cancer (UBC), a non–steroid-targeted cancer, remains unresolved. Here we show that diet-induced and Ldlr deficiency–induced hypercholesterolemia enhances both UBC stemness and progression. Inhibition of intestinal cholesterol absorption by ezetimibe reversed diet-induced hypercholesterolemia and cancer stemness. As a key component in hypercholesterolemic sera, oxidized low-density lipoprotein (ox-LDL), but not native low-density lipoprotein-cholesterol or metabolite 27-hydroxycholesterol, increased cancer stemness through its receptor CD36. Depletion of CD36, ectopic expression of an ox-LDL binding–disabled mutant form of CD36(K164A), and the neutralization of ox-LDL and CD36 via neutralizing antibodies all reversed ox-LDL–induced cancer stemness. Mechanistically, ox-LDL enhanced the interaction of CD36 and JAK2, inducing phosphorylation of JAK2 and subsequently activating STAT3 signaling, which was not mediated by JAK1 or Src in UBC cells. Finally, ox-LDL levels in serum predicted poor prognosis, and the ox-LDLhigh signature predicted worse survival in patients with UBC. These findings indicate that ox-LDL links hypercholesterolemia with UBC progression by enhancing cancer stemness. Lowering serum ox-LDL or targeting the CD36/JAK2/STAT3 axis might serve as a potential therapeutic strategy for UBCs with hypercholesterolemia. Moreover, elevated ox-LDL may serve as a biomarker for UBC.
Significance:
This study demonstrates how hypercholesterolemia-induced oxidized LDL promotes urinary bladder cancer stemness via a CD36/STAT3 signaling axis, highlighting these factors as biomarkers and potential therapeutic targets of aggressive disease.