bluuebunny/crossref_metadata_2025 huggingface dataset:
Figure S5 from LKB1-Dependent Regulation of TPI1 Creates a Divergent Metabolic Liability between Human and Mouse Lung Adenocarcinoma
Authors: Stein Benjamin D. , Ferrarone John R. , Gardner Eric E. , Chang Jae Won , Wu David , Hollstein Pablo E. , Liang Roger J. , Yuan Min , Chen Qiuying , Coukos John S. , Sindelar Miriam , Ngo Bryan , Gross Steven S. , Shaw Reuben J. , Zhang Chen , Asara John M. , Moellering Raymond E. , Varmus Harold , Cantley Lewis C.
Published: April 2023

Figure S5. LKB1 regulates the multimeric state of hTPI1 but not mTpi1 and substitution of Cys in hTPI1 causes formation of a covalent TPI1 dimer.
Supplementary Figures S1-S6, Figure Legends, and Table Legends from Blocking Genomic Instability Prevents Acquired Resistance to MAPK Inhibitor Therapy in Melanoma
Authors: Dharanipragada Prashanthi , Zhang Xiao , Liu Sixue , Lomeli Shirley H. , Hong Aayoung , Wang Yan , Yang Zhentao , Lo Kara Z. , Vega-Crespo Agustin , Ribas Antoni , Moschos Stergios J. , Moriceau Gatien , Lo Roger S.
Published: April 2023

Supplementary Figure S1. Associations of CGRs and ecDNAs with ploidy, expression, and enhancers. Supplementary Figure S2. Analysis of chromothripsis, ecDNAs, and CGRs in MAPKi-sensitive/-naïve versus -resistant melanoma. Supplementary Figure S3. Inferring double-stranded DNA break repair pathways underlying ecDNA and CGR breakpoint junctions. Supplementary Figure S4. Single-agent inhibitory potencies in human melanoma, PDAC, and NSCLC clonogenic growth assays. Supplementary Figure S5. DNA-PKi and/or PARPi co-treatment prevents acquired MAPKi-resistance in human melanoma cell lines. Supplementary Figure S6. In vivo impacts of DNA-PKi when combined with MAPKi.
Table S5 from Extrachromosomal DNA Amplification Contributes to Small Cell Lung Cancer Heterogeneity and Is Associated with Worse Outcomes
Authors: Pongor Lőrinc Sándor , Schultz Christopher W. , Rinaldi Lorenzo , Wangsa Darawalee , Redon Christophe E. , Takahashi Nobuyuki , Fialkoff Gavriel , Desai Parth , Zhang Yang , Burkett Sandra , Hermoni Nadav , Vilk Noa , Gutin Jenia , Gergely Rona , Zhao Yongmei , Nichols Samantha , Vilimas Rasa , Sciuto Linda , Graham Chante , Caravaca Juan Manuel , Turan Sevilay , Tsai-wei Shen , Rajapakse Vinodh N. , Kumar Rajesh , Upadhyay Deep , Kumar Suresh , Kim Yoo Sun , Roper Nitin , Tran Bao , Hewitt Stephen M. , Kleiner David E. , Aladjem Mirit I. , Friedman Nir , Hager Gordon L. , Pommier Yves , Ried Thomas , Thomas Anish
Published: April 2023

Amplicon design used for the targeted single-cell copy-number analysis. Normalized depth of MYC and MYCL amplicons in single-cells for the DMS-273 cell line are shown, as well as comparison of MYC amplicon depths in single cells between the patient derived Adrenal gland (ecDNA+) and Cerv.LN (HSR+) cell lines.
Table S4 from Extrachromosomal DNA Amplification Contributes to Small Cell Lung Cancer Heterogeneity and Is Associated with Worse Outcomes
Authors: Pongor Lőrinc Sándor , Schultz Christopher W. , Rinaldi Lorenzo , Wangsa Darawalee , Redon Christophe E. , Takahashi Nobuyuki , Fialkoff Gavriel , Desai Parth , Zhang Yang , Burkett Sandra , Hermoni Nadav , Vilk Noa , Gutin Jenia , Gergely Rona , Zhao Yongmei , Nichols Samantha , Vilimas Rasa , Sciuto Linda , Graham Chante , Caravaca Juan Manuel , Turan Sevilay , Tsai-wei Shen , Rajapakse Vinodh N. , Kumar Rajesh , Upadhyay Deep , Kumar Suresh , Kim Yoo Sun , Roper Nitin , Tran Bao , Hewitt Stephen M. , Kleiner David E. , Aladjem Mirit I. , Friedman Nir , Hager Gordon L. , Pommier Yves , Ried Thomas , Thomas Anish
Published: April 2023

Fusion analysis results calculated with STARfusion and summary of RLF exon1 and exon2 expression for the CCLE cohort. Table summarizes the RLF-MYCL expression qPCR results.
Table S3 from Extrachromosomal DNA Amplification Contributes to Small Cell Lung Cancer Heterogeneity and Is Associated with Worse Outcomes
Authors: Pongor Lőrinc Sándor , Schultz Christopher W. , Rinaldi Lorenzo , Wangsa Darawalee , Redon Christophe E. , Takahashi Nobuyuki , Fialkoff Gavriel , Desai Parth , Zhang Yang , Burkett Sandra , Hermoni Nadav , Vilk Noa , Gutin Jenia , Gergely Rona , Zhao Yongmei , Nichols Samantha , Vilimas Rasa , Sciuto Linda , Graham Chante , Caravaca Juan Manuel , Turan Sevilay , Tsai-wei Shen , Rajapakse Vinodh N. , Kumar Rajesh , Upadhyay Deep , Kumar Suresh , Kim Yoo Sun , Roper Nitin , Tran Bao , Hewitt Stephen M. , Kleiner David E. , Aladjem Mirit I. , Friedman Nir , Hager Gordon L. , Pommier Yves , Ried Thomas , Thomas Anish
Published: April 2023

Methylation array derived beta values derived from EPIC array used to compare methylation of ecDNA positive and negative regions within several cell lines at the MYC, MYCL and MYCN loci.
Table S2 from Extrachromosomal DNA Amplification Contributes to Small Cell Lung Cancer Heterogeneity and Is Associated with Worse Outcomes
Authors: Pongor Lőrinc Sándor , Schultz Christopher W. , Rinaldi Lorenzo , Wangsa Darawalee , Redon Christophe E. , Takahashi Nobuyuki , Fialkoff Gavriel , Desai Parth , Zhang Yang , Burkett Sandra , Hermoni Nadav , Vilk Noa , Gutin Jenia , Gergely Rona , Zhao Yongmei , Nichols Samantha , Vilimas Rasa , Sciuto Linda , Graham Chante , Caravaca Juan Manuel , Turan Sevilay , Tsai-wei Shen , Rajapakse Vinodh N. , Kumar Rajesh , Upadhyay Deep , Kumar Suresh , Kim Yoo Sun , Roper Nitin , Tran Bao , Hewitt Stephen M. , Kleiner David E. , Aladjem Mirit I. , Friedman Nir , Hager Gordon L. , Pommier Yves , Ried Thomas , Thomas Anish
Published: April 2023

Enhancer-enhancer interaction analysis derived from H3K27ac HiChIP in the NCI-H889 and NCI-H524 cell lines. Interaction strength of proximal enhancers was calculated from the “.hic” files generated by the JuiceBox suite.
Figure S5 from Extrachromosomal DNA Amplification Contributes to Small Cell Lung Cancer Heterogeneity and Is Associated with Worse Outcomes
Authors: Pongor Lőrinc Sándor , Schultz Christopher W. , Rinaldi Lorenzo , Wangsa Darawalee , Redon Christophe E. , Takahashi Nobuyuki , Fialkoff Gavriel , Desai Parth , Zhang Yang , Burkett Sandra , Hermoni Nadav , Vilk Noa , Gutin Jenia , Gergely Rona , Zhao Yongmei , Nichols Samantha , Vilimas Rasa , Sciuto Linda , Graham Chante , Caravaca Juan Manuel , Turan Sevilay , Tsai-wei Shen , Rajapakse Vinodh N. , Kumar Rajesh , Upadhyay Deep , Kumar Suresh , Kim Yoo Sun , Roper Nitin , Tran Bao , Hewitt Stephen M. , Kleiner David E. , Aladjem Mirit I. , Friedman Nir , Hager Gordon L. , Pommier Yves , Ried Thomas , Thomas Anish
Published: April 2023

Heterogeneity in patient derived samples, related to Figure 5
Figure S3 from Extrachromosomal DNA Amplification Contributes to Small Cell Lung Cancer Heterogeneity and Is Associated with Worse Outcomes
Authors: Pongor Lőrinc Sándor , Schultz Christopher W. , Rinaldi Lorenzo , Wangsa Darawalee , Redon Christophe E. , Takahashi Nobuyuki , Fialkoff Gavriel , Desai Parth , Zhang Yang , Burkett Sandra , Hermoni Nadav , Vilk Noa , Gutin Jenia , Gergely Rona , Zhao Yongmei , Nichols Samantha , Vilimas Rasa , Sciuto Linda , Graham Chante , Caravaca Juan Manuel , Turan Sevilay , Tsai-wei Shen , Rajapakse Vinodh N. , Kumar Rajesh , Upadhyay Deep , Kumar Suresh , Kim Yoo Sun , Roper Nitin , Tran Bao , Hewitt Stephen M. , Kleiner David E. , Aladjem Mirit I. , Friedman Nir , Hager Gordon L. , Pommier Yves , Ried Thomas , Thomas Anish
Published: April 2023

Fusion landscape and ecDNA RLF-MYCL fusions, related to Figure 3.
Figure S1 from Extrachromosomal DNA Amplification Contributes to Small Cell Lung Cancer Heterogeneity and Is Associated with Worse Outcomes
Authors: Pongor Lőrinc Sándor , Schultz Christopher W. , Rinaldi Lorenzo , Wangsa Darawalee , Redon Christophe E. , Takahashi Nobuyuki , Fialkoff Gavriel , Desai Parth , Zhang Yang , Burkett Sandra , Hermoni Nadav , Vilk Noa , Gutin Jenia , Gergely Rona , Zhao Yongmei , Nichols Samantha , Vilimas Rasa , Sciuto Linda , Graham Chante , Caravaca Juan Manuel , Turan Sevilay , Tsai-wei Shen , Rajapakse Vinodh N. , Kumar Rajesh , Upadhyay Deep , Kumar Suresh , Kim Yoo Sun , Roper Nitin , Tran Bao , Hewitt Stephen M. , Kleiner David E. , Aladjem Mirit I. , Friedman Nir , Hager Gordon L. , Pommier Yves , Ried Thomas , Thomas Anish
Published: April 2023

ecDNA in SCLC, related to Figure 1
Figure 2 extended data from Extrachromosomal DNA Amplification Contributes to Small Cell Lung Cancer Heterogeneity and Is Associated with Worse Outcomes
Authors: Pongor Lőrinc Sándor , Schultz Christopher W. , Rinaldi Lorenzo , Wangsa Darawalee , Redon Christophe E. , Takahashi Nobuyuki , Fialkoff Gavriel , Desai Parth , Zhang Yang , Burkett Sandra , Hermoni Nadav , Vilk Noa , Gutin Jenia , Gergely Rona , Zhao Yongmei , Nichols Samantha , Vilimas Rasa , Sciuto Linda , Graham Chante , Caravaca Juan Manuel , Turan Sevilay , Tsai-wei Shen , Rajapakse Vinodh N. , Kumar Rajesh , Upadhyay Deep , Kumar Suresh , Kim Yoo Sun , Roper Nitin , Tran Bao , Hewitt Stephen M. , Kleiner David E. , Aladjem Mirit I. , Friedman Nir , Hager Gordon L. , Pommier Yves , Ried Thomas , Thomas Anish
Published: April 2023

Cell line AmpliconArchitect assemblies, related to figure 1 and Figure 2
Table S1-S7 from Antibody–Exatecan Conjugates with a Novel Self-immolative Moiety Overcome Resistance in Colon and Lung Cancer
Authors: Weng Weining , Meng Tao , Zhao Qianqian , Shen Yi , Fu Guoxiang , Shi Jing , Zhang Yue , Wang Zhaohui , Wang Mingqiao , Pan Rong , Ma Linjie , Chen Caiwei , Wang Lijun , Zhou Biao , Zhang Hui , Pu Junyi , Zhang Jianjian , Hu Yi Peter , Hua Guoqiang , Qian Yu , Liu Shu-Hui , Hu Wenhao , Meng Xun
Published: April 2023

Supplementary Table S1 shows cytotoxicity of exatecan compared to DXd. Supplementary Table S2 shows selected hematologic parameters and biochemical parameters from the repeat-dose administration of exatecan mesylate studies in rats. Supplementary Table S3 shows in vitro ADC stability study of total antibody, ADC and free payload. Supplementary Table S4 shows pharmacokinetic parameters of total antibody, ADC and free payload. Supplementary Table S5 shows ADC (T: T-1000-e; D: DS-8201a) internalization rate on cell lines with different HER2 expression level. Supplementary Table S6 shows correlation of exatecan release and target expression. Supplementary Table S7 shows In vitro cytotoxicicity of HER-targeting MTX-1000, TROP2 targeting MTX-132 and HER3-targeting Patritumab-T1000-exatecan and their counterpart DXd-ADC.
Supplementary note from Antibody–Exatecan Conjugates with a Novel Self-immolative Moiety Overcome Resistance in Colon and Lung Cancer
Authors: Weng Weining , Meng Tao , Zhao Qianqian , Shen Yi , Fu Guoxiang , Shi Jing , Zhang Yue , Wang Zhaohui , Wang Mingqiao , Pan Rong , Ma Linjie , Chen Caiwei , Wang Lijun , Zhou Biao , Zhang Hui , Pu Junyi , Zhang Jianjian , Hu Yi Peter , Hua Guoqiang , Qian Yu , Liu Shu-Hui , Hu Wenhao , Meng Xun
Published: April 2023

Supplementary note shows the analytical characterization of the ADCs, and synthesis of drug-linkers
Supplementary Table S4 from Genomic Instability and Protumoral Inflammation Are Associated with Primary Resistance to Anti–PD-1 + Antiangiogenesis in Malignant Pleural Mesothelioma
Authors: Danlos François-Xavier , Texier Matthieu , Job Bastien , Mouraud Severine , Cassard Lydie , Baldini Capucine , Varga Andrea , Yurchenko Andrey A. , Rabeau Audrey , Champiat Stéphane , Letourneur Diane , Bredel Delphine , Susini Sandrine , Blum Yuna , Parpaleix Aurelien , Parlavecchio Cedric , Tselikas Lambros , Fahrner Jean-Eudes , Goubet Anne-Gaelle , Rouanne Mathieu , Rafie Saloomeh , Abbassi Alae , Kasraoui Ines , Breckler Marie , Farhane Siham , Ammari Samy , Laghouati Salim , Gazzah Anas , Lacroix Ludovic , Besse Benjamin , Droin Nathalie , Deloger Marc , Cotteret Sophie , Adam Julien , Zitvogel Laurence , Nikolaev Sergey I. , Chaput Nathalie , Massard Christophe , Soria Jean-Charles , Gomez-Roca Carlos , Zalcman Gerard , Planchard David , Marabelle Aurelien
Published: April 2023

Baseline characteristics of the patients treated according to their DCB status.
Table S4 from Targeting Microglial Metabolic Rewiring Synergizes with Immune-Checkpoint Blockade Therapy for Glioblastoma
Authors: Ye Zengpanpan , Ai Xiaolin , Yang Kailin , Yang Zhengnan , Fei Fan , Liao Xiaoling , Qiu Zhixin , Gimple Ryan C. , Yuan Huairui , Huang Hao , Gong Yanqiu , Xiao Chaoxin , Yue Jing , Huang Liang , Saulnier Olivier , Wang Wei , Zhang Peidong , Dai Lunzhi , Wang Xin , Wang Xiuxing , Ahn Young Ha , You Chao , Xu Jianguo , Wan Xiaoxiao , Taylor Michael D. , Zhao Linjie , Rich Jeremy N. , Zhou Shengtao
Published: April 2023

Table S4 describes list of literature-based immune marker panel selected to identity cell types of obtained clusters.
Table S2 from Targeting Microglial Metabolic Rewiring Synergizes with Immune-Checkpoint Blockade Therapy for Glioblastoma
Authors: Ye Zengpanpan , Ai Xiaolin , Yang Kailin , Yang Zhengnan , Fei Fan , Liao Xiaoling , Qiu Zhixin , Gimple Ryan C. , Yuan Huairui , Huang Hao , Gong Yanqiu , Xiao Chaoxin , Yue Jing , Huang Liang , Saulnier Olivier , Wang Wei , Zhang Peidong , Dai Lunzhi , Wang Xin , Wang Xiuxing , Ahn Young Ha , You Chao , Xu Jianguo , Wan Xiaoxiao , Taylor Michael D. , Zhao Linjie , Rich Jeremy N. , Zhou Shengtao
Published: April 2023

Table S2 describes information of key research agents, data deposition and software versions.
Table S1 from Targeting Microglial Metabolic Rewiring Synergizes with Immune-Checkpoint Blockade Therapy for Glioblastoma
Authors: Ye Zengpanpan , Ai Xiaolin , Yang Kailin , Yang Zhengnan , Fei Fan , Liao Xiaoling , Qiu Zhixin , Gimple Ryan C. , Yuan Huairui , Huang Hao , Gong Yanqiu , Xiao Chaoxin , Yue Jing , Huang Liang , Saulnier Olivier , Wang Wei , Zhang Peidong , Dai Lunzhi , Wang Xin , Wang Xiuxing , Ahn Young Ha , You Chao , Xu Jianguo , Wan Xiaoxiao , Taylor Michael D. , Zhao Linjie , Rich Jeremy N. , Zhou Shengtao
Published: April 2023

Table S1 describes glioma patients and tissue samples information for evaluating the relationship of oxidative stress in microglia and prognosis
Supplementary Figure S5 from Genomic Instability and Protumoral Inflammation Are Associated with Primary Resistance to Anti–PD-1 + Antiangiogenesis in Malignant Pleural Mesothelioma
Authors: Danlos François-Xavier , Texier Matthieu , Job Bastien , Mouraud Severine , Cassard Lydie , Baldini Capucine , Varga Andrea , Yurchenko Andrey A. , Rabeau Audrey , Champiat Stéphane , Letourneur Diane , Bredel Delphine , Susini Sandrine , Blum Yuna , Parpaleix Aurelien , Parlavecchio Cedric , Tselikas Lambros , Fahrner Jean-Eudes , Goubet Anne-Gaelle , Rouanne Mathieu , Rafie Saloomeh , Abbassi Alae , Kasraoui Ines , Breckler Marie , Farhane Siham , Ammari Samy , Laghouati Salim , Gazzah Anas , Lacroix Ludovic , Besse Benjamin , Droin Nathalie , Deloger Marc , Cotteret Sophie , Adam Julien , Zitvogel Laurence , Nikolaev Sergey I. , Chaput Nathalie , Massard Christophe , Soria Jean-Charles , Gomez-Roca Carlos , Zalcman Gerard , Planchard David , Marabelle Aurelien
Published: April 2023

Gating strategy for flow cytometry analyses of T cells infiltration on tumor biopsies.
Supplemental Figure S6 from Targeting Microglial Metabolic Rewiring Synergizes with Immune-Checkpoint Blockade Therapy for Glioblastoma
Authors: Ye Zengpanpan , Ai Xiaolin , Yang Kailin , Yang Zhengnan , Fei Fan , Liao Xiaoling , Qiu Zhixin , Gimple Ryan C. , Yuan Huairui , Huang Hao , Gong Yanqiu , Xiao Chaoxin , Yue Jing , Huang Liang , Saulnier Olivier , Wang Wei , Zhang Peidong , Dai Lunzhi , Wang Xin , Wang Xiuxing , Ahn Young Ha , You Chao , Xu Jianguo , Wan Xiaoxiao , Taylor Michael D. , Zhao Linjie , Rich Jeremy N. , Zhou Shengtao
Published: April 2023

Supplemental Figure S6 describes that inhibition of NR4A2 or SQLE improves the therapeutic efficacy of immune checkpoint blockade.
Supplementary Figure S2 from Genomic Instability and Protumoral Inflammation Are Associated with Primary Resistance to Anti–PD-1 + Antiangiogenesis in Malignant Pleural Mesothelioma
Authors: Danlos François-Xavier , Texier Matthieu , Job Bastien , Mouraud Severine , Cassard Lydie , Baldini Capucine , Varga Andrea , Yurchenko Andrey A. , Rabeau Audrey , Champiat Stéphane , Letourneur Diane , Bredel Delphine , Susini Sandrine , Blum Yuna , Parpaleix Aurelien , Parlavecchio Cedric , Tselikas Lambros , Fahrner Jean-Eudes , Goubet Anne-Gaelle , Rouanne Mathieu , Rafie Saloomeh , Abbassi Alae , Kasraoui Ines , Breckler Marie , Farhane Siham , Ammari Samy , Laghouati Salim , Gazzah Anas , Lacroix Ludovic , Besse Benjamin , Droin Nathalie , Deloger Marc , Cotteret Sophie , Adam Julien , Zitvogel Laurence , Nikolaev Sergey I. , Chaput Nathalie , Massard Christophe , Soria Jean-Charles , Gomez-Roca Carlos , Zalcman Gerard , Planchard David , Marabelle Aurelien
Published: April 2023

Gene expression network analysis.
Supplemental Figure S3 from Targeting Microglial Metabolic Rewiring Synergizes with Immune-Checkpoint Blockade Therapy for Glioblastoma
Authors: Ye Zengpanpan , Ai Xiaolin , Yang Kailin , Yang Zhengnan , Fei Fan , Liao Xiaoling , Qiu Zhixin , Gimple Ryan C. , Yuan Huairui , Huang Hao , Gong Yanqiu , Xiao Chaoxin , Yue Jing , Huang Liang , Saulnier Olivier , Wang Wei , Zhang Peidong , Dai Lunzhi , Wang Xin , Wang Xiuxing , Ahn Young Ha , You Chao , Xu Jianguo , Wan Xiaoxiao , Taylor Michael D. , Zhao Linjie , Rich Jeremy N. , Zhou Shengtao
Published: April 2023

Supplemental Figure S3 describes that inhibiting nuclear translocation of NR4A2 hampers immunosuppressive functions and promotes antigen presentation capacities of microglia.
Supplementary Figure S1 from Genomic Instability and Protumoral Inflammation Are Associated with Primary Resistance to Anti–PD-1 + Antiangiogenesis in Malignant Pleural Mesothelioma
Authors: Danlos François-Xavier , Texier Matthieu , Job Bastien , Mouraud Severine , Cassard Lydie , Baldini Capucine , Varga Andrea , Yurchenko Andrey A. , Rabeau Audrey , Champiat Stéphane , Letourneur Diane , Bredel Delphine , Susini Sandrine , Blum Yuna , Parpaleix Aurelien , Parlavecchio Cedric , Tselikas Lambros , Fahrner Jean-Eudes , Goubet Anne-Gaelle , Rouanne Mathieu , Rafie Saloomeh , Abbassi Alae , Kasraoui Ines , Breckler Marie , Farhane Siham , Ammari Samy , Laghouati Salim , Gazzah Anas , Lacroix Ludovic , Besse Benjamin , Droin Nathalie , Deloger Marc , Cotteret Sophie , Adam Julien , Zitvogel Laurence , Nikolaev Sergey I. , Chaput Nathalie , Massard Christophe , Soria Jean-Charles , Gomez-Roca Carlos , Zalcman Gerard , Planchard David , Marabelle Aurelien
Published: April 2023

Differential Gene Expression (DGE) of baseline tumor biopsies between patients with DCB and No DCB.
Supplemental Figure S1 from Targeting Microglial Metabolic Rewiring Synergizes with Immune-Checkpoint Blockade Therapy for Glioblastoma
Authors: Ye Zengpanpan , Ai Xiaolin , Yang Kailin , Yang Zhengnan , Fei Fan , Liao Xiaoling , Qiu Zhixin , Gimple Ryan C. , Yuan Huairui , Huang Hao , Gong Yanqiu , Xiao Chaoxin , Yue Jing , Huang Liang , Saulnier Olivier , Wang Wei , Zhang Peidong , Dai Lunzhi , Wang Xin , Wang Xiuxing , Ahn Young Ha , You Chao , Xu Jianguo , Wan Xiaoxiao , Taylor Michael D. , Zhao Linjie , Rich Jeremy N. , Zhou Shengtao
Published: April 2023

Supplemental Figure S1 describes elevated oxidative stress challenge in the microglia of glioma.
Data from Genomic Instability and Protumoral Inflammation Are Associated with Primary Resistance to Anti–PD-1 + Antiangiogenesis in Malignant Pleural Mesothelioma
Authors: Danlos François-Xavier , Texier Matthieu , Job Bastien , Mouraud Severine , Cassard Lydie , Baldini Capucine , Varga Andrea , Yurchenko Andrey A. , Rabeau Audrey , Champiat Stéphane , Letourneur Diane , Bredel Delphine , Susini Sandrine , Blum Yuna , Parpaleix Aurelien , Parlavecchio Cedric , Tselikas Lambros , Fahrner Jean-Eudes , Goubet Anne-Gaelle , Rouanne Mathieu , Rafie Saloomeh , Abbassi Alae , Kasraoui Ines , Breckler Marie , Farhane Siham , Ammari Samy , Laghouati Salim , Gazzah Anas , Lacroix Ludovic , Besse Benjamin , Droin Nathalie , Deloger Marc , Cotteret Sophie , Adam Julien , Zitvogel Laurence , Nikolaev Sergey I. , Chaput Nathalie , Massard Christophe , Soria Jean-Charles , Gomez-Roca Carlos , Zalcman Gerard , Planchard David , Marabelle Aurelien
Published: April 2023

Abstract
Cancer immunotherapy combinations have recently been shown to improve the overall survival of advanced mesotheliomas, especially for patients responding to those treatments. We aimed to characterize the biological correlates of malignant pleural mesotheliomas’ primary resistance to immunotherapy and antiangiogenics by testing the combination of pembrolizumab, an anti–PD-1 antibody, and nintedanib, a pan-antiangiogenic tyrosine kinase inhibitor, in the multicenter PEMBIB trial (NCT02856425). Thirty patients with advanced malignant pleural mesothelioma were treated and explored. Unexpectedly, we found that refractory patients were actively recruiting CD3+CD8+ cytotoxic T cells in their tumors through CXCL9 tumor release upon treatment. However, these patients displayed high levels of somatic copy-number alterations in their tumors that correlated with high blood and tumor levels of IL6 and CXCL8. Those proinflammatory cytokines resulted in higher tumor secretion of VEGF and tumor enrichment in regulatory T cells. Advanced mesothelioma should further benefit from stratified combination therapies adapted to their tumor biology.
Significance:
Sequential explorations of fresh tumor biopsies demonstrated that mesothelioma resistance to anti–PD-1 + antiangiogenics is not due to a lack of tumor T-cell infiltration but rather due to adaptive immunosuppressive pathways by tumors, involving molecules (e.g., IL6, CXCL8, VEGF, and CTLA4) that are amenable to targeted therapies.

This article is highlighted in the In This Issue feature, p. 799
Data from Antibody–Exatecan Conjugates with a Novel Self-immolative Moiety Overcome Resistance in Colon and Lung Cancer
Authors: Weng Weining , Meng Tao , Zhao Qianqian , Shen Yi , Fu Guoxiang , Shi Jing , Zhang Yue , Wang Zhaohui , Wang Mingqiao , Pan Rong , Ma Linjie , Chen Caiwei , Wang Lijun , Zhou Biao , Zhang Hui , Pu Junyi , Zhang Jianjian , Hu Yi Peter , Hua Guoqiang , Qian Yu , Liu Shu-Hui , Hu Wenhao , Meng Xun
Published: April 2023

Abstract
Antibody–drug conjugates (ADC) using DNA topoisomerase I inhibitor DXd/SN-38 have transformed cancer treatment, yet more effective ADCs are needed for overcoming resistance. We have designed an ADC class using a novel self-immolative T moiety for traceless conjugation and release of exatecan, a more potent topoisomerase I inhibitor with less sensitivity to multidrug resistance (MDR). Characterized by enhanced therapeutic indices, higher stability, and improved intratumoral pharmacodynamic response, antibody–T moiety–exatecan conjugates targeting HER2, HER3, and TROP2 overcome the intrinsic or treatment resistance of equivalent DXd/SN-38 ADCs in low-target-expression, large, and MDR+ tumors. T moiety–exatecan ADCs display durable antitumor activity in patient-derived xenograft and organoid models representative of unmet clinical needs, including EGFR ex19del/T790M/C797S triple-mutation lung cancer and BRAF/KRAS–TP53 double-mutant colon cancer, and show synergy with PARP/ATR inhibitor and anti–PD-1 treatment. High tolerability of the T moiety–exatecan ADC class in nonhuman primates supports its potential to expand the responding patient population and tumor types beyond current ADCs.
Significance:
ADCs combining a novel self-immolative moiety and topoisomerase I inhibitor exatecan as payload show deep and durable response in low-target-expressing and MDR+ tumors resistant to DXd/SN-38 ADCs without increasing toxicity. This new class of ADCs has the potential to benefit an additional patient population beyond current options.

See related commentary by Gupta et al., p. 817.

This article is highlighted in the In This Issue feature, p. 799
Data from Dynamics of Age- versus Therapy-Related Clonal Hematopoiesis in Long-term Survivors of Pediatric Cancer
Authors: Hagiwara Kohei , Natarajan Sivaraman , Wang Zhaoming , Zubair Haseeb , Mulder Heather L. , Dong Li , Plyler Emily M. , Thimmaiah Padma , Ma Xiaotu , Ness Kristen K. , Li Zhenghong , Mulrooney Daniel A. , Wilson Carmen L. , Yasui Yutaka , Hudson Melissa M. , Easton John , Robison Leslie L. , Zhang Jinghui
Published: April 2023

Abstract
We present the first comprehensive investigation of clonal hematopoiesis (CH) in 2,860 long-term survivors of pediatric cancer with a median follow-up time of 23.5 years. Deep sequencing over 39 CH-related genes reveals mutations in 15% of the survivors, significantly higher than the 8.5% in 324 community controls. CH in survivors is associated with exposures to alkylating agents, radiation, and bleomycin. Therapy-related CH shows significant enrichment in STAT3, characterized as a CH gene specific to survivors of Hodgkin lymphoma, and TP53. Single-cell profiling of peripheral blood samples revealed STAT3 mutations predominantly present in T cells and contributed by SBS25, a mutational signature associated with procarbazine exposure. Serial sample tracking reveals that larger clone size is a predictor for future expansion of age-related CH clones, whereas therapy-related CH remains stable decades after treatment. These data depict the distinct dynamics of these CH subtypes and support the need for longitudinal monitoring to determine the potential contribution to late effects.
Significance:
This first comprehensive CH analysis in long-term survivors of pediatric cancer presents the elevated prevalence and therapy exposures/diagnostic spectrum associated with CH. Due to the contrasting dynamics of clonal expansion for age-related versus therapy-related CH, longitudinal monitoring is recommended to ascertain the long-term effects of therapy-induced CH in pediatric cancer survivors.

See related commentary by Collord and Behjati, p. 811.

This article is highlighted in the In This Issue feature, p. 799
Data from Metformin Accelerates the Growth of BRAFV600E-Driven Melanoma by Upregulating VEGF-A
Authors: Martin Matthew J. , Hayward Robert , Viros Amaya , Marais Richard
Published: April 2023

Abstract
The antidiabetic drug metformin has antitumor activity in a variety of cancers because it blocks cell growth by inhibiting TORC1. Here, we show that melanoma cells that are driven by oncogenic BRAF are resistant to the growth-inhibitory effects of metformin because RSK sustains TORC1 activity even when AMP-activated protein kinase (AMPK) is activated. We further show that AMPK targets the dual-specificity protein phosphatase DUSP6 for degradation and this increases ERK activity, which then upregulates the VEGF-A protein. Critically, this drives angiogenesis and accelerates the growth of BRAF-driven tumors in mice. Unexpectedly, however, when VEGF signaling is inhibited, instead of accelerating tumor growth, metformin inhibits tumor growth. Thus, we show that BRAF-driven melanoma cells are resistant to the antigrowth effects of AMPK and that AMPK mediates cell-autonomous and cell-nonautonomous effects that accelerate the growth of these cells in vivo.

Significance: Metformin inhibits the growth of most tumor cells, but BRAF-mutant melanoma cells are resistant to metformin in vitro, and metformin accelerates their growth in vivo. Unexpectedly, VEGF inhibitors and metformin synergize to suppress the growth of BRAF-mutant tumors, revealing a combination of drugs that may be effective in these patients. Cancer Discov; 2(4); 344–55. ©2012 AACR.

This article is highlighted in the In This Issue feature, 288
Data from Evolutionary Pathways in BRCA1-Associated Breast Tumors
Authors: Martins Filipe C. , De Subhajyoti , Almendro Vanessa , Gönen Mithat , Park So Yeon , Blum Joanne L. , Herlihy William , Ethington Gabrielle , Schnitt Stuart J. , Tung Nadine , Garber Judy E. , Fetten Katharina , Michor Franziska , Polyak Kornelia
Published: April 2023

Abstract
BRCA1-associated breast tumors display loss of BRCA1 and frequent somatic mutations of PTEN and TP53. Here we describe the analysis of BRCA1, PTEN, and p53 at the single cell level in 55 BRCA1-associated breast tumors and computational methods to predict the relative temporal order of somatic events, on the basis of the frequency of cells with single or combined alterations. Although there is no obligatory order of events, we found that loss of PTEN is the most common first event and is associated with basal-like subtype, whereas in the majority of luminal tumors, mutation of TP53 occurs first and mutant PIK3CA is rarely detected. We also observed intratumor heterogeneity for the loss of wild-type BRCA1 and increased cell proliferation and centrosome amplification in the normal breast epithelium of BRCA1 mutation carriers. Our results have important implications for the design of chemopreventive and therapeutic interventions in this high-risk patient population.

Significance: Defining the temporal order of tumor-driving somatic events is critical for early detection, risk stratification, and the design of chemopreventive therapies. Our combined experimental and computational approach reveal that the loss of wild-type BRCA1 may not be the first event in the majority of BRCA1-associated breast tumors and may not be present in all cancer cells within tumors. Cancer Discov; 2(6); 503–11. ©2012 AACR.

This article is highlighted in the In This Issue feature, p. 473
Data from VEGF/Neuropilin-2 Regulation of Bmi-1 and Consequent Repression of IGF-IR Define a Novel Mechanism of Aggressive Prostate Cancer
Authors: Goel Hira Lal , Chang Cheng , Pursell Bryan , Leav Irwin , Lyle Stephen , Xi Hualin Simon , Hsieh Chung-Cheng , Adisetiyo Helty , Roy-Burman Pradip , Coleman Ilsa M. , Nelson Peter S. , Vessella Robert L. , Davis Roger J. , Plymate Stephen R. , Mercurio Arthur M.
Published: April 2023

Abstract
We show that the VEGF receptor neuropilin-2 (NRP2) is associated with high-grade, PTEN-null prostate cancer and that its expression in tumor cells is induced by PTEN loss as a consequence of c-Jun activation. VEGF/NRP2 signaling represses insulin-like growth factor-1 receptor (IGF-IR) expression and signaling, and the mechanism involves Bmi-1–mediated transcriptional repression of the IGF-IR. This mechanism has significant functional and therapeutic implications that were evaluated. IGF-IR expression positively correlates with PTEN and inversely correlates with NRP2 in prostate tumors. NRP2 is a robust biomarker for predicting response to IGF-IR therapy because prostate carcinomas that express NRP2 exhibit low levels of IGF-IR. Conversely, targeting NRP2 is only modestly effective because NRP2 inhibition induces compensatory IGF-IR signaling. Inhibition of both NRP2 and IGF-IR, however, completely blocks tumor growth in vivo.

Significance: These results identify a causal role for NRP2 and VEGF/NRP2 signaling in the behavior of aggressive prostate cancers by a mechanism that involves regulation of Bmi-1, a transcriptional repressor implicated in the etiology of prostate cancer induced by loss of PTEN function, and the repression of the IGF-IR. The therapeutic implications are significant because combined inhibition of NRP2 and IGF-IR overcomes the resistance induced by targeting each receptor individually. Cancer Discov; 2(10); 906–21. ©2012 AACR.

This article is highlighted in the In This Issue feature, p. 857.
Data from PI3Kδ Inhibitors in Cancer: Rationale and Serendipity Merge in the Clinic
Authors: Fruman David A. , Rommel Christian
Published: April 2023

Abstract
Several phosphoinositide 3-kinase (PI3K) inhibitors are in the clinic and many more are in preclinical development. CAL-101, a selective inhibitor of the PI3Kδ isoform, has shown remarkable success in certain hematologic malignancies. Although PI3Kδ signaling plays a central role in lymphocyte biology, the degree of single-agent therapeutic activity of CAL-101 during early-phase development has been somewhat unexpected. CAL-101 works in part by blocking signals from the microenvironment that normally sustain leukemia and lymphoma cells in a protective niche. As PI3Ks enter the arena of molecular-targeted therapies, CAL-101 provides proof of principle that isoform-selective compounds can be effective in selected cancer types and patient populations.

Significance: A key question is whether compounds targeting a single PI3K catalytic isoform can provide meaningful single agent efficacy in cancer cells that express multiple isoforms. Clinical studies of the drug CAL-101 have provided a significant advance by showing that selective targeting of PI3Kδ achieves efficacy in chronic lymphocytic leukemia, in part through targeting the tumor microenvironment. Cancer Discovery; 1(7); 562–72. ©2011 AACR.
Data from An LXR Agonist Promotes Glioblastoma Cell Death through Inhibition of an EGFR/AKT/SREBP-1/LDLR–Dependent Pathway
Authors: Guo Deliang , Reinitz Felicia , Youssef Mary , Hong Cynthia , Nathanson David , Akhavan David , Kuga Daisuke , Amzajerdi Ali Nael , Soto Horacio , Zhu Shaojun , Babic Ivan , Tanaka Kazuhiro , Dang Julie , Iwanami Akio , Gini Beatrice , DeJesus Jason , Lisiero Dominique D. , Huang Tiffany T. , Prins Robert M. , Wen Patrick Y. , Robins H. Ian , Prados Michael D. , DeAngelis Lisa M. , Mellinghoff Ingo K. , Mehta Minesh P. , James C. David , Chakravarti Arnab , Cloughesy Timothy F. , Tontonoz Peter , Mischel Paul S.
Published: April 2023

Abstract
Glioblastoma (GBM) is the most common malignant primary brain tumor of adults and one of the most lethal of all cancers. Epidermal growth factor receptor (EGFR) mutations (EGFRvIII) and phosphoinositide 3-kinase (PI3K) hyperactivation are common in GBM, promoting tumor growth and survival, including through sterol regulatory element-binding protein 1 (SREBP-1)–dependent lipogenesis. The role of cholesterol metabolism in GBM pathogenesis, its association with EGFR/PI3K signaling, and its potential therapeutic targetability are unknown. In our investigation, studies of GBM cell lines, xenograft models, and GBM clinical samples, including those from patients treated with the EGFR tyrosine kinase inhibitor lapatinib, uncovered an EGFRvIII-activated, PI3K/SREBP-1–dependent tumor survival pathway through the low-density lipoprotein receptor (LDLR). Targeting LDLR with the liver X receptor (LXR) agonist GW3965 caused inducible degrader of LDLR (IDOL)–mediated LDLR degradation and increased expression of the ABCA1 cholesterol efflux transporter, potently promoting tumor cell death in an in vivo GBM model. These results show that EGFRvIII can promote tumor survival through PI3K/SREBP-1–dependent upregulation of LDLR and suggest a role for LXR agonists in the treatment of GBM patients.

Significance: This study reveals that GBM cells have devised a mechanism to subvert the normal pathways for feedback inhibition of cholesterol homeostasis via EGFRvIII and PI3K-dependent activation of SREBP-1. We show that an LXR agonist causes IDOL-mediated LDLR degradation and increases expression of the ABCA1 cholesterol efflux transporter, potently promoting GBM cell death in vivo. These results suggest a role for LXR agonists in the treatment of GBM patients. Cancer Discovery; 1(5): 442–56. ©2011 AACR.

Read the Commentary on this article by Moschetta, p. 381

This article is highlighted in the In This Issue feature, p. 367
Data from Noncovalent Wild-type–Sparing Inhibitors of EGFR T790M
Authors: Lee Ho-June , Schaefer Gabriele , Heffron Timothy P. , Shao Lily , Ye Xiaofen , Sideris Steve , Malek Shiva , Chan Emily , Merchant Mark , La Hank , Ubhayakar Savita , Yauch Robert L. , Pirazzoli Valentina , Politi Katerina , Settleman Jeff
Published: April 2023

Abstract
Approximately half of EGFR-mutant non–small cell lung cancer (NSCLC) patients treated with small-molecule EGFR kinase inhibitors develop drug resistance associated with the EGF receptor (EGFR) T790M “gatekeeper” substitution, prompting efforts to develop covalent EGFR inhibitors, which can effectively suppress EGFR T790M in preclinical models. However, these inhibitors have yet to prove clinically efficacious, and their toxicity in skin, reflecting activity against wild-type EGFR, may limit dosing required to effectively suppress EGFR T790M in vivo. While profiling sensitivity to various kinase inhibitors across a large cancer cell line panel, we identified indolocarbazole compounds, including a clinically well-tolerated FLT3 inhibitor, as potent and reversible inhibitors of EGFR T790M that spare wild-type EGFR. These findings show the use of broad cancer cell profiling of kinase inhibitor efficacy to identify unanticipated novel applications, and they identify indolocarbazole compounds as potentially effective EGFR inhibitors in the context of T790M-mediated drug resistance in NSCLC.

Significance: EGFR-mutant lung cancer patients who respond to currently used EGFR kinase inhibitors invariably develop drug resistance, which is associated with the EGFR T790M resistance mutation in about half these cases. We unexpectedly identified a class of reversible potent inhibitors of EGFR T790M that do not inhibit wild-type EGFR, revealing a promising therapeutic strategy to overcome T790M-associated drug-resistant lung cancers. Cancer Discov; 3(2); 168–81. ©2012 AACR.

See related commentary by Brewer and Pao, p. 138

This article is highlighted in the In This Issue feature, p. 125
Data from Hypoxia Induces Phenotypic Plasticity and Therapy Resistance in Melanoma via the Tyrosine Kinase Receptors ROR1 and ROR2
Authors: O'Connell Michael P. , Marchbank Katie , Webster Marie R. , Valiga Alexander A. , Kaur Amanpreet , Vultur Adina , Li Ling , Herlyn Meenhard , Villanueva Jessie , Liu Qin , Yin Xiangfan , Widura Sandy , Nelson Janelle , Ruiz Nivia , Camilli Tura C. , Indig Fred E. , Flaherty Keith T. , Wargo Jennifer A. , Frederick Dennie T. , Cooper Zachary A. , Nair Suresh , Amaravadi Ravi K. , Schuchter Lynn M. , Karakousis Giorgos C. , Xu Wei , Xu Xiaowei , Weeraratna Ashani T.
Published: April 2023

Abstract
An emerging concept in melanoma biology is that of dynamic, adaptive phenotype switching, where cells switch from a highly proliferative, poorly invasive phenotype to a highly invasive, less proliferative one. This switch may hold significant implications not just for metastasis, but also for therapy resistance. We demonstrate that phenotype switching and subsequent resistance can be guided by changes in expression of receptors involved in the noncanonical Wnt5A signaling pathway, ROR1 and ROR2. ROR1 and ROR2 are inversely expressed in melanomas and negatively regulate each other. Furthermore, hypoxia initiates a shift of ROR1-positive melanomas to a more invasive, ROR2-positive phenotype. Notably, this receptor switch induces a 10-fold decrease in sensitivity to BRAF inhibitors. In patients with melanoma treated with the BRAF inhibitor vemurafenib, Wnt5A expression correlates with clinical response and therapy resistance. These data highlight the fact that mechanisms that guide metastatic progression may be linked to those that mediate therapy resistance.

Significance: These data show for the first time that a single signaling pathway, the Wnt signaling pathway, can effectively guide the phenotypic plasticity of tumor cells, when primed to do so by a hypoxic microenvironment. Importantly, this increased Wnt5A signaling can give rise to a subpopulation of highly invasive cells that are intrinsically less sensitive to novel therapies for melanoma, and targeting the Wnt5A/ROR2 axis could improve the efficacy and duration of response for patients with melanoma on vemurafenib. Cancer Discov; 3(12); 1378–93. ©2013 AACR.

This article is highlighted in the In This Issue feature, p. 1317
Data from A Genetic Platform to Model Sarcomagenesis from Primary Adult Mesenchymal Stem Cells
Authors: Guarnerio Jlenia , Riccardi Luisa , Taulli Riccardo , Maeda Takahiro , Wang Guocan , Hobbs Robin M. , Song Min Sup , Sportoletti Paolo , Bernardi Rosa , Bronson Roderick T. , Castillo-Martin Mireia , Cordon-Cardo Carlos , Lunardi Andrea , Pandolfi Pier Paolo
Published: April 2023

Abstract
The regulatory factors governing adult mesenchymal stem cell (MSC) physiology and their tumorigenic potential are still largely unknown, which substantially delays the identification of effective therapeutic approaches for the treatment of aggressive and lethal forms of MSC-derived mesenchymal tumors, such as undifferentiated sarcomas. Here, we have developed a novel platform to screen and quickly identify genes and pathways responsible for adult MSC transformation, modeled undifferentiated sarcoma in vivo, and, ultimately, tested the efficacy of targeting the identified oncopathways. Importantly, by taking advantage of this new platform, we demonstrate the key role of an aberrant LRF–DLK1–SOX9 pathway in the pathogenesis of undifferentiated sarcoma, with important therapeutic implications.

Significance: The paucity of therapeutic options for the treatment of sarcoma calls for a rapid and effective preclinical assessment of new therapeutic modalities. We have here developed a new platform to deconstruct the molecular genetics underlying the pathogenesis of sarcoma and to evaluatein vivo the efficacy of novel targeted therapies. Cancer Discov; 5(4); 396–409. ©2015 AACR.

This article is highlighted in the In This Issue feature, p. 333
Data from Essential Role of the Linear Ubiquitin Chain Assembly Complex in Lymphoma Revealed by Rare Germline Polymorphisms
Authors: Yang Yibin , Schmitz Roland , Mitala Joseph , Whiting Amanda , Xiao Wenming , Ceribelli Michele , Wright George W. , Zhao Hong , Yang Yandan , Xu Weihong , Rosenwald Andreas , Ott German , Gascoyne Randy D. , Connors Joseph M. , Rimsza Lisa M. , Campo Elias , Jaffe Elaine S. , Delabie Jan , Smeland Erlend B. , Braziel Rita M. , Tubbs Raymond R. , Cook James R. , Weisenburger Dennis D. , Chan Wing C. , Wiestner Adrian , Kruhlak Michael J. , Iwai Kazuhiro , Bernal Federico , Staudt Louis M.
Published: April 2023

Abstract
Constitutive activation of NF-κB is a hallmark of the activated B cell–like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL), owing to upstream signals from the B-cell receptor (BCR) and MYD88 pathways. The linear polyubiquitin chain assembly complex (LUBAC) attaches linear polyubiquitin chains to IκB kinase-γ, a necessary event in some pathways that engage NF-κB. Two germline polymorphisms affecting the LUBAC subunit RNF31 are rare among healthy individuals (∼1%) but enriched in ABC DLBCL (7.8%). These polymorphisms alter RNF31 α-helices that mediate binding to the LUBAC subunit RBCK1, thereby increasing RNF31–RBCK1 association, LUBAC enzymatic activity, and NF-κB engagement. In the BCR pathway, LUBAC associates with the CARD11–MALT1–BCL10 adapter complex and is required for ABC DLBCL viability. A stapled RNF31 α-helical peptide based on the ABC DLBCL–associated Q622L polymorphism inhibited RNF31–RBCK1 binding, decreased NF-κB activation, and killed ABC DLBCL cells, credentialing this protein–protein interface as a therapeutic target.

Significance: We provide genetic, biochemical, and functional evidence that the LUBAC ubiquitin ligase is a therapeutic target in ABC DLBCL, the DLBCL subtype that is most refractory to current therapy. More generally, our findings highlight the role of rare germline-encoded protein variants in cancer pathogenesis. Cancer Discov; 4(4); 480–93. ©2014 AACR.

See related commentary by Grumati and Dikic, p. 394

This article is highlighted in the In This Issue feature, p. 377
Data from Epithelial-to-Mesenchymal Transition Rewires the Molecular Path to PI3K-Dependent Proliferation
Authors: Salt Megan B. , Bandyopadhyay Sourav , McCormick Frank
Published: April 2023

Abstract
Tumors showing evidence of epithelial-to-mesenchymal transition (EMT) have been associated with metastasis, drug resistance, and poor prognosis. Heterogeneity along the EMT spectrum is observed between and within tumors. To develop effective therapeutics, a mechanistic understanding of how EMT affects the molecular requirements for proliferation is needed. We found that although cells use phosphoinositide 3-kinase (PI3K) for proliferation in both the epithelial and mesenchymal states, EMT rewires the mechanism of PI3K pathway activation. In epithelial cells, autocrine ERBB3 activation maintains PI3K signaling, whereas after EMT, downregulation of ERBB3 disrupts autocrine signaling to PI3K. Loss of ERBB3 leads to reduced serum-independent proliferation after EMT that can be rescued through reactivation of PI3K by enhanced signaling from p110α, ERBB3 reexpression, or growth factor stimulation. In vivo, we demonstrate that PIK3CA expression is upregulated in mesenchymal tumors with low levels of ERBB3. This study defines how ERBB3 downregulation after EMT affects PI3K-dependent proliferation.

Significance: This study describes a mechanism through which EMT transition alters the proliferative potential of cells by modulating ERBB3 expression. Furthermore, it demonstrates the potential for multiple molecular routes to drive proliferation in different cell states, illustrating how changes in EMT status can rewire signaling upstream of cell proliferation. Cancer Discov; 4(2); 186–199. ©2013 AACR.

See related commentary by Niederst and Benes, p. 149

This article is highlighted in the In This Issue feature, p. 131
Data from Next-Generation Sequencing of Stage IV Squamous Cell Lung Cancers Reveals an Association of PI3K Aberrations and Evidence of Clonal Heterogeneity in Patients with Brain Metastases
Authors: Paik Paul K. , Shen Ronglai , Won Helen , Rekhtman Natasha , Wang Lu , Sima Camelia S. , Arora Arshi , Seshan Venkatraman , Ladanyi Marc , Berger Michael F. , Kris Mark G.
Published: April 2023

Abstract
Large-scale genomic characterization of squamous cell lung cancers (SQCLC) has revealed several putative oncogenic drivers. There are, however, little data to suggest that these alterations have clinical relevance. We performed comprehensive genomic profiling (including next-generation sequencing) of 79 stage IV SQCLCs and analyzed differences in the clinical characteristics of two major SQCLC subtypes: FGFR1 amplified and PI3K aberrant. Patients with PI3K-aberrant tumors had aggressive disease marked by worse survival (median overall survival, 8.6 vs. 19.1 months, P < 0.001), higher metastatic burden (>3 organs, 18% vs. 3%, P = 0.025), and greater incidence of brain metastases (27% vs. 0% in others, P < 0.001). We performed whole-exome and RNA sequencing on paired brain metastases and primary lung cancers to elucidate the metastatic process to brain. SQCLC primaries that gave rise to brain metastases exhibited truncal PTEN loss. SQCLC brain metastases exhibited a high degree of genetic heterogeneity and evidence of clonal differences between their primary sites.

Significance: We performed next-generation sequencing of metastatic SQCLCs and primary lung–brain metastasis pairs, identifying PI3K-aberrant tumors as an aggressive subset associated with brain metastases. We identified genetic heterogeneity between lung primaries–brain metastases as well as clonal populations that may highlight alterations important in the metastatic process. Cancer Discov; 5(6); 610–21. ©2015 AACR.

This article is highlighted in the In This Issue feature, p. 565