bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Figure S5 from Trends of Ovarian Cancer Incidence by Histotype and Race/Ethnicity in the United States 1992–2019
Authors: Phung Minh Tung , Pearce Celeste Leigh , Meza Rafael , Jeon Jihyoun
Published: April 2023

Supplementary Figure 5 shows the distribution of histotype by race/ethnicity, SEER-12, 1992-2019
Figure S1 from Proteasome Inhibitors Silence Oncogenes in Multiple Myeloma through Localized Histone Deacetylase 3 Stabilization and Chromatin Condensation
Authors: Maneix Laure , Iakova Polina , Moree Shannon E. , Hsu Joanne I. , Mistry Ragini M. , Stossi Fabio , Lulla Premal , Sun Zheng , Sahin Ergun , Yellapragada Sarvari V. , Catic André
Published: April 2023

Genome-wide analysis of acute effects of proteasome inhibition on transcription and chromatin in MM cells.
Table TS2 from Detection of MET polysomy by next-generation sequencing and its clinical relevance for MET inhibitors
Authors: Sun Boyang , Qiu Tian , Zeng Xiaoling , Duan Jianchun , Bai Hua , Xu Jiachen , Li Jin , Li Junling , Hao Xuezhi , Liu Yutao , Lin Lin , Wang Hongyu , Zhang Xin , Zhong Jia , Wang Jie , Ying Jianming , Wang Zhijie
Published: April 2023

Summary of MET status tested by NGS, MET inhibitors with clinical outcome and dynamic changes in gene alterations in cohort 3
Supplemental Table 4 from Association Between Recreational Physical Activity and mTOR Signaling Pathway Protein Expression in Breast Tumor Tissue
Authors: Cheng Ting-Yuan David , Zhang Runzhi , Gong Zhihong , Qin Bo , Cannioto Rikki A. , Datta Susmita , Zhang Weizhou , Omilian Angela R. , Yao Song , Khoury Thaer , Hong Chi-Chen , Bandera Elisa V. , Ambrosone Christine B.
Published: April 2023

Supplemental Table 4 shows the associations adjusting covariates and total energy intake.
Figure S5 from Detection of MET polysomy by next-generation sequencing and its clinical relevance for MET inhibitors
Authors: Sun Boyang , Qiu Tian , Zeng Xiaoling , Duan Jianchun , Bai Hua , Xu Jiachen , Li Jin , Li Junling , Hao Xuezhi , Liu Yutao , Lin Lin , Wang Hongyu , Zhang Xin , Zhong Jia , Wang Jie , Ying Jianming , Wang Zhijie
Published: April 2023

One MET-FISH-negative patient was classified as having MET polysomy by NGS
Supplemental Table 3 from Association Between Recreational Physical Activity and mTOR Signaling Pathway Protein Expression in Breast Tumor Tissue
Authors: Cheng Ting-Yuan David , Zhang Runzhi , Gong Zhihong , Qin Bo , Cannioto Rikki A. , Datta Susmita , Zhang Weizhou , Omilian Angela R. , Yao Song , Khoury Thaer , Hong Chi-Chen , Bandera Elisa V. , Ambrosone Christine B.
Published: April 2023

Supplemental Table 3 shows protein expression distribution in adjacent normal tissue by PA level.
Figure S3 from Detection of MET polysomy by next-generation sequencing and its clinical relevance for MET inhibitors
Authors: Sun Boyang , Qiu Tian , Zeng Xiaoling , Duan Jianchun , Bai Hua , Xu Jiachen , Li Jin , Li Junling , Hao Xuezhi , Liu Yutao , Lin Lin , Wang Hongyu , Zhang Xin , Zhong Jia , Wang Jie , Ying Jianming , Wang Zhijie
Published: April 2023

One MET-FISH-positive tumor was identified as negative by NGS
Supplemental Table 13 from Association Between Recreational Physical Activity and mTOR Signaling Pathway Protein Expression in Breast Tumor Tissue
Authors: Cheng Ting-Yuan David , Zhang Runzhi , Gong Zhihong , Qin Bo , Cannioto Rikki A. , Datta Susmita , Zhang Weizhou , Omilian Angela R. , Yao Song , Khoury Thaer , Hong Chi-Chen , Bandera Elisa V. , Ambrosone Christine B.
Published: April 2023

Supplemental Table 13 reported stratified analysis for tumors <2cm and ≥2 cm in diameter.
Supplemental Table 11 from Association Between Recreational Physical Activity and mTOR Signaling Pathway Protein Expression in Breast Tumor Tissue
Authors: Cheng Ting-Yuan David , Zhang Runzhi , Gong Zhihong , Qin Bo , Cannioto Rikki A. , Datta Susmita , Zhang Weizhou , Omilian Angela R. , Yao Song , Khoury Thaer , Hong Chi-Chen , Bandera Elisa V. , Ambrosone Christine B.
Published: April 2023

Supplemental Table 11 reported stratified analysis for breast cancer stage 0/I and stage II/III/IV.
Supplementary Table ST2 from Analysis of N-linked Glycan Alterations in Tissue and Serum Reveals Promising Biomarkers for Intrahepatic Cholangiocarcinoma
Authors: Ochoa-Rios Shaaron , Blaschke Calvin R.K. , Wang Mengjun , Peterson Kendell D. , DelaCourt Andrew , Grauzam Stéphane Elie , Lewin David , Angel Peggi , Roberts Lewis R. , Drake Richard , Mehta Anand S.
Published: April 2023

Lists individual N-glycans, ALT (Alanine transaminase), AST (aspartate aminotransferase), ALK (Alkaline phosphatase), and AFP (Alpha-fetoprotein) of analysis to differentiate patients with iCCA from PSC.
1Possible biomarkers 2n: number of total patients 3distribution of iCCA (n=30) and PSC (n=17) patients. 4AUC (Area Under the Curve) 5CI (confidence interval) 6p value. Some iCCA patients were excluded from the analysis due to missing clinical information.
Supplementary Table ST1 from Analysis of N-linked Glycan Alterations in Tissue and Serum Reveals Promising Biomarkers for Intrahepatic Cholangiocarcinoma
Authors: Ochoa-Rios Shaaron , Blaschke Calvin R.K. , Wang Mengjun , Peterson Kendell D. , DelaCourt Andrew , Grauzam Stéphane Elie , Lewin David , Angel Peggi , Roberts Lewis R. , Drake Richard , Mehta Anand S.
Published: April 2023

Peak list of N-glycans detected in tissue (TMA) and serum samples.
Supplementary Figure FS4 from Quantitative, Spatially Defined Expression of Leukocyte-associated Immunoglobulin-like Receptor in Non–small Cell Lung Cancer
Authors: Aung Thazin N. , Gavrielatou Niki , Vathiotis Ioannis A. , Fernandez Aileen I. , Shafi Saba , Yaghoobi Vesal , Burela Sneha , MacNeil Tyler , Ahmed Fahad Shabbir , Myint Han , Flies Dallas B. , Langermann Solomon , Rimm David L.
Published: April 2023

LAIR-1 expression in different compartments and its association with survival in Validation Cohort 250 (YTMA-250). (A) LAIR-1 protein expression in tumor and stroma compartments. (B) LAIR-1 tumor and stromal protein expression in both LUAD and LUSC-NSCLC subtypes. (C) Association of LAIR-1 expression in tumor and CD68 compartments with the outcome.
Supplementary Figure SF1 from Analysis of N-linked Glycan Alterations in Tissue and Serum Reveals Promising Biomarkers for Intrahepatic Cholangiocarcinoma
Authors: Ochoa-Rios Shaaron , Blaschke Calvin R.K. , Wang Mengjun , Peterson Kendell D. , DelaCourt Andrew , Grauzam Stéphane Elie , Lewin David , Angel Peggi , Roberts Lewis R. , Drake Richard , Mehta Anand S.
Published: April 2023

Hematoxylin & Eosin (H&E) staining of A. Intrahepatic Cholangiocarcinoma (iCCA) tissue, 10x (right) and 40x (left) magnification images from respective areas of the tissue, and B. Hepatocellular Carcinoma (HCC) tissue, 10x magnification images from respective areas of the tissue. Tumor regions are outlined in red, normal areas are outlined in black and fibrotic regions are outlined in blue. C. TMA H&E staining with an outline that specifies the diagnosis for each core for TMA 1 (left) and TMA 2 (right). Mixed carcinoma: HCC and iCCA. Small (yellow) and large (purple) ducts classifications for each TMA.
Figure S8 from S100A8/S100A9 Promote Progression of Multiple Myeloma via Expansion of Megakaryocytes
Authors: Lin Cindy , Garcia-Gerique Laura , Bonner Erin E. , Mastio Jerome , Rosenwasser Matthew , Cruz Zachary , Lawler Michael , Bernabei Luca , Muthumani Kar , Liu Qin , Poncz Mortimer , Vogl Thomas , Törngren Marie , Eriksson Helena , Vogl Dan T. , Gabrilovich Dmitry I. , Nefedova Yulia
Published: April 2023

Effect of TQ on MM cells.
Table TS1 from Tumor-derived GCSF Alters Tumor and Systemic Immune System Cell Subset Composition and Signaling
Authors: Matos Israel , Barvalia Maunish , Chehal Manreet K. , Robertson A. Gordon , Kulic Iva , Silva Jessica A.F.D. , Ranganathan Abhinandan , Short Amy , Huang Yu-Hsuan , Long Erin , Priatel John J. , Dhanji Salim , Nelson Brad H. , Krebs Danielle L. , Harder Kenneth W.
Published: April 2023

CyTOF panels
Supplemental Figure 4 from Digital spatial profiling links beta-2-microglobulin expression with immune checkpoint blockade outcomes in head and neck squamous cell carcinoma
Authors: Gavrielatou Niki , Vathiotis Ioannis A. , Aung Thazin Nwe , Shafi Saba , Burela Sneha , Fernandez Aileen I. , Moutafi Myrto , Burtness Barbara A. , Economopoulou Panagiota , Anastasiou Maria , Foukas Periklis , Psyrri Amanda , Rimm David L.
Published: April 2023

b2m expression range, multivariate analysis of pfs and os and association with response and disease control in Yale cohort
Table S1 from IOA-244 is a non-ATP-competitive, highly selective, tolerable phosphoinositide 3-kinase delta inhibitor that targets solid tumors and breaks immune tolerance
Authors: Johnson Zoë , Tarantelli Chiara , Civanelli Elisa , Cascione Luciano , Spriano Filippo , Fraser Amy , Shah Pritom , Nomanbhoy Tyzoon , Napoli Sara , Rinaldi Andrea , Niewola-Staszkowska Karolina , Lahn Michael , Perrin Dominique , Wenes Mathias , Migliorini Denis , Bertoni Francesco , van der Veen Lars , Di Conza Giusy
Published: April 2023

Table summarizing the IC50 values derived from previous published experiments performed with IOA-244
Supplementary Table S3 from Whole-genome and epigenomic landscapes of malignant gastrointestinal stromal tumors harboring KIT exon 11 557–558 deletion mutations
Authors: Ohshima Keiichi , Nagashima Takeshi , Fujiya Keiichi , Hatakeyama Keiichi , Watanabe Yuko , Morimoto Kimiko , Kamada Fukumi , Shimoda Yuji , Ohnami Sumiko , Naruoka Akane , Serizawa Masakuni , Ohnami Shumpei , Kenmotsu Hirotsugu , Shiomi Akio , Tsubosa Yasuhiro , Bando Etsuro , Sugiura Teiichi , Sugino Takashi , Terashima Masanori , Uesaka Katsuhiko , Urakami Kenichi , Akiyama Yasuto , Yamaguchi Ken
Published: April 2023

Probes for genes with specific expression alterations in malignant GISTs with KIT Δ557–558.
Supplementary Figure S9 from Whole-genome and epigenomic landscapes of malignant gastrointestinal stromal tumors harboring KIT exon 11 557–558 deletion mutations
Authors: Ohshima Keiichi , Nagashima Takeshi , Fujiya Keiichi , Hatakeyama Keiichi , Watanabe Yuko , Morimoto Kimiko , Kamada Fukumi , Shimoda Yuji , Ohnami Sumiko , Naruoka Akane , Serizawa Masakuni , Ohnami Shumpei , Kenmotsu Hirotsugu , Shiomi Akio , Tsubosa Yasuhiro , Bando Etsuro , Sugiura Teiichi , Sugino Takashi , Terashima Masanori , Uesaka Katsuhiko , Urakami Kenichi , Akiyama Yasuto , Yamaguchi Ken
Published: April 2023

Genome-wide relationship between DNA methylation and gene expression in malignant GISTs with KIT Δ557–558.
Supplementary Figure 2 from Induction of PARP7 Creates a Vulnerability for Growth
Inhibition by RBN2397 in Prostate Cancer Cells
Authors: Yang Chunsong , Wierbilowicz Krzysztof , Dworak Natalia M , Bae Song Yi , Tengse Sachi B , Abianeh Nicki , Drake Justin M , Abbas Tarek , Ratan Aakrosh , Wotton David , Paschal Bryce M
Published: April 2023

BBQ and FICZ treatment activates AHR signaling in prostate cancer cells
Supplementary Figure S7 from Whole-genome and epigenomic landscapes of malignant gastrointestinal stromal tumors harboring KIT exon 11 557–558 deletion mutations
Authors: Ohshima Keiichi , Nagashima Takeshi , Fujiya Keiichi , Hatakeyama Keiichi , Watanabe Yuko , Morimoto Kimiko , Kamada Fukumi , Shimoda Yuji , Ohnami Sumiko , Naruoka Akane , Serizawa Masakuni , Ohnami Shumpei , Kenmotsu Hirotsugu , Shiomi Akio , Tsubosa Yasuhiro , Bando Etsuro , Sugiura Teiichi , Sugino Takashi , Terashima Masanori , Uesaka Katsuhiko , Urakami Kenichi , Akiyama Yasuto , Yamaguchi Ken
Published: April 2023

DNA methylation in each autosome of GISTs. Genome-wide DNA methylation sites are shown in 300-kb bins.
Supplementary Figure S6 from Whole-genome and epigenomic landscapes of malignant gastrointestinal stromal tumors harboring KIT exon 11 557–558 deletion mutations
Authors: Ohshima Keiichi , Nagashima Takeshi , Fujiya Keiichi , Hatakeyama Keiichi , Watanabe Yuko , Morimoto Kimiko , Kamada Fukumi , Shimoda Yuji , Ohnami Sumiko , Naruoka Akane , Serizawa Masakuni , Ohnami Shumpei , Kenmotsu Hirotsugu , Shiomi Akio , Tsubosa Yasuhiro , Bando Etsuro , Sugiura Teiichi , Sugino Takashi , Terashima Masanori , Uesaka Katsuhiko , Urakami Kenichi , Akiyama Yasuto , Yamaguchi Ken
Published: April 2023

Visualization of methylation status in GISTs.
Supplementary Figure S5 from Whole-genome and epigenomic landscapes of malignant gastrointestinal stromal tumors harboring KIT exon 11 557–558 deletion mutations
Authors: Ohshima Keiichi , Nagashima Takeshi , Fujiya Keiichi , Hatakeyama Keiichi , Watanabe Yuko , Morimoto Kimiko , Kamada Fukumi , Shimoda Yuji , Ohnami Sumiko , Naruoka Akane , Serizawa Masakuni , Ohnami Shumpei , Kenmotsu Hirotsugu , Shiomi Akio , Tsubosa Yasuhiro , Bando Etsuro , Sugiura Teiichi , Sugino Takashi , Terashima Masanori , Uesaka Katsuhiko , Urakami Kenichi , Akiyama Yasuto , Yamaguchi Ken
Published: April 2023

SVs and expression levels of DMD in 30 GIST samples.
Table S1 from Predicting Cancer Risk from Germline Whole-exome Sequencing Data Using a Novel Context-based Variant Aggregation Approach
Authors: Guan Zoe , Begg Colin B. , Shen Ronglai
Published: April 2023

Table S1: Known risk genes (from Rahman 2014) and SNPs (from NHGRI-EBI GWAS Catalog) in WES models.
Supplementary Data S3 from Whole-genome and epigenomic landscapes of malignant gastrointestinal stromal tumors harboring KIT exon 11 557–558 deletion mutations
Authors: Ohshima Keiichi , Nagashima Takeshi , Fujiya Keiichi , Hatakeyama Keiichi , Watanabe Yuko , Morimoto Kimiko , Kamada Fukumi , Shimoda Yuji , Ohnami Sumiko , Naruoka Akane , Serizawa Masakuni , Ohnami Shumpei , Kenmotsu Hirotsugu , Shiomi Akio , Tsubosa Yasuhiro , Bando Etsuro , Sugiura Teiichi , Sugino Takashi , Terashima Masanori , Uesaka Katsuhiko , Urakami Kenichi , Akiyama Yasuto , Yamaguchi Ken
Published: April 2023

CNAs identified in the 30 GIST cases in our study cohort.
Supplementary Figure S3 from Whole-genome and epigenomic landscapes of malignant gastrointestinal stromal tumors harboring KIT exon 11 557–558 deletion mutations
Authors: Ohshima Keiichi , Nagashima Takeshi , Fujiya Keiichi , Hatakeyama Keiichi , Watanabe Yuko , Morimoto Kimiko , Kamada Fukumi , Shimoda Yuji , Ohnami Sumiko , Naruoka Akane , Serizawa Masakuni , Ohnami Shumpei , Kenmotsu Hirotsugu , Shiomi Akio , Tsubosa Yasuhiro , Bando Etsuro , Sugiura Teiichi , Sugino Takashi , Terashima Masanori , Uesaka Katsuhiko , Urakami Kenichi , Akiyama Yasuto , Yamaguchi Ken
Published: April 2023

Kaplan-Meier curves.
Figure S6 from Systemic LRG1 expression in melanoma is associated with disease progression and recurrence
Authors: Hoefsmit Esmee P. , Völlmy Franziska , Rozeman Elisa A. , Reijers Irene L. M. , Versluis Judith M. , Hoekman Liesbeth , van Akkooi Alexander C. J. , Long Georgina V. , Schadendorf Dirk , Dummer Reinhard , Altelaar Maarten , Blank Christian U.
Published: April 2023

Figure S6 shows that neutrophil count and neutrophil-to-lymphocyte ratio (NLR) are not associated with recurrence in non-responding patients
Figure S5 from Systemic LRG1 expression in melanoma is associated with disease progression and recurrence
Authors: Hoefsmit Esmee P. , Völlmy Franziska , Rozeman Elisa A. , Reijers Irene L. M. , Versluis Judith M. , Hoekman Liesbeth , van Akkooi Alexander C. J. , Long Georgina V. , Schadendorf Dirk , Dummer Reinhard , Altelaar Maarten , Blank Christian U.
Published: April 2023

Figure S5 shows that complement factor B (CFB), component 7 (C7) and alpha-1B-glycoportein (A1BG) expression are increased upon melanoma progression and recurrence.
Figure S3 from Systemic LRG1 expression in melanoma is associated with disease progression and recurrence
Authors: Hoefsmit Esmee P. , Völlmy Franziska , Rozeman Elisa A. , Reijers Irene L. M. , Versluis Judith M. , Hoekman Liesbeth , van Akkooi Alexander C. J. , Long Georgina V. , Schadendorf Dirk , Dummer Reinhard , Altelaar Maarten , Blank Christian U.
Published: April 2023

Figure S3 shows that SAA1, CRP and LDHB are associated with melanoma disease progression.
Figure SF9 from Plexin-B1 Mutation Drives Metastasis in Prostate Cancer Mouse Models
Authors: Shorning Boris , Trent Neil , Griffiths David F. , Worzfeld Thomas , Offermanns Stefan , Smalley Matthew J. , Williamson Magali
Published: April 2023

Proliferation and ROCK activation in Ptenfl/flKrasG12V PlxnB1-/- and Ptenfl/flp53fl/fl PlxnB1-/- mice
Supplementary Video SV1 from Toll-like Receptor Signaling–deficient Cells Enhance Antitumor Activity of Cell-based Immunotherapy by Increasing Tumor Homing
Authors: Morales-Molina Alvaro , Rodriguez-Milla Miguel Ángel , Gambera Stefano , Cejalvo Teresa , de Andrés Belén , Gaspar María-Luisa , García-Castro Javier
Published: April 2023

OAd-MSC WT
Figure SF5 from Plexin-B1 Mutation Drives Metastasis in Prostate Cancer Mouse Models
Authors: Shorning Boris , Trent Neil , Griffiths David F. , Worzfeld Thomas , Offermanns Stefan , Smalley Matthew J. , Williamson Magali
Published: April 2023

Metastatic deposit in Ptenfl/flKrasG12VPLXNB1WT mouse
Figure SF4 from Plexin-B1 Mutation Drives Metastasis in Prostate Cancer Mouse Models
Authors: Shorning Boris , Trent Neil , Griffiths David F. , Worzfeld Thomas , Offermanns Stefan , Smalley Matthew J. , Williamson Magali
Published: April 2023

Metastatic deposits in Ptenfl/flKrasG12VPLXNB1P1597L mice
Supplementary Figure S2 from Toll-like Receptor Signaling–deficient Cells Enhance Antitumor Activity of Cell-based Immunotherapy by Increasing Tumor Homing
Authors: Morales-Molina Alvaro , Rodriguez-Milla Miguel Ángel , Gambera Stefano , Cejalvo Teresa , de Andrés Belén , Gaspar María-Luisa , García-Castro Javier
Published: April 2023

High dose OAd-MSC TLR4−/− improves the antitumor efficacy of high dose OAd-MSC WT in vivo
Supplementary Table TS1 from Distinct IDH1/2-associated Methylation Profile and Enrichment of TP53 and TERT Mutations Distinguish Dedifferentiated Chondrosarcoma from Conventional Chondrosarcoma
Authors: Dermawan Josephine Kam Tai , Nafa Khedoujia , Mohanty Abhinita , Xu Yingjuan , Rijo Ivelise , Casanova Jacklyn , Villafania Liliana , Benhamida Jamal , Kelly Ciara M. , Tap William D. , Boland Patrick J. , Fabbri Nicola , Healey John H. , Ladanyi Marc , Lu Chao , Hameed Meera
Published: April 2023

Gene set enrichment analysis
Supplementary Figure S7 from Structurally complex osteosarcoma genomes exhibit limited heterogeneity within individual tumors and across evolutionary time
Authors: Rajan Sanjana , Zaccaria Simone , Cannon Matthew , Cam Maren , Gross Amy C , Raphael Benjamin J , Roberts Ryan D.
Published: April 2023

CHISEL plot for SJOS003939 samples
Supplementary Figure S1 from Structurally complex osteosarcoma genomes exhibit limited heterogeneity within individual tumors and across evolutionary time
Authors: Rajan Sanjana , Zaccaria Simone , Cannon Matthew , Cam Maren , Gross Amy C , Raphael Benjamin J , Roberts Ryan D.
Published: April 2023

Cell count and fraction of clones
Data from MYC Inhibition Halts Metastatic Breast Cancer Progression by Blocking Growth, Invasion, and Seeding
Authors: Massó-Vallés Daniel , Beaulieu Marie-Eve , Jauset Toni , Giuntini Fabio , Zacarías-Fluck Mariano F. , Foradada Laia , Martínez-Martín Sandra , Serrano Erika , Martín-Fernández Génesis , Casacuberta-Serra Sílvia , Castillo Cano Virginia , Kaur Jastrinjan , López-Estévez Sergio , Morcillo Miguel Ángel , Alzrigat Mohammad , Mahmoud Loay , Luque-García Antonio , Escorihuela Marta , Guzman Marta , Arribas Joaquín , Serra Violeta , Larsson Lars-Gunnar , Whitfield Jonathan R. , Soucek Laura
Published: April 2023

MYC's role in promoting tumorigenesis is beyond doubt, but its function in the metastatic process is still controversial. Omomyc is a MYC dominant negative that has shown potent antitumor activity in multiple cancer cell lines and mouse models, regardless of their tissue of origin or driver mutations, by impacting on several of the hallmarks of cancer. However, its therapeutic efficacy against metastasis has not been elucidated yet. Here we demonstrate for the first time that MYC inhibition by transgenic Omomyc is efficacious against all breast cancer molecular subtypes, including triple-negative breast cancer, where it displays potent antimetastatic properties both in vitro and in vivo. Importantly, pharmacologic treatment with the recombinantly produced Omomyc miniprotein, recently entering a clinical trial in solid tumors, recapitulates several key features of expression of the Omomyc transgene, confirming its clinical applicability to metastatic breast cancer, including advanced triple-negative breast cancer, a disease in urgent need of better therapeutic options.
Significance:
While MYC role in metastasis has been long controversial, this manuscript demonstrates that MYC inhibition by either transgenic expression or pharmacologic use of the recombinantly produced Omomyc miniprotein exerts antitumor and antimetastatic activity in breast cancer models in vitro and in vivo, suggesting its clinical applicability.
Data from Increased Microtubule Growth Triggered by Microvesicle-mediated Paracrine Signaling is Required for Melanoma Cancer Cell Invasion
Authors: Pudelko Karoline , Wieland Angela , Hennecke Magdalena , Räschle Markus , Bastians Holger
Published: April 2023

The acquisition of cell invasiveness is the key transition from benign melanocyte hyperplasia to aggressive melanoma. Recent work has provided an intriguing new link between the presence of supernumerary centrosomes and increased cell invasion. Moreover, supernumerary centrosomes were shown to drive non–cell-autonomous invasion of cancer cells. Although centrosomes are the principal microtubule organizing centers, the role of dynamic microtubules for non–cell-autonomous invasion remains unexplored, in particular, in melanoma. We investigated the role of supernumerary centrosomes and dynamic microtubules in melanoma cell invasion and found that highly invasive melanoma cells are characterized by the presence of supernumerary centrosomes and by increased microtubule growth rates, both of which are functionally interlinked. We demonstrate that enhanced microtubule growth is required for increased three-dimensional melanoma cell invasion. Moreover, we show that the activity to enhance microtubule growth can be transferred onto adjacent noninvasive cells through microvesicles involving HER2. Hence, our study suggests that suppressing microtubule growth, either directly using anti-microtubule drugs or through HER2 inhibitors might be therapeutically beneficial to inhibit cell invasiveness and thus, metastasis of malignant melanoma.
Significance:
This study shows that increased microtubule growth is required for melanoma cell invasion and can be transferred onto adjacent cells in a non–cell-autonomous manner through microvesicles involving HER2.
Data from The Tumor Immune Profile of Murine Ovarian Cancer Models: An Essential Tool for Ovarian Cancer Immunotherapy Research
Authors: Rodriguez Galaxia M. , Galpin Kristianne J.C. , Cook David P. , Yakubovich Edward , Maranda Vincent , Macdonald Elizabeth A. , Wilson-Sanchez Juliette , Thomas Anjali L. , Burdette Joanna E. , Vanderhyden Barbara C.
Published: April 2023

Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer with an imperative need for new treatments. Immunotherapy has had marked success in some cancer types; however, clinical trials studying the efficacy of immune checkpoint inhibitors for the treatment of EOC benefited less than 15% of patients. Given that EOC develops from multiple tissues in the reproductive system and metastasizes widely throughout the peritoneal cavity, responses to immunotherapy are likely hindered by heterogeneous tumor microenvironments (TME) containing a variety of immune profiles. To fully characterize and compare syngeneic model systems that may reflect this diversity, we determined the immunogenicity of six ovarian tumor models in vivo, the T and myeloid profile of orthotopic tumors and the immune composition and cytokine profile of ascites, by single-cell RNA sequencing, flow cytometry, and IHC. The selected models reflect the different cellular origins of EOC (ovarian and fallopian tube epithelium) and harbor mutations relevant to human disease, including Tp53 mutation, PTEN suppression, and constitutive KRAS activation. ID8-p53−/− and ID8-C3 tumors were most highly infiltrated by T cells, whereas STOSE and MOE-PTEN/KRAS tumors were primarily infiltrated by tumor-associated macrophages and were unique in MHC class I and II expression. MOE-PTEN/KRAS tumors were capable of forming T-cell clusters. This panel of well-defined murine EOC models reflects some of the heterogeneity found in human disease and can serve as a valuable resource for studies that aim to test immunotherapies, explore the mechanisms of immune response to therapy, and guide selection of treatments for patient populations.
Significance:
This study highlights the main differences in the immunogenicity and immune composition found in six different models of orthotopic ovarian cancer as an essential tool for future preclinical investigations of cancer immunotherapy.
Data from Brain Neural Progenitors are New Predictive Biomarkers for Breast Cancer Hormonotherapy
Authors: Basseville Agnes , Cordier Chiara , Ben Azzouz Fadoua , Gouraud Wilfried , Lasla Hamza , Panloup Fabien , Campone Mario , Jézéquel Pascal
Published: April 2023

Heterogeneity of the tumor microenvironment (TME) is one of the major causes of treatment resistance in breast cancer. Among TME components, nervous system role in clinical outcome has been underestimated. Identifying neuronal signatures associated with treatment response will help to characterize neuronal influence on tumor progression and identify new treatment targets. The search for hormonotherapy-predictive biomarkers was implemented by supervised machine learning (ML) analysis on merged transcriptomics datasets from public databases. ML-derived genes were investigated by pathway enrichment analysis, and potential gene signatures were curated by removing the variables that were not strictly nervous system specific. The predictive and prognostic abilities of the generated signatures were examined by Cox models, in the initial cohort and seven external cohorts. Generated signature performances were compared with 14 other published signatures, in both the initial and external cohorts. Underlying biological mechanisms were explored using deconvolution tools (CIBERSORTx and xCell). Our pipeline generated two nervous system-related signatures of 24 genes and 97 genes (NervSign24 and NervSign97). These signatures were prognostic and hormonotherapy-predictive, but not chemotherapy-predictive. When comparing their predictive performance with 14 published risk signatures in six hormonotherapy-treated cohorts, NervSign97 and NervSign24 were the two best performers. Pathway enrichment score and deconvolution analysis identified brain neural progenitor presence and perineural invasion as nervous system-related mechanisms positively associated with NervSign97 and poor clinical prognosis in hormonotherapy-treated patients. Transcriptomic profiling has identified two nervous system–related signatures that were validated in clinical samples as hormonotherapy-predictive signatures, meriting further exploration of neuronal component involvement in tumor progression.
Significance:
The development of personalized and precision medicine is the future of cancer therapy. With only two gene expression signatures approved by FDA for breast cancer, we are in need of new ones that can reliably stratify patients for optimal treatment. This study provides two hormonotherapy-predictive and prognostic signatures that are related to nervous system in TME. It highlights tumor neuronal components as potential new targets for breast cancer therapy.
Data from Bintrafusp Alfa, an Anti-PD-L1:TGFβ Trap Fusion Protein, in Patients with ctDNA-positive, Liver-limited Metastatic Colorectal Cancer
Authors: Morris Van K. , Overman Michael J. , Lam Michael , Parseghian Christine M. , Johnson Benny , Dasari Arvind , Raghav Kanwal , Kee Bryan K. , Huey Ryan , Wolff Robert A. , Shen John Paul , Li June , Zorrilla Isabel , Tzeng Ching-Wei D. , Tran Cao Hop S. , Chun Yun Shin , Newhook Timothy E. , Vauthey Nicolas , Duose Dzifa , Luthra Raja , Haymaker Cara , Kopetz Scott
Published: April 2023

Identification of circulating tumor DNA (ctDNA) following curative intent therapies is a surrogate for microscopic residual disease for patients with metastatic colorectal cancer (mCRC). Preclinically, in micrometastatic microsatellite stable (MSS) colorectal cancer, increased TGFβ signaling results in exclusion of antitumor cytotoxic T cells from the tumor microenvironment. Bintrafusp alfa (BA) is a bifunctional fusion protein composed of the extracellular domain of the TGFβRII receptor (“TGFβ trap”) and anti-PD-L1 antibody. Patients with liver-limited, MSS mCRC and with detected ctDNA after complete resection of all known tumors and standard-of-care therapy were treated with 1,200 mg of BA intravenously every 14 days for six doses. The primary endpoint was ctDNA clearance. Radiographic characteristics at recurrence were compared using independent t tests to historical data from a similar cohort of patients with liver-limited mCRC who underwent observation. Only 4 of 15 planned patients received BA before the study was stopped early for loss of equipoise. There was no grade ≥3 adverse event. None of the patients cleared ctDNA. All patients developed radiographic recurrence by the first planned restaging. Although not detectable at prior to treatment, TGFβ3 was found in circulation in all patients at cycle 2 day 1. Compared with a historical cohort, patients administered BA developed more metastases (15 vs. 2, P = 0.005) and greater tumor volumes (9 cm vs. 2 cm, P = 0.05). Treatment with BA in patients with ctDNA-detected, liver-limited mCRC did not clear ctDNA and was associated with large-volume recurrence, highlighting the potential context-specific complexity of dual TGFβ and PD-L1 inhibition.
Significance:
Use of ctDNA to identify patients with micrometastatic disease for therapeutic intervention is feasible. Treatment with BA in patients with liver-limited mCRC and with detectable ctDNA after resection generated rapid progression. Approaches targeting TGFβ signaling must consider its pathway complexity in future immunotherapy combination strategies.
Data from Circulating Tumor DNA Monitoring Reveals Molecular Progression before Radiologic Progression in a Real-life Cohort of Patients with Advanced Non–small Cell Lung Cancer
Authors: Frank Malene S. , Andersen Christina S.A. , Ahlborn Lise B. , Pallisgaard Niels , Bodtger Uffe , Gehl Julie
Published: April 2023

Purpose:
The clinical potential of liquid biopsy in patients with advanced cancer is real-time monitoring for early detection of treatment failure. Our study aimed to investigate the clinical validity of circulating tumor DNA (ctDNA) treatment monitoring in a real-life cohort of patients with advanced non–small cell lung cancer (NSCLC).
Experimental Design:
Patients with advanced or noncurative locally advanced NSCLC were prospectively included in an exploratory study (NCT03512847). Selected cancer-specific mutations were measured in plasma by standard or uniquely designed droplet digital PCR assays before every treatment cycle during first-line treatment until progressive disease (PD). Correlation between an increase in ctDNA (= molecular progression) and radiologic PD was investigated, defined as lead time, and the corresponding numbers of likely futile treatment cycles were determined. Utility of ctDNA measurements in clarifying the results of nonconclusive radiologic evaluation scans was evaluated.
Results:
Cancer-specific mutations and longitudinal plasma sampling were present in 132 of 150 patients. ctDNA was detectable in 88 (67%) of 132 patients treated by respectively chemotherapy (n = 41), immunotherapy (n = 43), or combination treatment (n = 4). In 66 (90%) of 73 patients experiencing PD, a ctDNA increase was observed with a median lead time of 1.5 months before radiologic PD. Overall, 119 (33%) of 365 treatment cycles were administered after molecular progression. In addition, ctDNA measurements could clarify the results in 38 (79%) of 48 nonconclusive radiologic evaluations.
Conclusions:
ctDNA monitoring leads to earlier detection of treatment failure, and clarifies the majority of nonconclusive radiologic evaluations, giving the potential of sparing patients from likely futile treatments and needless adverse events.
Significance:
Treatment monitoring by ctDNA has the clinical potential to reveal PD before radiologic evaluation and consequently spare patients with advanced cancer from likely ineffective, costly cancer treatments and adverse events.
Data from Pharmaceutical Reactivation of Attenuated Apoptotic Pathways Leads to Elimination of Osimertinib Drug-Tolerant Cells
Authors: Martin Matthew J. , Floc'h Nicolas , Pfeifer Matthias , Criscione Steven , Delpuech Oona , Gagrica Sladjana , Yao Yi , McDermott Ultan , Smith Paul D.
Published: April 2023

Osimertinib is an EGFR tyrosine kinase inhibitor (TKI) with proven clinical efficacy; however, acquired resistance presents an obstacle to curing EGFR-driven disease. Recent studies have shown that drug-tolerant persister cells (DTP) have a distinct transcriptional profile that may confer specific vulnerabilities. By definition these cells avoid apoptosis, yet little is known about how their survival is regulated. We found that paradoxically, the proapoptotic gene BIM was upregulated in osimertinib DTPs, and cotreatment with BH3 mimetics could trigger DTP cell death. Furthermore, cIAP proteins, antiapoptotic members of the extrinsic pathway, were significantly elevated in DTPs. cIAP antagonists could block DTP formation as an up-front combination, and could eliminate preformed DTPs. Critically, when treated at the time of maximal osimertinib response, cIAP or MCL1 inhibitor treatment could significantly attenuate the regrowth of EGFRm cell line mouse xenografts. Finally, we show that apoptosis can be maximized in cell lines with acquired osimertinib resistance by combining BH3 or SMAC mimetics with agents that target the resistance driver in these models. Taken together, these data suggest novel therapeutic strategies at the point of minimal residual disease or full osimertinib resistance for patients in this critical area of unmet need.
Significance:
These studies uncover strategies to use targeted agents that activate apoptosis in non–small cell lung cancer cells that survive initial EGFR TKI treatment.
Data from A Novel PHD2/VHL-mediated Regulation of YAP1 Contributes to VEGF Expression and Angiogenesis
Authors: Bora-Singhal Namrata , Saha Biswarup , Mohankumar Durairaj , Padmanabhan Jaya , Coppola Domenico , Chellappan Srikumar
Published: April 2023

The transcriptional coactivator YAP1 is the major oncogenic component of the Hippo signaling pathway and contributes to the genesis and progression of various tumors, including non–small cell lung cancer (NSCLC). YAP1 levels are regulated by the canonical Hippo kinases, MST1/2 and LATS1/2, which modulate its cytoplasmic retention and proteasomal degradation. While noncanonical regulation of YAP1 has been reported, its role in hypoxic response is not fully elucidated. The studies presented here show that YAP1 levels and function are modulated by von Hippel–Lindau (VHL) and prolyl hydroxylase 2 (PHD2). YAP1 could regulate multiple genes involved in angiogenesis through E2F1; it also associates with HIF1α in cancer cells under hypoxic conditions, inducing the VEGF-A promoter. Under normoxic conditions, PHD2 associates with and hydroxylates specific proline residues on YAP1, facilitating its interaction with VHL and promoting ubiquitination and subsequent proteasomal degradation. Exposure to hypoxia dissociates YAP1 from PHD2 and VHL, elevating YAP1 levels and enhancing its association with HIF1α. YAP1–HIF1α interaction was higher in NSCLC and renal cell carcinoma samples, indicating a role for this interaction in the genesis of these cancers. Our results thus reveal a novel mode of regulation of YAP1 by PHD2 and VHL in normoxic cells, suggesting that YAP1-mediated induction of VEGF and other genes contributes to hypoxic response in tumors.
Significance:
YAP1 under normoxic conditions is regulated by a novel nonclassical regulatory pathway involving PHD2-mediated prolylhydroxylation and proteasomal degradation; absence of this regulation under hypoxic conditions stabilizes YAP1, contributing to neoangiogenesis.
Data from Diagnostic Accuracy of Blood-based Biomarkers for Pancreatic Cancer: A Systematic Review and Meta-analysis
Authors: Kane Laura E. , Mellotte Gregory S. , Mylod Eimear , O'Brien Rebecca M. , O'Connell Fiona , Buckley Croí E. , Arlow Jennifer , Nguyen Khanh , Mockler David , Meade Aidan D. , Ryan Barbara M. , Maher Stephen G.
Published: April 2023

Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate below 5%. Carbohydrate antigen 19-9 (CA19-9) is the most commonly used blood-based biomarker for PDAC in current clinical practice, despite having been shown repeatedly to be inaccurate and have poor diagnostic performance. This review aims to assess the reported diagnostic accuracy of all blood-based biomarkers investigated to date in PDAC, by directly comparing individual biomarkers and multi-biomarker panels, both containing CA19-9 and not (novel). A systematic review was conducted in accordance with PRISMA standards in July 2020. Individualized search strategies for three academic databases identified 5,885 studies between the years 1973 and 2020. After two rounds of screening, 250 studies were included. Data were extracted and assessed for bias. A multivariate three-level meta-analysis with subgroup moderators was run in R using AUC values as effect size. On the basis of this model, the pooled AUC value for all multi-biomarker panels (AUC = 0.898; 95% confidence interval (CI): 0.88–0.91) was significantly higher than all single biomarkers (AUC = 0.803; 95% CI: 0.78–0.83; P < 0.0001). The pooled AUC value for CA19-9 alone was significantly lower compared with the multi-biomarker panels containing CA19-9 (P < 0.0001). For the novel biomarkers, the pooled AUC for single biomarkers was also significantly lower compared with multi-biomarker panels (P < 0.0001). Novel biomarkers that have been repeatedly examined across the literature, such as TIMP-1, CEA, and CA125, are highlighted as promising. These results suggest that CA19-9 may be best used as an addition to a panel of biomarkers rather than alone, and that multi-biomarker panels generate the most robust results in blood-based PDAC diagnosis.
Significance:
In a systematic review and three-level multivariate meta-analysis, it is shown for the first time that blood-based multi-biomarker panels for the diagnosis of PDAC exhibit superior performance in comparison with single biomarkers. CA19-9 is demonstrated to have limited utility alone, and to perform poorly in patient control cohorts of both healthy and benign individuals. Multi-biomarker panels containing CA19-9 produce the best diagnostic performance overall.
Data from Cell-free DNA Predicts Prolonged Response to Multi-agent Chemotherapy in Pancreatic Ductal Adenocarcinoma
Authors: Christenson Eric S. , Lim Su Jin , Durham Jennifer , De Jesus-Acosta Ana , Bever Katherine , Laheru Daniel , Ryan Amy , Agarwal Parul , Scharpf Robert B. , Le Dung T. , Wang Hao
Published: April 2023

The treatment of metastatic pancreatic ductal adenocarcinoma (PDAC) is frequently characterized by significant toxicity and rapid development of resistance to current approved therapies. More reliable biomarkers of response are needed to guide clinical decision making.

We evaluated cell-free DNA (cfDNA) using a tumor-agnostic platform and traditional biomarkers (CEA and CA19-9) levels in 12 patients treated at Johns Hopkins University on NCT02324543 “Study of Gemcitabine/Nab-Paclitaxel/Xeloda (GAX) in Combination With Cisplatin and Irinotecan in Subjects With Metastatic Pancreatic Cancer.” The pretreatment values, levels after 2 months of treatment, and change in biomarker levels with treatment were compared with clinical outcomes to determine their predictive value.

The variant allele frequency (VAF) of KRAS and TP53 mutations in cfDNA after 2 months of treatment was predictive of progression-free survival (PFS) and overall survival (OS). In particular, patients with a lower-than-average KRAS VAF after 2 months of treatment had a substantially longer PFS than patients with higher posttreatment KRAS VAF (20.96 vs. 4.39 months). Changes in CEA and CA19-9 after 2 months of treatment were also good predictors of PFS.

Comparison via concordance index demonstrated KRAS or TP53 VAF after 2 months of treatment to be better predictors of PFS and OS than CA19-9 or CEA. This pilot study requires validation but suggests cfDNA measurement is a useful adjunct to traditional protein biomarkers and imaging evaluation and could distinguish between patients who are likely to achieve prolonged responses versus those that will have early progression and may benefit from a change in treatment approach.
Significance:
We report on the association of cfDNA with response durability for patients undergoing treatment with a novel metronomic chemotherapy regimen (gemcitabine, nab-paclitaxel, capecitabine, cisplatin, irinotecan; GAX-CI) for metastatic PDAC. This investigation offers encouraging evidence that cfDNA may prove to be a valuable diagnostic tool to guide clinical management.
Data from Classifying cGAS-STING Activity Links Chromosomal Instability with Immunotherapy Response in Metastatic Bladder Cancer
Authors: Sokač Mateo , Ahrenfeldt Johanne , Litchfield Kevin , Watkins Thomas B.K. , Knudsen Michael , Dyrskjøt Lars , Jakobsen Martin R. , Birkbak Nicolai J.
Published: April 2023

The cGAS-STING pathway serves a critical role in anticancer therapy. Particularly, response to immunotherapy is likely driven by both active cGAS-STING signaling that attracts immune cells, and by the presence of cancer neoantigens that presents as targets for cytotoxic T cells. Chromosomal instability (CIN) is a hallmark of cancer, but also leads to an accumulation of cytosolic DNA that in turn results in increased cGAS-STING signaling. To avoid triggering the cGAS-STING pathway, it is commonly disrupted by cancer cells, either through mutations in the pathway or through transcriptional silencing. Given its effect on the immune system, determining the cGAS-STING activation status prior to treatment initiation is likely of clinical relevance. Here, we used combined expression data from 2,307 tumors from five cancer types from The Cancer Genome Atlas to define a novel cGAS-STING activity score based on eight genes with a known role in the pathway. Using unsupervised clustering, four distinct categories of cGAS-STING activation were identified. In multivariate models, the cGAS-STING active tumors show improved prognosis. Importantly, in an independent bladder cancer immunotherapy-treated cohort, patients with low cGAS-STING expression showed limited response to treatment, while patients with high expression showed improved response and prognosis, particularly among patients with high CIN and more neoantigens. In a multivariate model, a significant interaction was observed between CIN, neoantigens, and cGAS-STING activation. Together, this suggests a potential role of cGAS-STING activity as a predictive biomarker for the application of immunotherapy.
Significance:
The cGAS-STING pathway is induced by CIN, triggers inflammation and is often deficient in cancer. We provide a tool to evaluate cGAS-STING activity and demonstrate clinical significance in immunotherapy response.
Data from A Phase IB Trial of the PI3K Inhibitor Alpelisib and Weekly Cisplatin in Patients with Solid Tumor Malignancies
Authors: Tsang Erica S. , Aggarwal Rahul R. , Dhawan Mallika S. , Bergsland Emily K. , Alvarez Edwin A. , Calabrese Susan , Pacaud Romain , Garcia Jose , Fattah Delaire , Thomas Scott , Grabowsky Jennifer , Moasser Mark M. , Munster Pamela N.
Published: April 2023

The PI3K pathway may be a potential mechanism to overcome cisplatin resistance. We conducted a phase Ib trial of alpelisib and cisplatin for patients with solid tumor malignancies with planned dose expansion in HPV-associated tumors. The primary objective was to determine the MTD and recommended phase II dose. Two different weekly doses of cisplatin (30 and 35 mg/m2) were evaluated with escalating doses of alpelisib, administered daily during a 21-day treatment cycle. Twenty-three patients were enrolled: 91% received >3 prior regimens with median of 4 (range 1–10), and 78% progressed on prior platinum. The MTD was alpelisib 250 mg daily with weekly cisplatin 30 mg/m2. There were 3 DLTs: all grade 4 hyperglycemia. Frequent treatment-related adverse events of any grade included fatigue (52%), diarrhea (39%), nausea (38%), hyperglycemia (30%), anemia (22%), and nephropathy (17%). Hyperglycemia was linked to baseline hemoglobin A1C, but not body mass index. Twelve patients discontinued treatment for toxicity (n = 9 during cycle 1) and 11 discontinued for progression. Of 14 evaluable patients who received at least one treatment cycle, 4 (29%) patients demonstrated partial response, and 7 had stable disease for a disease control rate of 79%. The median PFS measured 4.3 months (95% CI, 1.6–4.5). No difference in PFS was observed between PIK3CA-mutated and wild-type tumors. While the combination of alpelisib and cisplatin demonstrated preliminary evidence of activity despite platinum resistance, toxicities hindered prolonged treatment. Prospective studies are planned using carboplatin and alpelisib to improve toxicity and tolerability.
Significance:
The PI3K inhibitor alpelisib has limited activity alone, but there is interest in combinations in platinum-resistant tumors. In this phase Ib study of alpelisib with cisplatin, the objective response rate measured 29% but adverse events limited dose intensity. These promising results provide rationale for studying combinations with better tolerated platinum agents.
Data from Loss of Vascular Endothelial Glutaminase Inhibits Tumor Growth and Metastasis, and Increases Sensitivity to Chemotherapy
Authors: Ngwa Verra M. , Edwards Deanna N. , Hwang Yoonha , Karno Breelyn , Wang Xiaoyong , Yan Chi , Richmond Ann , Brantley-Sieders Dana M. , Chen Jin
Published: April 2023

Glutamine is the most abundant nonessential amino acid in blood stream; yet its concentration in tumor interstitium is markedly lower than that in the serum, reflecting the huge demand of various cell types in tumor microenvironment for glutamine. While many studies have investigated glutamine metabolism in tumor epithelium and infiltrating immune cells, the role of glutamine metabolism in tumor blood vessels remains unknown. Here, we report that inducible genetic deletion of glutaminase (GLS) specifically in host endothelium, GLSECKO, impairs tumor growth and metastatic dissemination in vivo. Loss of GLS decreased tumor microvascular density, increased perivascular support cell coverage, improved perfusion, and reduced hypoxia in mammary tumors. Importantly, chemotherapeutic drug delivery and therapeutic efficacy were improved in tumor-bearing GLSECKO hosts or in combination with GLS inhibitor, CB-839. Mechanistically, loss of GLS in tumor endothelium resulted in decreased leptin levels, and exogenous recombinant leptin rescued tumor growth defects in GLSECKO mice. Together, these data demonstrate that inhibition of endothelial glutamine metabolism normalizes tumor vessels, reducing tumor growth and metastatic spread, improving perfusion, reducing hypoxia, and enhancing chemotherapeutic delivery. Thus, targeting glutamine metabolism in host vasculature may improve clinical outcome in patients with solid tumors.
Significance:
This study demonstrates a crucial role for glutamine metabolism in tumor endothelium, which may be exploited therapeutically to induce vascular normalization and improve drug delivery in solid tumors.