bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Figure 6 from Targeting the Epigenetic Reader ENL Inhibits Super-Enhancer–Driven Oncogenic Transcription and Synergizes with BET Inhibition to Suppress Tumor Progression
Authors: Chen Yongheng , Ying Ying , Ma Wenlong , Ma Hongchao , Shi Liang , Gao Xuefeng , Jia Min , Li Meiqi , Song Xiaoman , Kong Weixiao , Chen Wei , Zheng Xiangyi , Muluh Tobias Achu , Wang Xiaobin , Wang Maolin , Shu Xing-sheng
Published: April 2024

Related to Figure 6.
Supplementary Figure 4 from Targeting the Epigenetic Reader ENL Inhibits Super-Enhancer–Driven Oncogenic Transcription and Synergizes with BET Inhibition to Suppress Tumor Progression
Authors: Chen Yongheng , Ying Ying , Ma Wenlong , Ma Hongchao , Shi Liang , Gao Xuefeng , Jia Min , Li Meiqi , Song Xiaoman , Kong Weixiao , Chen Wei , Zheng Xiangyi , Muluh Tobias Achu , Wang Xiaobin , Wang Maolin , Shu Xing-sheng
Published: April 2024

Related to Figure 4.
Supplementary Figure 1 from Targeting the Epigenetic Reader ENL Inhibits Super-Enhancer–Driven Oncogenic Transcription and Synergizes with BET Inhibition to Suppress Tumor Progression
Authors: Chen Yongheng , Ying Ying , Ma Wenlong , Ma Hongchao , Shi Liang , Gao Xuefeng , Jia Min , Li Meiqi , Song Xiaoman , Kong Weixiao , Chen Wei , Zheng Xiangyi , Muluh Tobias Achu , Wang Xiaobin , Wang Maolin , Shu Xing-sheng
Published: April 2024

Related to Figure 1.
Supplementary Table 2 from Targeting the Epigenetic Reader ENL Inhibits Super-Enhancer–Driven Oncogenic Transcription and Synergizes with BET Inhibition to Suppress Tumor Progression
Authors: Chen Yongheng , Ying Ying , Ma Wenlong , Ma Hongchao , Shi Liang , Gao Xuefeng , Jia Min , Li Meiqi , Song Xiaoman , Kong Weixiao , Chen Wei , Zheng Xiangyi , Muluh Tobias Achu , Wang Xiaobin , Wang Maolin , Shu Xing-sheng
Published: April 2024

Antibodies used in this study.
Supplementary Table 1 from Targeting the Epigenetic Reader ENL Inhibits Super-Enhancer–Driven Oncogenic Transcription and Synergizes with BET Inhibition to Suppress Tumor Progression
Authors: Chen Yongheng , Ying Ying , Ma Wenlong , Ma Hongchao , Shi Liang , Gao Xuefeng , Jia Min , Li Meiqi , Song Xiaoman , Kong Weixiao , Chen Wei , Zheng Xiangyi , Muluh Tobias Achu , Wang Xiaobin , Wang Maolin , Shu Xing-sheng
Published: April 2024

Target sequences of shRNAs and sgRNAs used in this study.
Supplementary Figure 2 from Targeting the Epigenetic Reader ENL Inhibits Super-Enhancer–Driven Oncogenic Transcription and Synergizes with BET Inhibition to Suppress Tumor Progression
Authors: Chen Yongheng , Ying Ying , Ma Wenlong , Ma Hongchao , Shi Liang , Gao Xuefeng , Jia Min , Li Meiqi , Song Xiaoman , Kong Weixiao , Chen Wei , Zheng Xiangyi , Muluh Tobias Achu , Wang Xiaobin , Wang Maolin , Shu Xing-sheng
Published: April 2024

Related to Figure 2.
Supplementary Table S8 from TFE3-Splicing Factor Fusions Represent Functional Drivers and Druggable Targets in Translocation Renal Cell Carcinoma
Authors: Damayanti Nur P. , Cordova Ricardo A. , Rupert Christopher , Delle Fontane Ilaria , Shen Li , Orsi Sabrina , Klunk Angela J. , Linehan W. Marston , Staschke Kirk A. , Hollenhorst Peter C. , Heppner David E. , Pili Roberto
Published: April 2024

Supplementary Table S8
Supplementary Table S5 from TFE3-Splicing Factor Fusions Represent Functional Drivers and Druggable Targets in Translocation Renal Cell Carcinoma
Authors: Damayanti Nur P. , Cordova Ricardo A. , Rupert Christopher , Delle Fontane Ilaria , Shen Li , Orsi Sabrina , Klunk Angela J. , Linehan W. Marston , Staschke Kirk A. , Hollenhorst Peter C. , Heppner David E. , Pili Roberto
Published: April 2024

Supplementary Table S5
Supplementary Table S1 from TFE3-Splicing Factor Fusions Represent Functional Drivers and Druggable Targets in Translocation Renal Cell Carcinoma
Authors: Damayanti Nur P. , Cordova Ricardo A. , Rupert Christopher , Delle Fontane Ilaria , Shen Li , Orsi Sabrina , Klunk Angela J. , Linehan W. Marston , Staschke Kirk A. , Hollenhorst Peter C. , Heppner David E. , Pili Roberto
Published: April 2024

Supplementary Table S1
Supplementary Figure S9 from TFE3-Splicing Factor Fusions Represent Functional Drivers and Druggable Targets in Translocation Renal Cell Carcinoma
Authors: Damayanti Nur P. , Cordova Ricardo A. , Rupert Christopher , Delle Fontane Ilaria , Shen Li , Orsi Sabrina , Klunk Angela J. , Linehan W. Marston , Staschke Kirk A. , Hollenhorst Peter C. , Heppner David E. , Pili Roberto
Published: April 2024

Supplementary Figure S9
Supplementary Figure S17 from TFE3-Splicing Factor Fusions Represent Functional Drivers and Druggable Targets in Translocation Renal Cell Carcinoma
Authors: Damayanti Nur P. , Cordova Ricardo A. , Rupert Christopher , Delle Fontane Ilaria , Shen Li , Orsi Sabrina , Klunk Angela J. , Linehan W. Marston , Staschke Kirk A. , Hollenhorst Peter C. , Heppner David E. , Pili Roberto
Published: April 2024

Supplementary Figure S17
Supplementary Figure S13 from TFE3-Splicing Factor Fusions Represent Functional Drivers and Druggable Targets in Translocation Renal Cell Carcinoma
Authors: Damayanti Nur P. , Cordova Ricardo A. , Rupert Christopher , Delle Fontane Ilaria , Shen Li , Orsi Sabrina , Klunk Angela J. , Linehan W. Marston , Staschke Kirk A. , Hollenhorst Peter C. , Heppner David E. , Pili Roberto
Published: April 2024

Supplementary Figure S13
Figure S6 from Th17 Cells Secrete TWEAK to Trigger Epithelial–Mesenchymal Transition and Promote Colorectal Cancer Liver Metastasis
Authors: Liu Xin , Wang Xin , Yang Qingxia , Luo Li , Liu Ziqin , Ren Xiaoxue , Lei Kai , Li Shangru , Xie Zonglin , Zheng Gaomin , Zhang Yifan , Hao Yijie , Zhou Qianying , Hou Yingdong , Fang Fei , Song Wu , Cui Ji , Ma Jinping , Xie Wenxuan , Shen Shunli , Tang Ce , Peng Sui , Yu Jun , Kuang Ming , Song Xinming , Wang Fang , Xu Lixia
Published: April 2024

Figure S6. Pseudotime analysis of tumor cells by Palantir and CellRank.
Supplementary Data Figure S7 from KDM5C-Mediated Recruitment of BRD4 to Chromatin Regulates Enhancer Activation and BET Inhibitor Sensitivity
Authors: Qiang Yulong , Fan Jiachen , Xie Chuanshuai , Yan Leilei , Song Xiaofei , Zhang Nan , Lin Yan , Xiong Jie , Zhang Wei , Liu Yu , Wei Lei , Li Yu , Chen Shizhen , Liang Kaiwei , Li Feng
Published: April 2024

KDM5C influence H3K4me3 peaks width via its histone demethylase activity.
Figure S2 from Th17 Cells Secrete TWEAK to Trigger Epithelial–Mesenchymal Transition and Promote Colorectal Cancer Liver Metastasis
Authors: Liu Xin , Wang Xin , Yang Qingxia , Luo Li , Liu Ziqin , Ren Xiaoxue , Lei Kai , Li Shangru , Xie Zonglin , Zheng Gaomin , Zhang Yifan , Hao Yijie , Zhou Qianying , Hou Yingdong , Fang Fei , Song Wu , Cui Ji , Ma Jinping , Xie Wenxuan , Shen Shunli , Tang Ce , Peng Sui , Yu Jun , Kuang Ming , Song Xinming , Wang Fang , Xu Lixia
Published: April 2024

Figure S2. Evaluation of the accuracy of reference mapping.
Supplementary Data Figure S4 from KDM5C-Mediated Recruitment of BRD4 to Chromatin Regulates Enhancer Activation and BET Inhibitor Sensitivity
Authors: Qiang Yulong , Fan Jiachen , Xie Chuanshuai , Yan Leilei , Song Xiaofei , Zhang Nan , Lin Yan , Xiong Jie , Zhang Wei , Liu Yu , Wei Lei , Li Yu , Chen Shizhen , Liang Kaiwei , Li Feng
Published: April 2024

Tumor cells defective in KDM5C exhibits lower BRD4 chromatin enrichment.
Table S2 from ASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts
Authors: Hu Bomiao , Wiesehöfer Marc , de Miguel Fernando J. , Liu Zongzhi , Chan Lok-Hei , Choi Jungmin , Melnick Mary Ann , Arnal Estape Anna , Walther Zenta , Zhao Dejian , Lopez-Giraldez Francesc , Wurtz Anna , Cai Guoping , Fan Rong , Gettinger Scott , Xiao Andrew , Yan Qin , Homer Robert , Nguyen Don X. , Politi Katerina
Published: April 2024

WES Summary
Supplementary Data Figure S1 from KDM5C-Mediated Recruitment of BRD4 to Chromatin Regulates Enhancer Activation and BET Inhibitor Sensitivity
Authors: Qiang Yulong , Fan Jiachen , Xie Chuanshuai , Yan Leilei , Song Xiaofei , Zhang Nan , Lin Yan , Xiong Jie , Zhang Wei , Liu Yu , Wei Lei , Li Yu , Chen Shizhen , Liang Kaiwei , Li Feng
Published: April 2024

BRD4 is a vulnerability of KDM5C deficient tumor cells.
Figure S5 from ASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts
Authors: Hu Bomiao , Wiesehöfer Marc , de Miguel Fernando J. , Liu Zongzhi , Chan Lok-Hei , Choi Jungmin , Melnick Mary Ann , Arnal Estape Anna , Walther Zenta , Zhao Dejian , Lopez-Giraldez Francesc , Wurtz Anna , Cai Guoping , Fan Rong , Gettinger Scott , Xiao Andrew , Yan Qin , Homer Robert , Nguyen Don X. , Politi Katerina
Published: April 2024

Characterization of mutant EGFR lung cancer PDXs at single-cell resolution. Workflow for scRNA-seq on PDXs and single cell data for an additional PDX.
Figure S9 from Fibroblasts in the Aged Pancreas Drive Pancreatic Cancer Progression
Authors: Zabransky Daniel J. , Chhabra Yash , Fane Mitchell E. , Kartalia Emma , Leatherman James M. , Hüser Laura , Zimmerman Jacquelyn W. , Delitto Daniel , Han Song , Armstrong Todd D. , Charmsaz Soren , Guinn Samantha , Pramod Sneha , Thompson Elizabeth D. , Hughes Steven J. , O'Connell Jennifer , Egan Josephine M. , Jaffee Elizabeth M. , Weeraratna Ashani T.
Published: April 2024

Figure S9
Supplementary Figure S3 from Breast Cancer Stem Cells Secrete MIF to Mediate Tumor Metabolic Reprogramming That Drives Immune Evasion
Authors: Yan Linlin , Wu Mingming , Wang Tianyu , Yuan Hui , Zhang Xiao , Zhang Huafeng , Li Tao , Pandey Vijay , Han Xinghua , Lobie Peter E. , Zhu Tao
Published: April 2024

Supplementary Figure S3 shows that MIF is identified as a key cytokine secreted by BCSC.
Supplementary Materials and Methods from Tumor Cell–Intrinsic p38 MAPK Signaling Promotes IL1α-Mediated Stromal Inflammation and Therapeutic Resistance in Pancreatic Cancer
Authors: Singh Samara P. , Dosch Austin R. , Mehra Siddharth , De Castro Silva Iago , Bianchi Anna , Garrido Vanessa T. , Zhou Zhiqun , Adams Andrew , Amirian Haleh , Box Edmond W. , Sun Xiaodian , Ban Yuguang , Datta Jashodeep , Nagathihalli Nagaraj S. , Merchant Nipun B.
Published: April 2024

Supplementary Materials and Methods
Supplementary Figure S7 from Tumor Cell–Intrinsic p38 MAPK Signaling Promotes IL1α-Mediated Stromal Inflammation and Therapeutic Resistance in Pancreatic Cancer
Authors: Singh Samara P. , Dosch Austin R. , Mehra Siddharth , De Castro Silva Iago , Bianchi Anna , Garrido Vanessa T. , Zhou Zhiqun , Adams Andrew , Amirian Haleh , Box Edmond W. , Sun Xiaodian , Ban Yuguang , Datta Jashodeep , Nagathihalli Nagaraj S. , Merchant Nipun B.
Published: April 2024

Supplementary data for figure 5 and 6
Supplementary Figure S2 from Tumor Cell–Intrinsic p38 MAPK Signaling Promotes IL1α-Mediated Stromal Inflammation and Therapeutic Resistance in Pancreatic Cancer
Authors: Singh Samara P. , Dosch Austin R. , Mehra Siddharth , De Castro Silva Iago , Bianchi Anna , Garrido Vanessa T. , Zhou Zhiqun , Adams Andrew , Amirian Haleh , Box Edmond W. , Sun Xiaodian , Ban Yuguang , Datta Jashodeep , Nagathihalli Nagaraj S. , Merchant Nipun B.
Published: April 2024

Supplementary Data for figure 2
Supplementary Data from Tumor Cell–Intrinsic p38 MAPK Signaling Promotes IL1α-Mediated Stromal Inflammation and Therapeutic Resistance in Pancreatic Cancer
Authors: Singh Samara P. , Dosch Austin R. , Mehra Siddharth , De Castro Silva Iago , Bianchi Anna , Garrido Vanessa T. , Zhou Zhiqun , Adams Andrew , Amirian Haleh , Box Edmond W. , Sun Xiaodian , Ban Yuguang , Datta Jashodeep , Nagathihalli Nagaraj S. , Merchant Nipun B.
Published: April 2024

Supplementary data for TCGA analysis in Figure 1 without the normalized tumor cellularity analysis
Data from Breast Cancer Stem Cells Secrete MIF to Mediate Tumor Metabolic Reprogramming That Drives Immune Evasion
Authors: Yan Linlin , Wu Mingming , Wang Tianyu , Yuan Hui , Zhang Xiao , Zhang Huafeng , Li Tao , Pandey Vijay , Han Xinghua , Lobie Peter E. , Zhu Tao
Published: April 2024

Abstract
Reprogramming of energy metabolism exerts pivotal functions in cancer progression and immune surveillance. Identification of the mechanisms mediating metabolic changes in cancer may lead to improved strategies to suppress tumor growth and stimulate antitumor immunity. Here, it was observed that the secretomes of hypoxic breast cancer cells and breast cancer stem cells (BCSC) induced reprogramming of metabolic pathways, particularly glycolysis, in normoxic breast cancer cells. Screening of the BCSC secretome identified MIF as a pivotal factor potentiating glycolysis. Mechanistically, MIF increased c-MYC–mediated transcriptional upregulation of the glycolytic enzyme aldolase C by activating WNT/β-catenin signaling. Targeting MIF attenuated glycolysis and impaired xenograft growth and metastasis. MIF depletion in breast cancer cells also augmented intratumoral cytolytic CD8+ T cells and proinflammatory macrophages while decreasing regulatory T cells and tumor-associated neutrophils in the tumor microenvironment. Consequently, targeting MIF improved the therapeutic efficacy of immune checkpoint blockade in triple-negative breast cancer. Collectively, this study proposes MIF as an attractive therapeutic target to circumvent metabolic reprogramming and immunosuppression in breast cancer.
Significance:
MIF secreted by breast cancer stem cells induces metabolic reprogramming in bulk tumor cells and engenders an immunosuppressive microenvironment, identifying MIF targeting as a strategy to improve immunotherapy efficacy in breast cancer.
Data from KDM5C-Mediated Recruitment of BRD4 to Chromatin Regulates Enhancer Activation and BET Inhibitor Sensitivity
Authors: Qiang Yulong , Fan Jiachen , Xie Chuanshuai , Yan Leilei , Song Xiaofei , Zhang Nan , Lin Yan , Xiong Jie , Zhang Wei , Liu Yu , Wei Lei , Li Yu , Chen Shizhen , Liang Kaiwei , Li Feng
Published: April 2024

Abstract
The BET family member BRD4 is a bromodomain-containing protein that plays a vital role in driving oncogene expression. Given their pivotal role in regulating oncogenic networks in various cancer types, BET inhibitors (BETi) have been developed, but the clinical application has been impeded by dose-limiting toxicity and resistance. Understanding the mechanisms of BRD4 activity and identifying predictive biomarkers could facilitate the successful clinical use of BETis. Herein, we show that KDM5C and BRD4 cooperate to sustain tumor cell growth. Mechanistically, KDM5C interacted with BRD4 and stimulated BRD4 enhancer recruitment. Moreover, binding of the BRD4 C-terminus to KDM5C stimulated the H3K4 demethylase activity of KDM5C. The abundance of both KDM5C-associated BRD4 and H3K4me1/3 determined the transcriptional activation of many oncogenes. Notably, depletion or pharmacologic degradation of KDM5C dramatically reduced BRD4 chromatin enrichment and significantly increased BETi efficacy across multiple cancer types in both tumor cell lines and patient-derived organoid models. Furthermore, targeting KDM5C in combination with BETi suppressed tumor growth in vivo in a xenograft mouse model. Collectively, this work reveals a KDM5C-mediated mechanism by which BRD4 regulates transcription, providing a rationale for incorporating BETi into combination therapies with KDM5C inhibitors to enhance treatment efficacy.
Significance:
BRD4 is recruited to enhancers in a bromodomain-independent manner by binding KDM5C and stimulates KDM5C H3K4 demethylase activity, leading to synergistic effects of BET and KDM5C inhibitor combinations in cancer.
Unlocking the Role of Age-Related Changes to Fibroblasts in Pancreatic Cancer
Authors: Isaacson Achinoam , Barki Debra , Scherz-Shouval Ruth
Published: April 2024

Pancreatic cancer prevalence increases with age, and disease prognosis is poorer in older individuals. The increased prevalence is driven, undoubtedly, by the multistep accumulation of oncogenic mutations in cancer cells with age. However, fibroblasts are major constituents and key players in pancreatic cancer, and they too undergo age-related changes that may contribute to disease severity. In this issue of Cancer Research, Zabransky and colleagues set out to dissect the effect of age-related changes in pancreatic fibroblasts on pancreatic ductal adenocarcinoma growth and metastasis. They discovered that aged fibroblasts secrete GDF-15, which in turn activates AKT signaling and accelerates tumor progression. These findings provide a mechanistic role for aged fibroblasts in pancreatic cancer, underpinning the importance of normal physiologic processes in tumor progression.

See related article by Zabransky et al., p. 1221
Pushing the Frontiers of Cancer Research: Highlights from the Frontiers in Cancer Science Conference 2023
Authors: Lee Yi Fei , Chen Leilei , Chew Valerie , Chow Edward Kai-Hua , Deng Lih-Wen , Hunziker Walter , Lee Ann Siew Gek , Leong Geraldine , Ngeow Joanne , Pervaiz Shazib , Sabapathy Kanaga , Skanderup Anders J. , Sundar Raghav , Tay Yvonne , Virshup David M. , Wong Sunny H. , Tergaonkar Vinay , Tam Wai Leong
Published: April 2024

The 15th annual Frontiers in Cancer Science (FCS) conference gathered scientific experts who shared the latest research converging upon several themes of cancer biology. These themes included the dysregulation of metabolism, cell death, and other signaling processes in cancer cells; using patient “omics” datasets and single-cell and spatial approaches to investigate heterogeneity, understand therapy resistance, and identify targets; innovative strategies for inhibiting tumors, including rational drug combinations and improved drug delivery mechanisms; and advances in models that can facilitate screening for cancer vulnerabilities and drug testing. We hope the insights from this meeting will stimulate further progress in the field.
Supplemental Table 1 from ERBB3 Overexpression is Enriched in Diverse Patient Populations with Castration-sensitive Prostate Cancer and is Associated with a Unique AR Activity Signature
Authors: Vellky Jordan E. , Kirkpatrick Brenna J. , Gutgesell Lisa C. , Morales Mathias , Brown Ryan M. , Wu Yaqi , Maienschein-Cline Mark , Notardonato Lucia D. , Weinfeld Michael S. , Nguyen Ryan H. , Brister Eileen , Sverdlov Maria , Liu Li , Xu Ziqiao , Kregel Steven , Nonn Larisa , Vander Griend Donald J. , Reizine Natalie M.
Published: April 2024

Supplemental Table 1. Self-reported Race vs. Ancestry Admixture.
Supplementary Figure S7 from Development of Chromosome 1q+ Specific Treatment for Highest Risk Pediatric Posterior Fossa Ependymoma
Authors: Griesinger Andrea M. , Calzadilla Annaliese J. , Grimaldo Enrique , Donson Andrew M. , Amani Vladimir , Pierce Angela M. , Steiner Jenna , Kargar Soudabeh , Serkova Natalie J. , Bertrand Kelsey C. , Wright Karen D. , Vibhakar Rajeev , Hankinson Todd , Handler Michael , Lindsay Holly B. , Foreman Nicholas K. , Dorris Kathleen
Published: April 2024

Tretinoin (ATRA) identified as an EPN specific target
Supplementary Figure S5 from Development of Chromosome 1q+ Specific Treatment for Highest Risk Pediatric Posterior Fossa Ependymoma
Authors: Griesinger Andrea M. , Calzadilla Annaliese J. , Grimaldo Enrique , Donson Andrew M. , Amani Vladimir , Pierce Angela M. , Steiner Jenna , Kargar Soudabeh , Serkova Natalie J. , Bertrand Kelsey C. , Wright Karen D. , Vibhakar Rajeev , Hankinson Todd , Handler Michael , Lindsay Holly B. , Foreman Nicholas K. , Dorris Kathleen
Published: April 2024

MAF-811_XC in vivo survival with radiation and chemotherapy.
Supplementary Figure S4 from Development of Chromosome 1q+ Specific Treatment for Highest Risk Pediatric Posterior Fossa Ependymoma
Authors: Griesinger Andrea M. , Calzadilla Annaliese J. , Grimaldo Enrique , Donson Andrew M. , Amani Vladimir , Pierce Angela M. , Steiner Jenna , Kargar Soudabeh , Serkova Natalie J. , Bertrand Kelsey C. , Wright Karen D. , Vibhakar Rajeev , Hankinson Todd , Handler Michael , Lindsay Holly B. , Foreman Nicholas K. , Dorris Kathleen
Published: April 2024

MDM4 gene expression with 5FU treatment
Supplementary figure 1-4 from Clinical Activity of TGF-β Inhibitor Vactosertib in Combination with Imatinib in Desmoid Tumors: A Multicenter Phase Ib/II Study
Authors: Ahn Jin-Hee , Lee Jeeyun , Park Changhee , Beom Seung-Hoon , Kim Seung Hyun , Lee Young Han , Yun Kum-Hee , Kim Jeung Eun , Baek Wooyeol , Han Yoon Dae , Kim Sang Kyum , Ryu Hyang Joo , Jung Inkyung , Lee JooHee , Yoon Hong In , Kim Hyo Song
Published: April 2024

Supplementary figure 1-4
Supplementary Table S3 from A Phase I Study of Acapatamab, a Half-life Extended, PSMA-Targeting Bispecific T-cell Engager for Metastatic Castration-Resistant Prostate Cancer
Authors: Dorff Tanya , Horvath Lisa G. , Autio Karen , Bernard-Tessier Alice , Rettig Matthew B. , Machiels Jean-Pascal , Bilen Mehmet A. , Lolkema Martijn P. , Adra Nabil , Rottey Sylvie , Greil Richard , Matsubara Nobuaki , Tan Daniel S.W. , Wong Alvin , Uemura Hiroji , Lemech Charlotte , Meran Johannes , Yu Youfei , Minocha Mukul , McComb Mason , Penny Hweixian Leong , Gupta Vinita , Hu Xuguang , Jurida Gabor , Kouros-Mehr Hosein , Janát-Amsbury Margit M. , Eggert Tobias , Tran Ben
Published: April 2024

List of prior therapies in patients who received acapatamab monotherapy
Supplementary Figure S1 from Paclitaxel and Carboplatin in Combination with Low-intensity Pulsed Ultrasound for Glioblastoma
Authors: Habashy Karl J. , Dmello Crismita , Chen Li , Arrieta Victor A. , Kim Kwang-Soo , Gould Andrew , Youngblood Mark W. , Bouchoux Guillaume , Burdett Kirsten B. , Zhang Hui , Canney Michael , Stupp Roger , Sonabend Adam M.
Published: April 2024

Supplementary Figure 1. Paclitaxel delivered with low-intensity pulsed ultrasound and microbubbles leads to variable local tumor control. 
Coronal T1 with contrast MRI images of patients from our phase I clinical trial (NCT04528680) who received the highest dose of Abraxane (260 mg/m2). We illustrate in green the area covered by the sonication, and observe a variable local tumor control within this region. The five patients presented in the upper (blue) panel exhibited tumor control, while the remaining patients (in red) had tumor growth while on therapy.
Supplementary Fig. S6 from Cooperative Armoring of CAR and TCR T Cells by T Cell–Restricted IL15 and IL21 Universally Enhances Solid Tumor Efficacy
Authors: Nguyen Rosa , Doubrovina Ekaterina , Mousset Charlotte M. , Jin Benjamin Y. , Okada Reona , Zhang Xiyuan , Clavel Arina , Reyes-Gonzalez Jeyshka M. , Dyomin Vadim , Diaz Louis , Zhang Ling , Abbas Shahroze , Sun Ming , Hsieh Chao-Ming , Ho Mitchell , Shern Jack F. , Gulley James L. , Hinrichs Christian S.
Published: April 2024

Growth kinetics and copy number analysis of transgene.
Supplementary Table 1 from CB307: A Dual Targeting Costimulatory Humabody VH Therapeutic for Treating PSMA-Positive Tumors
Authors: Archer Sophie , Brailey Phillip M. , Song Minjung , Bartlett Phillip D. , Figueiredo Ines , Gurel Bora , Guo Christina , Brucklacher-Waldert Verena , Thompson H. Lorraine , Akinwale Jude , Boyle Samantha E. , Rossant Christine , Birkett Neil R. , Pizzey Julia , Maginn Mark , Legg James , Williams Richard , Johnston Colette M. , Bland-Ward Philip , de Bono Johann S. , Pierce Andrew J.
Published: April 2024

Supplementary Table 1: Mouse PK summary statistics
Supplementary Figure 3 from CB307: A Dual Targeting Costimulatory Humabody VH Therapeutic for Treating PSMA-Positive Tumors
Authors: Archer Sophie , Brailey Phillip M. , Song Minjung , Bartlett Phillip D. , Figueiredo Ines , Gurel Bora , Guo Christina , Brucklacher-Waldert Verena , Thompson H. Lorraine , Akinwale Jude , Boyle Samantha E. , Rossant Christine , Birkett Neil R. , Pizzey Julia , Maginn Mark , Legg James , Williams Richard , Johnston Colette M. , Bland-Ward Philip , de Bono Johann S. , Pierce Andrew J.
Published: April 2024

Supplementary Figure 3: PK/TK dosing strategies
Supplementary Figure 2 from CB307: A Dual Targeting Costimulatory Humabody VH Therapeutic for Treating PSMA-Positive Tumors
Authors: Archer Sophie , Brailey Phillip M. , Song Minjung , Bartlett Phillip D. , Figueiredo Ines , Gurel Bora , Guo Christina , Brucklacher-Waldert Verena , Thompson H. Lorraine , Akinwale Jude , Boyle Samantha E. , Rossant Christine , Birkett Neil R. , Pizzey Julia , Maginn Mark , Legg James , Williams Richard , Johnston Colette M. , Bland-Ward Philip , de Bono Johann S. , Pierce Andrew J.
Published: April 2024

Supplementary Figure 2: aCD137 antibody clone E6Z7F specificity
Supplementary Table S1 from Nicotinamide in Combination with EGFR-TKIs for the Treatment of Stage IV Lung Adenocarcinoma with EGFR Mutations: A Randomized Double-Blind (Phase IIb) Trial
Authors: Oh Hyung-Joo , Bae Suk-Chul , Oh In-Jae , Park Cheol-Kyu , Jung Kyoung-Mi , Kim Da-Mi , Lee Jung-Won , Kang Chang Kyun , Park Il Yeong , Kim Young-Chul
Published: April 2024

Table S1. Inclusion and Exclusion Criteria
Supplementary Figure S4 from Nicotinamide in Combination with EGFR-TKIs for the Treatment of Stage IV Lung Adenocarcinoma with EGFR Mutations: A Randomized Double-Blind (Phase IIb) Trial
Authors: Oh Hyung-Joo , Bae Suk-Chul , Oh In-Jae , Park Cheol-Kyu , Jung Kyoung-Mi , Kim Da-Mi , Lee Jung-Won , Kang Chang Kyun , Park Il Yeong , Kim Young-Chul
Published: April 2024

Figure S4. Serial quality of life (QoL) assessments in nicotinamide vs. placebo groups over 2 years
Supplementary Figure S3 from Nicotinamide in Combination with EGFR-TKIs for the Treatment of Stage IV Lung Adenocarcinoma with EGFR Mutations: A Randomized Double-Blind (Phase IIb) Trial
Authors: Oh Hyung-Joo , Bae Suk-Chul , Oh In-Jae , Park Cheol-Kyu , Jung Kyoung-Mi , Kim Da-Mi , Lee Jung-Won , Kang Chang Kyun , Park Il Yeong , Kim Young-Chul
Published: April 2024

Figure S3. Spider plot showing individual patient responses over time in both the nicotinamide and placebo groups.
Supplementary Table S1 from Germline Mutations of Holliday Junction Resolvase Genes in Multiple Primary Malignancies Involving Lung Cancer Lead to PARP Inhibitor Sensitization
Authors: Wang Haoran , Chen Yuping , Wang Xinshu , Huang Binhao , Xie Juntao , Yin Hui , Yang Jie , Wu Jinhuan , Yuan Jian , Zhang Jie
Published: April 2024

Supplementary Table S1: The gene list for pathway enrichment analysis.
Supplementary Figure S9 from A B7-H4–Targeting Antibody–Drug Conjugate Shows Antitumor Activity in PARPi and Platinum-Resistant Cancers with B7-H4 Expression
Authors: Gitto Sarah B. , Whicker Margaret , Davies Gareth , Kumar Sushil , Kinneer Krista , Xu Haineng , Lewis Arthur , Mamidi Srinivas , Medvedev Sergey , Kim Hyoung , Anderton Judith , Tang E. Jessica , Ferman Benjamin , Coats Steven , Wilkinson Robert W. , Brown Eric , Powell Daniel J. , Simpkins Fiona
Published: April 2024

Individual mouse data and statistical analysis of WO-2 PDX in vivo study.
Supplementary Figure S8 from A B7-H4–Targeting Antibody–Drug Conjugate Shows Antitumor Activity in PARPi and Platinum-Resistant Cancers with B7-H4 Expression
Authors: Gitto Sarah B. , Whicker Margaret , Davies Gareth , Kumar Sushil , Kinneer Krista , Xu Haineng , Lewis Arthur , Mamidi Srinivas , Medvedev Sergey , Kim Hyoung , Anderton Judith , Tang E. Jessica , Ferman Benjamin , Coats Steven , Wilkinson Robert W. , Brown Eric , Powell Daniel J. , Simpkins Fiona
Published: April 2024

Western blot analysis of apoptosis markers after B7-H4-ADC treatment and cell viability with apoptosis inhibitors.
Supplementary Figure S7 from A B7-H4–Targeting Antibody–Drug Conjugate Shows Antitumor Activity in PARPi and Platinum-Resistant Cancers with B7-H4 Expression
Authors: Gitto Sarah B. , Whicker Margaret , Davies Gareth , Kumar Sushil , Kinneer Krista , Xu Haineng , Lewis Arthur , Mamidi Srinivas , Medvedev Sergey , Kim Hyoung , Anderton Judith , Tang E. Jessica , Ferman Benjamin , Coats Steven , Wilkinson Robert W. , Brown Eric , Powell Daniel J. , Simpkins Fiona
Published: April 2024

Flow plots for yH2AX expression after B7-H4-ADC treatment.
Supplementary Figure S6 from A B7-H4–Targeting Antibody–Drug Conjugate Shows Antitumor Activity in PARPi and Platinum-Resistant Cancers with B7-H4 Expression
Authors: Gitto Sarah B. , Whicker Margaret , Davies Gareth , Kumar Sushil , Kinneer Krista , Xu Haineng , Lewis Arthur , Mamidi Srinivas , Medvedev Sergey , Kim Hyoung , Anderton Judith , Tang E. Jessica , Ferman Benjamin , Coats Steven , Wilkinson Robert W. , Brown Eric , Powell Daniel J. , Simpkins Fiona
Published: April 2024

Flow plots for cell cycle arrest after B7-H4-ADC treatment.
Supplementary Table 6 from RAS/RAF Comutation and ERBB2 Copy Number Modulates HER2 Heterogeneity and Responsiveness to HER2-directed Therapy in Colorectal Cancer
Authors: Singh Harshabad , Sahgal Pranshu , Kapner Kevin , Corsello Steven M. , Gupta Hersh , Gujrathi Rahul , Li Yvonne Y. , Cherniack Andrew D. , El Alam Raquelle , Kerfoot Joseph , Andrews Elizabeth , Lee Annette , Nambiar Chetan , Hannigan Alison M. , Remland Joshua , Brais Lauren , Leahy Meghan E. , Rubinson Douglas A. , Schlechter Benjamin L. , Meyerson Matthew , Kuang Yanan , Paweletz Cloud P. , Lee Jessica K. , Quintanilha Julia C.F. , Aguirre Andrew J. , Perez Kimberly J. , Huffman Brandon M. , Rossi Humberto , Abrams Thomas A. , Kabraji Sheheryar , Trusolino Livio , Bertotti Andrea , Sicinska Ewa T. , Parikh Aparna R. , Wolpin Brian M. , Schrock Alexa B. , Giannakis Marios , Ng Kimmie , Meyerhardt Jeffrey A. , Hornick Jason L. , Sethi Nilay S. , Cleary James M.
Published: April 2024

Supplementary Table 6. Variant allele frequencies (VAF) of RAS/RAF co-altered genes in HER2 amplified CRC suggests heterozygous clonal nature of these mutations.
Supplementary Figure S5 from A B7-H4–Targeting Antibody–Drug Conjugate Shows Antitumor Activity in PARPi and Platinum-Resistant Cancers with B7-H4 Expression
Authors: Gitto Sarah B. , Whicker Margaret , Davies Gareth , Kumar Sushil , Kinneer Krista , Xu Haineng , Lewis Arthur , Mamidi Srinivas , Medvedev Sergey , Kim Hyoung , Anderton Judith , Tang E. Jessica , Ferman Benjamin , Coats Steven , Wilkinson Robert W. , Brown Eric , Powell Daniel J. , Simpkins Fiona
Published: April 2024

B7-H4-ADC lack of activity in B7-H4 negative cell lines.
Supplementary Table 5 from RAS/RAF Comutation and ERBB2 Copy Number Modulates HER2 Heterogeneity and Responsiveness to HER2-directed Therapy in Colorectal Cancer
Authors: Singh Harshabad , Sahgal Pranshu , Kapner Kevin , Corsello Steven M. , Gupta Hersh , Gujrathi Rahul , Li Yvonne Y. , Cherniack Andrew D. , El Alam Raquelle , Kerfoot Joseph , Andrews Elizabeth , Lee Annette , Nambiar Chetan , Hannigan Alison M. , Remland Joshua , Brais Lauren , Leahy Meghan E. , Rubinson Douglas A. , Schlechter Benjamin L. , Meyerson Matthew , Kuang Yanan , Paweletz Cloud P. , Lee Jessica K. , Quintanilha Julia C.F. , Aguirre Andrew J. , Perez Kimberly J. , Huffman Brandon M. , Rossi Humberto , Abrams Thomas A. , Kabraji Sheheryar , Trusolino Livio , Bertotti Andrea , Sicinska Ewa T. , Parikh Aparna R. , Wolpin Brian M. , Schrock Alexa B. , Giannakis Marios , Ng Kimmie , Meyerhardt Jeffrey A. , Hornick Jason L. , Sethi Nilay S. , Cleary James M.
Published: April 2024

Supplementary Table 5. Subset of foundation medicine genomic cohort of patients with HER2 amplified CRC with multi-site NGS profiling.
Supplementary Figure 2 from RAS/RAF Comutation and ERBB2 Copy Number Modulates HER2 Heterogeneity and Responsiveness to HER2-directed Therapy in Colorectal Cancer
Authors: Singh Harshabad , Sahgal Pranshu , Kapner Kevin , Corsello Steven M. , Gupta Hersh , Gujrathi Rahul , Li Yvonne Y. , Cherniack Andrew D. , El Alam Raquelle , Kerfoot Joseph , Andrews Elizabeth , Lee Annette , Nambiar Chetan , Hannigan Alison M. , Remland Joshua , Brais Lauren , Leahy Meghan E. , Rubinson Douglas A. , Schlechter Benjamin L. , Meyerson Matthew , Kuang Yanan , Paweletz Cloud P. , Lee Jessica K. , Quintanilha Julia C.F. , Aguirre Andrew J. , Perez Kimberly J. , Huffman Brandon M. , Rossi Humberto , Abrams Thomas A. , Kabraji Sheheryar , Trusolino Livio , Bertotti Andrea , Sicinska Ewa T. , Parikh Aparna R. , Wolpin Brian M. , Schrock Alexa B. , Giannakis Marios , Ng Kimmie , Meyerhardt Jeffrey A. , Hornick Jason L. , Sethi Nilay S. , Cleary James M.
Published: April 2024

Supplementary Figure 2. HER2 amplification shows uniform expression in CRC.
Supplementary Data 1 from Noninvasive Stratification of Colon Cancer by Multiplex PET Imaging
Authors: Malviya Gaurav , Lannagan Tamsin R.M. , Johnson Emma , Mackintosh Agata , Bielik Robert , Peters Adam , Soloviev Dmitry , Brown Gavin , Jackstadt Rene , Nixon Colin , Gilroy Kathryn , Campbell Andrew , Sansom Owen J. , Lewis David Y.
Published: April 2024

Supplementary Figures S1-S8
Supplementary Table S2 from Cadonilimab Combined with Chemotherapy with or without Bevacizumab as First-Line Treatment in Recurrent or Metastatic Cervical Cancer (COMPASSION-13): A Phase 2 Study
Authors: Lou Hanmei , Cai Hongbing , Huang Xin , Li Guiling , Wang Li , Liu Fei , Qin Wenjing , Liu Ting , Liu Wei , Wang Zhongmin Maxwell , Li Baiyong , Xia Yu , Wang Jing
Published: April 2024

Supplementary Table S2. The summary of confirmed best overall response.
Supplementary Figure S5 from Obinutuzumab Pretreatment as a Novel Approach to Mitigate Formation of Anti-Drug Antibodies Against Cergutuzumab Amunaleukin in Patients with Solid Tumors
Authors: Peters Solange , Angevin Eric , Alonso-Gordoa Teresa , Rohrberg Kristoffer , Melero Ignacio , Mellado Begoña , Perez-Gracia Jose-Luis , Tabernero Josep , Adessi Celine , Boetsch Christophe , Watson Carl , Dal Porto Joseph , Dejardin David , Del Nagro Christopher , Nicolini Valeria , Evers Stefan , Klein Christian , Leutgeb Barbara , Pisa Pavel , Rossmann Eva , Saro José , Umana Pablo , Charo Jehad , Teichgräber Volker , Steeghs Neeltje
Published: April 2024

Supplementary Figure S5. The detailed effect of obinutuzumab pretreatment followed by CEA-IL2v on six timepoints from
screening to Cycle 4 Day 5 of treatment. A, Peripheral blood natural killer cell count. B, Proliferating peripheral blood
CD8+ T-cell count. C, Peripheral blood CD19+ B-cell count. C, cycle; CEA-IL2v, cergutuzumab amunaleukin; D, Day
Supplementary Table 5 from Multi-omics Analysis Reveals Immune Features Associated with Immunotherapy Benefit in Patients with Squamous Cell Lung Cancer from Phase III Lung-MAP S1400I Trial
Authors: Parra Edwin Roger , Zhang Jiexin , Duose Dzifa Yawa , Gonzalez-Kozlova Edgar , Redman Mary W. , Chen Hong , Manyam Ganiraju C. , Kumar Gayatri , Zhang Jianhua , Song Xingzhi , Lazcano Rossana , Marques-Piubelli Mario L. , Laberiano-Fernandez Caddie , Rojas Frank , Zhang Baili , Taing Len , Jhaveri Aashna , Geisberg Jacob , Altreuter Jennifer , Michor Franziska , Provencher James , Yu Joyce , Cerami Ethan , Moravec Radim , Kannan Kasthuri , Luthra Rajyalakshmi , Alatrash Gheath , Huang Hsin-Hui , Xie Hui , Patel Manishkumar , Nie Kai , Harris Jocelyn , Argueta Kimberly , Lindsay James , Biswas Roshni , Van Nostrand Stephen , Kim-Schulze Seunghee , Gray Jhanelle E. , Herbst Roy S. , Wistuba Ignacio I. , Gettinger Scott , Kelly Karen , Bazhenova Lyudmila , Gnjatic Sacha , Lee J. Jack , Zhang Jianjun , Haymaker Cara
Published: April 2024

Supplementary Table 5. Overall associations between cell phenotypes by compartment in both arms.
Supplementary Figure S2 from Obinutuzumab Pretreatment as a Novel Approach to Mitigate Formation of Anti-Drug Antibodies Against Cergutuzumab Amunaleukin in Patients with Solid Tumors
Authors: Peters Solange , Angevin Eric , Alonso-Gordoa Teresa , Rohrberg Kristoffer , Melero Ignacio , Mellado Begoña , Perez-Gracia Jose-Luis , Tabernero Josep , Adessi Celine , Boetsch Christophe , Watson Carl , Dal Porto Joseph , Dejardin David , Del Nagro Christopher , Nicolini Valeria , Evers Stefan , Klein Christian , Leutgeb Barbara , Pisa Pavel , Rossmann Eva , Saro José , Umana Pablo , Charo Jehad , Teichgräber Volker , Steeghs Neeltje
Published: April 2024

Supplementary Figure S2. Percent reduction in B cell numbers and B cell/T cell ratios in human CD20 transgenic mice
treated with obinutuzumab or rituximab in A, Spleen and B, Lymph nodes. C, Reduction in splenic marginal zone B cells
in human CD20 transgenic mice treated with obinutuzumab or rituximab (n = 2 per group).
Supplementary Table 2 from Multi-omics Analysis Reveals Immune Features Associated with Immunotherapy Benefit in Patients with Squamous Cell Lung Cancer from Phase III Lung-MAP S1400I Trial
Authors: Parra Edwin Roger , Zhang Jiexin , Duose Dzifa Yawa , Gonzalez-Kozlova Edgar , Redman Mary W. , Chen Hong , Manyam Ganiraju C. , Kumar Gayatri , Zhang Jianhua , Song Xingzhi , Lazcano Rossana , Marques-Piubelli Mario L. , Laberiano-Fernandez Caddie , Rojas Frank , Zhang Baili , Taing Len , Jhaveri Aashna , Geisberg Jacob , Altreuter Jennifer , Michor Franziska , Provencher James , Yu Joyce , Cerami Ethan , Moravec Radim , Kannan Kasthuri , Luthra Rajyalakshmi , Alatrash Gheath , Huang Hsin-Hui , Xie Hui , Patel Manishkumar , Nie Kai , Harris Jocelyn , Argueta Kimberly , Lindsay James , Biswas Roshni , Van Nostrand Stephen , Kim-Schulze Seunghee , Gray Jhanelle E. , Herbst Roy S. , Wistuba Ignacio I. , Gettinger Scott , Kelly Karen , Bazhenova Lyudmila , Gnjatic Sacha , Lee J. Jack , Zhang Jianjun , Haymaker Cara
Published: April 2024

Supplementary Table 2. Characteristics of multiplex immunofluorescence panels using Opal 7 IHC Kit (Akoya Biosciences).
Data from One CD4+TCR and One CD8+TCR Targeting Autochthonous Neoantigens Are Essential and Sufficient for Tumor Eradication
Authors: Wolf Steven P. , Anastasopoulou Vasiliki , Drousch Kimberley , Diehl Markus I. , Engels Boris , Yew Poh Yin , Kiyotani Kazuma , Nakamura Yusuke , Schreiber Karin , Schreiber Hans , Leisegang Matthias
Published: April 2024

AbstractPurpose:
To achieve eradication of solid tumors, we examined how many neoantigens need to be targeted with how many T-cell receptors (TCR) by which type of T cells.
Experimental Design:
Unmanipulated, naturally expressed (autochthonous) neoantigens were targeted with adoptively transferred TCR-engineered autologous T cells (TCR-therapy). TCR-therapy used CD8+ T-cell subsets engineered with TCRs isolated from CD8+ T cells (CD8+TCR-therapy), CD4+ T-cell subsets engineered with TCRs isolated from CD4+ T cells (CD4+TCR-therapy), or combinations of both. The targeted tumors were established for at least 3 weeks and derived from primary autochthonous cancer cell cultures, resembling natural solid tumors and their heterogeneity as found in humans.
Results:
Relapse was common with CD8+TCR-therapy even when targeting multiple different autochthonous neoantigens on heterogeneous solid tumors. CD8+TCR-therapy was only effective against homogenous tumors artificially derived from a cancer cell clone. In contrast, a combination of CD8+TCR-therapy with CD4+TCR-therapy, each targeting one neoantigen, eradicated large and established solid tumors of natural heterogeneity. CD4+TCR-therapy targeted a mutant neoantigen on tumor stroma while direct cancer cell recognition by CD8+TCR-therapy was essential for cure. In vitro data were consistent with elimination of cancer cells requiring a four-cell cluster composed of TCR-engineered CD4+ and CD8+ T cells together with antigen-presenting cells and cancer cells.
Conclusions:
Two cancer-specific TCRs can be essential and sufficient to eradicate heterogeneous solid tumors expressing unmanipulated, autochthonous targets. We demonstrate that simplifications to adoptive TCR-therapy are possible without compromising efficacy.
Mutation Patterns Predict Drug Sensitivity in Acute Myeloid Leukemia
Authors: Qin Guangrong , Dai Jin , Chien Sylvia , Martins Timothy J. , Loera Brenda , Nguyen Quy H. , Oakes Melanie L. , Tercan Bahar , Aguilar Boris , Hagen Lauren , McCune Jeannine , Gelinas Richard , Monnat Raymond J. , Shmulevich Ilya , Becker Pamela S.
Published: April 2024

Purpose:

The inherent genetic heterogeneity of acute myeloid leukemia (AML) has challenged the development of precise and effective therapies. The objective of this study was to elucidate the genomic basis of drug resistance or sensitivity, identify signatures for drug response prediction, and provide resources to the research community.

Experimental Design:

We performed targeted sequencing, high-throughput drug screening, and single-cell genomic profiling on leukemia cell samples derived from patients with AML. Statistical approaches and machine learning models were applied to identify signatures for drug response prediction. We also integrated large public datasets to understand the co-occurring mutation patterns and further investigated the mutation profiles in the single cells. The features revealed in the co-occurring or mutual exclusivity pattern were further subjected to machine learning models.

Results:

We detected genetic signatures associated with sensitivity or resistance to specific agents, and identified five co-occurring mutation groups. The application of single-cell genomic sequencing unveiled the co-occurrence of variants at the individual cell level, highlighting the presence of distinct subclones within patients with AML. Using the mutation pattern for drug response prediction demonstrates high accuracy in predicting sensitivity to some drug classes, such as MEK inhibitors for RAS-mutated leukemia.

Conclusions:

Our study highlights the importance of considering the gene mutation patterns for the prediction of drug response in AML. It provides a framework for categorizing patients with AML by mutations that enable drug sensitivity prediction.
Abstract LT05: METTL8-MEDIATED EPITRANSCRIPTOMIC REGULATION OF GBM CYCLING STATE IS DEPENDENT ON RTK/PI3K/AKT SIGNALING
Authors: Lee Bernice Woon Li , Chuah You Heng , Yoon Jeehyun , Grinchuk Oleg V. , Feng Jia , Liang Yajing , Hirpara Jayshree L , Shen Ya Ting , Wang Loo Chien , Lim Yan Ting , Zhao Tianyun , Sobota Radoslaw M , Toh Tan Boon , Pervaiz Shazib , Lin Zhewang , Ong Derrick Sek Tong
Published: April 2024

Glioblastoma (GBM) is a lethal brain tumor with limited treatment options. Treatment failures are often attributed to the existence of glioma stem cells (GSCs), which confer intratumoral heterogeneity and therapy resistance. Contrary to common belief that cancer cells employ aerobic glycolysis (Warburg effect) to sustain their metabolic requirements, GSCs rely on oxidative phosphorylation (OXPHOS) for energy production. As a result, GSCs are uniquely sensitive to OXPHOS inhibitors (Gboxin), as well as mitochondrial translation inhibitors which disrupt OXPHOS. METTL8 is a newly discovered mitochondrial methyltransferase which catalyzes m3C32 modifications in mitochondrial tRNAsThr/Ser(UCN) (mt-tRNAs). This post-transcriptional modification ensures the optimal structure of mt-tRNAs to facilitate efficient translation of mitochondrial proteins involved in electron transport chain (ETC). Although the epitranscriptomic functions of METTL8 have been well characterized, its roles in cancers (i.e. glioblastoma) remain largely unexplored. In this study, we showed that METTL8 is overexpressed in GBM and high METTL8 expression portends poor patient prognosis. In GSC, METTL8 is under the transcriptional regulation of HIF-1α, and the chromatin accessibility at METTL8 promoter is facilitated by the deposition of histone variant H2AZ. METTL8 depletion downregulated m3C32 modifications in mt-tRNAsThr/Ser(UCN) in GSC, leading to impaired mitochondrial translation and OXPHOS defects. Phenotypically, METTL8 knockdown (KD) compromised GSCs’ self-renewal, proliferation, invasiveness and tumorigenicity. Interestingly, METTL8-KD GSC acquired a slow cycling state which is linked to reduced receptor tyrosine kinase (RTK) signaling. Consistently, METTL8-KD GSC showed lower Akt phosphorylation and exhibited increased sensitivity to mTOR/Akt inhibitors. Finally, our mechanistic findings led to the identification of a novel HIF1-α/Akt inhibitor drug combination which faithfully recapitulates the phenotypes of METTL8-KD GSCs. In conclusion, our findings provide the first in-depth study of METTL8 roles in GBM pathogenesis, and highlights a novel drug combination which could potentially be used to treat this dreadful disease.

Citation Format: Bernice Woon Li Lee, You Heng Chuah, Jeehyun Yoon, Oleg V. Grinchuk, Jia Feng, Yajing Liang, Jayshree L Hirpara, Ya Ting Shen, Loo Chien Wang, Yan Ting Lim, Tianyun Zhao, Radoslaw M Sobota, Tan Boon Toh, Shazib Pervaiz, Zhewang Lin, Derrick Sek Tong Ong. METTL8-MEDIATED EPITRANSCRIPTOMIC REGULATION OF GBM CYCLING STATE IS DEPENDENT ON RTK/PI3K/AKT SIGNALING [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr LT05.
Abstract P42: Beyond the Canonical: uORF-encoded Micro Peptides as Novel Kinase Inhibitors in Cancer Therapy
Authors: Jayaram Divya Ram , Frost Sigal , Argov Chanan , Liju Vijayasteltar Belsamma , Anto Nikhil Ponnoor , Muraleedharan Amitha , Ben-Ari Assaf , Sinay Rose , Smoly Ilan , Novoplansky Ofra , Isakov Noah , Toiber Debra , Keasar Chen , Elkabets Moshe , Yeger-Lotem Esti , Livneh Etta
Published: April 2024

About 40% of human mRNAs contain upstream open reading frames (uORFs) in their 5’-untranslated regions. Some of these uORF sequences thought to attenuate scanning ribosomes or lead to mRNA degradation were recently shown to be translated, although the function of most encoded peptides remains unknown. Our recent study was the first to reveal a uORF-encoded peptide exhibiting kinase inhibitory activity (Jayaram DR, et al. PNAS (2021)). This uORF (uORF2), upstream of a protein kinase C (PKC) family member (PKCeta) main ORF, encodes for a peptide (uPEP2) containing the typical PKC pseudosubstrate (PS) motif present in all PKCs that auto-inhibits their kinase activity. We show direct binding and selective inhibition of the catalytic activity of novel PKCs by uPEP2 (but not of classical or atypical PKCs). Functionally, treatment of breast cancer cells with uPEP2 diminished cell survival and their migration and synergized with chemotherapy by interfering with the response to DNA damage. Furthermore, in a xenograft of MDA-MB-231 triple-negative breast cancer in mice models, uPEP2 suppressed tumor progression, invasion, and metastasis. The endogenous deletion of uORF2 by CRISPR/Cas9 in the non-tumorigenic MCF-7 cells showed that it impedes cell proliferation, acting as a growth suppressor. Its role in tumor formation and metastasis is presently studied in breast cancer models with metastasis to the lungs. Together, we point to a new layer of protein regulation by a uORF-encoded kinase inhibitor, which could present a forerunner for other uORFs, possessing kinase inhibitory function. Notably, we have recently identified an additional uORF with a PS motif upstream of another PKC. As kinase inhibitors, uORF-encoded peptides may play a role in signaling and stress, acting in cis and/or in trans, forming diverse regulatory networks, thereby opening new views into eukaryotic protein regulation and cancer biology.

Citation Format: Divya Ram Jayaram, Sigal Frost, Chanan Argov, Vijayasteltar Belsamma Liju, Nikhil Ponnoor Anto, Amitha Muraleedharan, Assaf Ben-Ari, Rose Sinay, Ilan Smoly, Ofra Novoplansky, Noah Isakov, Debra Toiber, Chen Keasar, Moshe Elkabets, Esti Yeger-Lotem, Etta Livneh. Beyond the Canonical: uORF-encoded Micro Peptides as Novel Kinase Inhibitors in Cancer Therapy [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P42.