bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Somatic ERCC2 Mutations Correlate with Cisplatin Sensitivity in Muscle-Invasive Urothelial Carcinoma
Authors: Van Allen Eliezer M. , Mouw Kent W. , Kim Philip , Iyer Gopa , Wagle Nikhil , Al-Ahmadie Hikmat , Zhu Cong , Ostrovnaya Irina , Kryukov Gregory V. , O'Connor Kevin W. , Sfakianos John , Garcia-Grossman Ilana , Kim Jaegil , Guancial Elizabeth A. , Bambury Richard , Bahl Samira , Gupta Namrata , Farlow Deborah , Qu Angela , Signoretti Sabina , Barletta Justine A. , Reuter Victor , Boehm Jesse , Lawrence Michael , Getz Gad , Kantoff Philip , Bochner Bernard H. , Choueiri Toni K. , Bajorin Dean F. , Solit David B. , Gabriel Stacey , D'Andrea Alan , Garraway Levi A. , Rosenberg Jonathan E.
Published: March 2024

Abstract
Cisplatin-based chemotherapy is the standard of care for patients with muscle-invasive urothelial carcinoma. Pathologic downstaging to pT0/pTis after neoadjuvant cisplatin-based chemotherapy is associated with improved survival, although molecular determinants of cisplatin response are incompletely understood. We performed whole-exome sequencing on pretreatment tumor and germline DNA from 50 patients with muscle-invasive urothelial carcinoma who received neoadjuvant cisplatin-based chemotherapy followed by cystectomy (25 pT0/pTis “responders,” 25 pT2+ “nonresponders”) to identify somatic mutations that occurred preferentially in responders. ERCC2, a nucleotide excision repair gene, was the only significantly mutated gene enriched in the cisplatin responders compared with nonresponders (q < 0.01). Expression of representative ERCC2 mutants in an ERCC2-deficient cell line failed to rescue cisplatin and UV sensitivity compared with wild-type ERCC2. The lack of normal ERCC2 function may contribute to cisplatin sensitivity in urothelial cancer, and somatic ERCC2 mutation status may inform cisplatin-containing regimen usage in muscle-invasive urothelial carcinoma.

Significance: Somatic ERCC2 mutations correlate with complete response to cisplatin-based chemosensitivity in muscle-invasive urothelial carcinoma, and clinically identified mutations lead to cisplatin sensitivity in vitro. Nucleotide excision repair pathway defects may drive exceptional response to conventional chemotherapy. Cancer Discov; 4(10); 1140–53. ©2014 AACR.

See related commentary by Turchi et al., p. 1118

This article is highlighted in the In This Issue feature, p. 1103
Data from RHOA-FAK Is a Required Signaling Axis for the Maintenance of KRAS-Driven Lung Adenocarcinomas
Authors: Konstantinidou Georgia , Ramadori Giorgio , Torti Francesca , Kangasniemi Kim , Ramirez Rachel E. , Cai Yiran , Behrens Carmen , Dellinger Michael T. , Brekken Rolf A. , Wistuba Ignacio I. , Heguy Adriana , Teruya-Feldstein Julie , Scaglioni Pier Paolo
Published: March 2024

Abstract
Non–small cell lung cancer (NSCLC) often expresses mutant KRAS together with tumor-associated mutations of the CDKN2A locus, which are associated with aggressive, therapy-resistant tumors. Here, we unravel specific requirements for the maintenance of NSCLC that carries this genotype. We establish that the extracellular signal-regulated kinase (ERK)/RHOA/focal adhesion kinase (FAK) network is deregulated in high-grade lung tumors. Suppression of RHOA or FAK induces cell death selectively in mutant KRAS;INK4A/ARF-deficient lung cancer cells. Furthermore, pharmacologic inhibition of FAK caused tumor regression specifically in the high-grade lung cancer that developed in mutant Kras;Cdkn2a-null mice. These findings provide a rationale for the rapid implementation of genotype-specific targeted therapies using FAK inhibitors in patients with cancer.

Significance: Targeted therapies are effective for only a small fraction of patients with cancer. We report that FAK inhibitors exert potent antitumor effects in NSCLCs that express mutant KRAS in association with INK4A/ARF deficiency. These results reveal a novel genotype-specific vulnerability of cancer cells that can be exploited for therapeutic purposes. Cancer Discov; 3(4); 444–57. ©2013 AACR.

This article is highlighted in the In This Issue feature, p. 363
Data from Mutant N-RAS Protects Colorectal Cancer Cells from Stress-Induced Apoptosis and Contributes to Cancer Development and Progression
Authors: Wang Yufang , Velho Sérgia , Vakiani Efsevia , Peng Shouyong , Bass Adam J. , Chu Gerald C. , Gierut Jessica , Bugni James M. , Der Channing J. , Philips Mark , Solit David B. , Haigis Kevin M.
Published: March 2024

Abstract
N-RAS is one member of a family of oncoproteins that are commonly mutated in cancer. Activating mutations in NRAS occur in a subset of colorectal cancers, but little is known about how the mutant protein contributes to the onset and progression of the disease. Using genetically engineered mice, we find that mutant N-RAS strongly promotes tumorigenesis in the context of inflammation. The protumorigenic nature of mutant N-RAS is related to its antiapoptotic function, which is mediated by activation of a noncanonical mitogen-activated protein kinase pathway that signals through STAT3. As a result, inhibition of MAP–ERK kinase selectively induces apoptosis in autochthonous colonic tumors expressing mutant N-RAS. The translational significance of this finding is highlighted by our observation that NRAS mutation correlates with a less favorable clinical outcome for patients with colorectal cancer. These data show for the first time the important role that N-RAS plays in colorectal cancer.

Significance: Little is known about N-RAS function in normal biology or in cancer. Our study links the antiapoptotic function of mutant N-RAS to its ability to promote colorectal cancer in an inflammatory context. In addition, our study pinpoints a therapeutic strategy for this distinct colorectal cancer subtype. Cancer Discov; 3(3); 294–307. ©2013 AACR.

This article is highlighted in the In This Issue feature, p. 239
Data from Development of siRNA Payloads to Target KRAS-Mutant Cancer
Authors: Yuan Tina L. , Fellmann Christof , Lee Chih-Shia , Ritchie Cayde D. , Thapar Vishal , Lee Liam C. , Hsu Dennis J. , Grace Danielle , Carver Joseph O. , Zuber Johannes , Luo Ji , McCormick Frank , Lowe Scott W.
Published: March 2024

Abstract
RNAi is a powerful tool for target identification and can lead to novel therapies for pharmacologically intractable targets such as KRAS. RNAi therapy must combine potent siRNA payloads with reliable in vivo delivery for efficient target inhibition. We used a functional “Sensor” assay to establish a library of potent siRNAs against RAS pathway genes and to show that they efficiently suppress their targets at low dose. This reduces off-target effects and enables combination gene knockdown. We administered Sensor siRNAs in vitro and in vivo and validated the delivery of KRAS siRNA alone and siRNA targeting the complete RAF effector node (A/B/CRAF) as promising strategies to treat KRAS-mutant colorectal cancer. We further demonstrate that improved therapeutic efficacy is achieved by formulating siRNA payloads that combine both single-gene siRNA and node-targeted siRNAs (KRAS + PIK3CA/B). The customizable nature of Sensor siRNA payloads offers a universal platform for the combination target identification and development of RNAi therapeutics.

Significance: To advance RNAi therapy for KRAS-mutant cancer, we developed a validated siRNA library against RAS pathway genes that enables combination gene silencing. Using an in vivo model for real-time siRNA delivery tracking, we show that siRNA-mediated inhibition of KRAS as well as RAF or PI3K combinations can impair KRAS-mutant colorectal cancer in xenograft models. Cancer Discov; 4(10); 1182–97. ©2014 AACR.

This article is highlighted in the In This Issue feature, p. 1103
Data from NF2 Loss Promotes Oncogenic RAS-Induced Thyroid Cancers via YAP-Dependent Transactivation of RAS Proteins and Sensitizes Them to MEK Inhibition
Authors: Garcia-Rendueles Maria E.R. , Ricarte-Filho Julio C. , Untch Brian R. , Landa Iňigo , Knauf Jeffrey A. , Voza Francesca , Smith Vicki E. , Ganly Ian , Taylor Barry S. , Persaud Yogindra , Oler Gisele , Fang Yuqiang , Jhanwar Suresh C. , Viale Agnes , Heguy Adriana , Huberman Kety H. , Giancotti Filippo , Ghossein Ronald , Fagin James A.
Published: March 2024

Abstract
Ch22q LOH is preferentially associated with RAS mutations in papillary and in poorly differentiated thyroid cancer (PDTC). The 22q tumor suppressor NF2, encoding merlin, is implicated in this interaction because of its frequent loss of function in human thyroid cancer cell lines. Nf2 deletion or Hras mutation is insufficient for transformation, whereas their combined disruption leads to murine PDTC with increased MAPK signaling. Merlin loss induces RAS signaling in part through inactivation of Hippo, which activates a YAP–TEAD transcriptional program. We find that the three RAS genes are themselves YAP–TEAD1 transcriptional targets, providing a novel mechanism of promotion of RAS-induced tumorigenesis. Moreover, pharmacologic disruption of YAP–TEAD with verteporfin blocks RAS transcription and signaling and inhibits cell growth. The increased MAPK output generated by NF2 loss in RAS-mutant cancers may inform therapeutic strategies, as it generates greater dependency on the MAPK pathway for viability.

Significance: Intensification of mutant RAS signaling through copy-number imbalances is commonly associated with transformation. We show that NF2/merlin inactivation augments mutant RAS signaling by promoting YAP/TEAD-driven transcription of oncogenic and wild-type RAS, resulting in greater MAPK output and increased sensitivity to MEK inhibitors. Cancer Discov; 5(11); 1178–93. ©2015 AACR.

This article is highlighted in the In This Issue feature, p. 1111
Data from The Immune Microenvironment Confers Resistance to MAPK Pathway Inhibitors through Macrophage-Derived TNFα
Authors: Smith Michael P. , Sanchez-Laorden Berta , O'Brien Kate , Brunton Holly , Ferguson Jennifer , Young Helen , Dhomen Nathalie , Flaherty Keith T. , Frederick Dennie T. , Cooper Zachary A. , Wargo Jennifer A. , Marais Richard , Wellbrock Claudia
Published: March 2024

Abstract
Recently, the rationale for combining targeted therapy with immunotherapy has come to light, but our understanding of the immune response during MAPK pathway inhibitor treatment is limited. We discovered that the immune microenvironment can act as a source of resistance to MAPK pathway–targeted therapy, and moreover during treatment this source becomes reinforced. In particular, we identified macrophage-derived TNFα as a crucial melanoma growth factor that provides resistance to MAPK pathway inhibitors through the lineage transcription factor MITF (microphthalmia transcription factor). Most strikingly, in BRAF-mutant melanomas of patients and BRAFV600E melanoma allografts, MAPK pathway inhibitors increased the number of tumor-associated macrophages, and TNFα and MITF expression. Inhibiting TNFα signaling with IκB kinase inhibitors profoundly enhanced the efficacy of MAPK pathway inhibitors by targeting not only the melanoma cells but also the microenvironment. In summary, we identify the immune microenvironment as a novel source of resistance and reveal a new strategy to improve the efficacy of targeted therapy in melanoma.

Significance: This study identifies the immune microenvironment as a source of resistance to MAPK pathway inhibitors through macrophage-derived TNFα, and reveals that in patients on treatment this source becomes reinforced. Inhibiting IκB kinase enhances the efficacy of MAPK pathway inhibitors, which identifies this approach as a potential novel strategy to improve targeted therapy in melanoma. Cancer Discov; 4(10); 1214–29. ©2014 AACR.

This article is highlighted in the In This Issue feature, p. 1103
Data from Application of Sequencing, Liquid Biopsies, and Patient-Derived Xenografts for Personalized Medicine in Melanoma
Authors: Girotti Maria Romina , Gremel Gabriela , Lee Rebecca , Galvani Elena , Rothwell Dominic , Viros Amaya , Mandal Amit Kumar , Lim Kok Haw Jonathan , Saturno Grazia , Furney Simon J. , Baenke Franziska , Pedersen Malin , Rogan Jane , Swan Jacqueline , Smith Matthew , Fusi Alberto , Oudit Deemesh , Dhomen Nathalie , Brady Ged , Lorigan Paul , Dive Caroline , Marais Richard
Published: March 2024

Abstract
Targeted therapies and immunotherapies have transformed melanoma care, extending median survival from ∼9 to over 25 months, but nevertheless most patients still die of their disease. The aim of precision medicine is to tailor care for individual patients and improve outcomes. To this end, we developed protocols to facilitate individualized treatment decisions for patients with advanced melanoma, analyzing 364 samples from 214 patients. Whole exome sequencing (WES) and targeted sequencing of circulating tumor DNA (ctDNA) allowed us to monitor responses to therapy and to identify and then follow mechanisms of resistance. WES of tumors revealed potential hypothesis-driven therapeutic strategies for BRAF wild-type and inhibitor-resistant BRAF-mutant tumors, which were then validated in patient-derived xenografts (PDX). We also developed circulating tumor cell–derived xenografts (CDX) as an alternative to PDXs when tumors were inaccessible or difficult to biopsy. Thus, we describe a powerful technology platform for precision medicine in patients with melanoma.

Significance: Although recent developments have revolutionized melanoma care, most patients still die of their disease. To improve melanoma outcomes further, we developed a powerful precision medicine platform to monitor patient responses and to identify and validate hypothesis-driven therapies for patients who do not respond, or who develop resistance to current treatments. Cancer Discov; 6(3); 286–99. ©2015 AACR.

This article is highlighted in the In This Issue feature, p. 217
Data from Response to MET Inhibitors in Patients with Stage IV Lung Adenocarcinomas Harboring MET Mutations Causing Exon 14 Skipping
Authors: Paik Paul K. , Drilon Alexander , Fan Pang-Dian , Yu Helena , Rekhtman Natasha , Ginsberg Michelle S. , Borsu Laetitia , Schultz Nikolaus , Berger Michael F. , Rudin Charles M. , Ladanyi Marc
Published: March 2024

Abstract
Mutations in the MET exon 14 RNA splice acceptor and donor sites, which lead to exon skipping, deletion of the juxtamembrane domain containing the CBL E3-ubiquitin ligase-binding site, and decreased turnover of the resultant aberrant MET protein, were previously reported to be oncogenic in preclinical models. We now report responses to the MET inhibitors crizotinib and cabozantinib in four patients with stage IV lung adenocarcinomas harboring mutations leading to MET exon 14 skipping, highlighting a new therapeutic strategy for the 4% of lung adenocarcinoma patients whose tumors harbor this previously underappreciated genetic alteration.

Significance: Oncogenic mutations in the MET exon 14 splice sites that cause exon 14 skipping occur in 4% of lung adenocarcinomas. We report responses to the MET inhibitors crizotinib and cabozantinib in patients with lung adenocarcinomas harboring MET exon 14 splice site mutations, identifying a new potential therapeutic target in this disease. Cancer Discov; 5(8); 842–9. ©2015 AACR.

See related commentary by Ma, p. 802.

See related article by Frampton et al., p. 850.

This article is highlighted in the In This Issue feature, p. 783
Data from MACROD2 Haploinsufficiency Impairs Catalytic Activity of PARP1 and Promotes Chromosome Instability and Growth of Intestinal Tumors
Authors: Sakthianandeswaren Anuratha , Parsons Marie J. , Mouradov Dmitri , MacKinnon Ruth N. , Catimel Bruno , Liu Sheng , Palmieri Michelle , Love Christopher , Jorissen Robert N. , Li Shan , Whitehead Lachlan , Putoczki Tracy L. , Preaudet Adele , Tsui Cary , Nowell Cameron J. , Ward Robyn L. , Hawkins Nicholas J. , Desai Jayesh , Gibbs Peter , Ernst Matthias , Street Ian , Buchert Michael , Sieber Oliver M.
Published: March 2024

Abstract
ADP-ribosylation is an important posttranslational protein modification that regulates diverse biological processes, controlled by dedicated transferases and hydrolases. Here, we show that frequent deletions (∼30%) of the MACROD2 mono-ADP-ribosylhydrolase locus in human colorectal cancer cause impaired PARP1 transferase activity in a gene dosage–dependent manner. MACROD2 haploinsufficiency alters DNA repair and sensitivity to DNA damage and results in chromosome instability. Heterozygous and homozygous depletion of Macrod2 enhances intestinal tumorigenesis in ApcMin/+ mice and the growth of human colorectal cancer xenografts. MACROD2 deletion in sporadic colorectal cancer is associated with the extent of chromosome instability, independent of clinical parameters and other known genetic drivers. We conclude that MACROD2 acts as a haploinsufficient tumor suppressor, with loss of function promoting chromosome instability, thereby driving cancer evolution.

Significance: Chromosome instability (CIN) is a hallmark of cancer. We identify MACROD2 deletion as a cause of CIN in human colorectal cancer. MACROD2 loss causes repression of PARP1 activity, impairing DNA repair. MACROD2 haploinsufficiency promotes CIN and intestinal tumor growth. Our results reveal MACROD2 as a major caretaker tumor suppressor gene. Cancer Discov; 8(8); 988–1005. ©2018 AACR.

See related commentary by Jin and Burkard, p. 921.

This article is highlighted in the In This Issue feature, p. 899
Data from Impaired HLA Class I Antigen Processing and Presentation as a Mechanism of Acquired Resistance to Immune Checkpoint Inhibitors in Lung Cancer
Authors: Gettinger Scott , Choi Jungmin , Hastings Katherine , Truini Anna , Datar Ila , Sowell Ryan , Wurtz Anna , Dong Weilai , Cai Guoping , Melnick Mary Ann , Du Victor Y. , Schlessinger Joseph , Goldberg Sarah B. , Chiang Anne , Sanmamed Miguel F. , Melero Ignacio , Agorreta Jackeline , Montuenga Luis M. , Lifton Richard , Ferrone Soldano , Kavathas Paula , Rimm David L. , Kaech Susan M. , Schalper Kurt , Herbst Roy S. , Politi Katerina
Published: March 2024

Abstract
Mechanisms of acquired resistance to immune checkpoint inhibitors (ICI) are poorly understood. We leveraged a collection of 14 ICI-resistant lung cancer samples to investigate whether alterations in genes encoding HLA Class I antigen processing and presentation machinery (APM) components or interferon signaling play a role in acquired resistance to PD-1 or PD-L1 antagonistic antibodies. Recurrent mutations or copy-number changes were not detected in our cohort. In one case, we found acquired homozygous loss of B2M that caused lack of cell-surface HLA Class I expression in the tumor and a matched patient-derived xenograft (PDX). Downregulation of B2M was also found in two additional PDXs established from ICI-resistant tumors. CRISPR-mediated knockout of B2m in an immunocompetent lung cancer mouse model conferred resistance to PD-1 blockade in vivo, proving its role in resistance to ICIs. These results indicate that HLA Class I APM disruption can mediate escape from ICIs in lung cancer.

Significance: As programmed death 1 axis inhibitors are becoming more established in standard treatment algorithms for diverse malignancies, acquired resistance to these therapies is increasingly being encountered. Here, we found that defective antigen processing and presentation can serve as a mechanism of such resistance in lung cancer. Cancer Discov; 7(12); 1420–35. ©2017 AACR.

This article is highlighted in the In This Issue feature, p. 1355
Data from Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine
Authors: Aguirre Andrew J. , Nowak Jonathan A. , Camarda Nicholas D. , Moffitt Richard A. , Ghazani Arezou A. , Hazar-Rethinam Mehlika , Raghavan Srivatsan , Kim Jaegil , Brais Lauren K. , Ragon Dorisanne , Welch Marisa W. , Reilly Emma , McCabe Devin , Marini Lori , Anderka Kristin , Helvie Karla , Oliver Nelly , Babic Ana , Da Silva Annacarolina , Nadres Brandon , Van Seventer Emily E. , Shahzade Heather A. , St. Pierre Joseph P. , Burke Kelly P. , Clancy Thomas , Cleary James M. , Doyle Leona A. , Jajoo Kunal , McCleary Nadine J. , Meyerhardt Jeffrey A. , Murphy Janet E. , Ng Kimmie , Patel Anuj K. , Perez Kimberly , Rosenthal Michael H. , Rubinson Douglas A. , Ryou Marvin , Shapiro Geoffrey I. , Sicinska Ewa , Silverman Stuart G. , Nagy Rebecca J. , Lanman Richard B. , Knoerzer Deborah , Welsch Dean J. , Yurgelun Matthew B. , Fuchs Charles S. , Garraway Levi A. , Getz Gad , Hornick Jason L. , Johnson Bruce E. , Kulke Matthew H. , Mayer Robert J. , Miller Jeffrey W. , Shyn Paul B. , Tuveson David A. , Wagle Nikhil , Yeh Jen Jen , Hahn William C. , Corcoran Ryan B. , Carter Scott L. , Wolpin Brian M.
Published: March 2024

Abstract
Clinically relevant subtypes exist for pancreatic ductal adenocarcinoma (PDAC), but molecular characterization is not yet standard in clinical care. We implemented a biopsy protocol to perform time-sensitive whole-exome sequencing and RNA sequencing for patients with advanced PDAC. Therapeutically relevant genomic alterations were identified in 48% (34/71) and pathogenic/likely pathogenic germline alterations in 18% (13/71) of patients. Overall, 30% (21/71) of enrolled patients experienced a change in clinical management as a result of genomic data. Twenty-six patients had germline and/or somatic alterations in DNA-damage repair genes, and 5 additional patients had mutational signatures of homologous recombination deficiency but no identified causal genomic alteration. Two patients had oncogenic in-frame BRAF deletions, and we report the first clinical evidence that this alteration confers sensitivity to MAPK pathway inhibition. Moreover, we identified tumor/stroma gene expression signatures with clinical relevance. Collectively, these data demonstrate the feasibility and value of real-time genomic characterization of advanced PDAC.

Significance: Molecular analyses of metastatic PDAC tumors are challenging due to the heterogeneous cellular composition of biopsy specimens and rapid progression of the disease. Using an integrated multidisciplinary biopsy program, we demonstrate that real-time genomic characterization of advanced PDAC can identify clinically relevant alterations that inform management of this difficult disease. Cancer Discov; 8(9); 1096–111. ©2018 AACR.

See related commentary by Collisson, p. 1062.

This article is highlighted in the In This Issue feature, p. 1047
Data from Akt/PKB-Mediated Phosphorylation of Twist1 Promotes Tumor Metastasis via Mediating Cross-Talk between PI3K/Akt and TGF-β Signaling Axes
Authors: Xue Gongda , Restuccia David F. , Lan Qiang , Hynx Debby , Dirnhofer Stephan , Hess Daniel , Rüegg Curzio , Hemmings Brian A.
Published: March 2024

Abstract
Metastatic breast tumor cells display an epithelial–mesenchymal transition (EMT) that increases cell motility, invasion, and dissemination. Although the transcription factor Twist1 has been shown to contribute to EMT and cancer metastasis, the signaling pathways regulating Twist1 activity are poorly understood. Here, we show that Twist1 is ubiquitously phosphorylated in 90% of 1,532 invasive human breast tumors. Akt/protein kinase B (PKB)–mediated Twist1 phosphorylation promotes EMT and breast cancer metastasis by modulating its transcriptional target TGF-β2, leading to enhanced TGF-β receptor signaling, which in turn maintains hyperactive phosphoinositide 3-kinase (PI3K)/Akt signaling. Preventing phosphorylation of Twist1, as well as depletion of TGF-β2, significantly impaired the metastatic potential of cancer cells in vivo, indicating a key role of phosphorylated Twist1 (phospho-Twist1) in mediating cross-talk between the PI3K/Akt and TGF-β/Smad signaling axes that supports metastatic tumor development. Our results describe a novel signaling event linking PI3K/Akt hyperactivation in tumor cells to direct regulation of Twist1 activation and tumor metastasis.

Significance: We identified the first phospho-Twist1 transcriptional target TGF-β2, which mediates cross-talk between PI3K/Akt and TGF-β signaling and promotes tumor metastasis. Our results thus illustrate a direct role of PI3K/Akt signaling in metastatic cancer development and suggest that Twist1 phosphorylation could be a potential therapeutic target in clinical cancer treatment. Cancer Discovery; 2(3); 248–59. ©2012 AACR.

This article is highlighted in the In This Issue feature, p. 193
Data from MYC Instructs and Maintains Pancreatic Adenocarcinoma Phenotype
Authors: Sodir Nicole M. , Kortlever Roderik M. , Barthet Valentin J.A. , Campos Tania , Pellegrinet Luca , Kupczak Steven , Anastasiou Panayiotis , Swigart Lamorna Brown , Soucek Laura , Arends Mark J. , Littlewood Trevor D. , Evan Gerard I.
Published: March 2024

Abstract
The signature features of pancreatic ductal adenocarcinoma (PDAC) are its fibroinflammatory stroma, poor immune activity, and dismal prognosis. We show that acute activation of Myc in indolent pancreatic intraepithelial neoplasm (PanIN) epithelial cells in vivo is, alone, sufficient to trigger immediate release of instructive signals that together coordinate changes in multiple stromal and immune-cell types and drive transition to pancreatic adenocarcinomas that share all the characteristic stromal features of their spontaneous human counterpart. We also demonstrate that this Myc-driven PDAC switch is completely and immediately reversible: Myc deactivation/inhibition triggers meticulous disassembly of advanced PDAC tumor and stroma and concomitant death of tumor cells. Hence, both the formation and deconstruction of the complex PDAC phenotype are continuously dependent on a single, reversible Myc switch.
Significance:
We show that Myc activation in indolent KrasG12D-induced PanIN epithelium acts as an immediate pleiotropic switch, triggering tissue-specific signals that instruct all the diverse signature stromal features of spontaneous human PDAC. Subsequent Myc deactivation or inhibition immediately triggers a program that coordinately disassembles PDAC back to PanIN.

See related commentary by English and Sears, p. 495.
Data from Disabled Homolog 2 Controls Prometastatic Activity of Tumor-Associated Macrophages
Authors: Marigo Ilaria , Trovato Rosalinda , Hofer Francesca , Ingangi Vincenzo , De Sanctis Francesco , Ugel Stefano , Canè Stefania , Simonelli Anna , Lamolinara Alessia , Iezzi Manuela , Fassan Matteo , Rugge Massimo , Boschi Federico , Borile Giulia , Eisenhaure Thomas , Sarkizova Siranush , Lieb David , Hacohen Nir , Azzolin Luca , Piccolo Stefano , Lawlor Rita , Scarpa Aldo , Carbognin Luisa , Bria Emilio , Bicciato Silvio , Murray Peter J. , Bronte Vincenzo
Published: March 2024

Abstract
Tumor-associated macrophages (TAM) are regulators of extracellular matrix (ECM) remodeling and metastatic progression, the main cause of cancer-associated death. We found that disabled homolog 2 mitogen-responsive phosphoprotein (DAB2) is highly expressed in tumor-infiltrating TAMs and that its genetic ablation significantly impairs lung metastasis formation. DAB2-expressing TAMs, mainly localized along the tumor-invasive front, participate in integrin recycling, ECM remodeling, and directional migration in a tridimensional matrix. DAB2+ macrophages escort the invasive dissemination of cancer cells by a mechanosensing pathway requiring the transcription factor YAP. In human lobular breast and gastric carcinomas, DAB2+ TAMs correlated with a poor clinical outcome, identifying DAB2 as potential prognostic biomarker for stratification of patients with cancer. DAB2 is therefore central for the prometastatic activity of TAMs.
Significance:
DAB2 expression in macrophages is essential for metastasis formation but not primary tumor growth. Mechanosensing cues, activating the complex YAP–TAZ, regulate DAB2 in macrophages, which in turn controls integrin recycling and ECM remodeling in 3-D tissue matrix. The presence of DAB2+ TAMs in patients with cancer correlates with worse prognosis.

This article is highlighted in the In This Issue feature, p. 1611
Data from An In Vivo Kras Allelic Series Reveals Distinct Phenotypes of Common Oncogenic Variants
Authors: Zafra Maria Paz , Parsons Marie J. , Kim Jangkyung , Alonso-Curbelo Direna , Goswami Sukanya , Schatoff Emma M. , Han Teng , Katti Alyna , Fernandez Maria Teresa Calvo , Wilkinson John E. , Piskounova Elena , Dow Lukas E.
Published: March 2024

Abstract
KRAS is the most frequently mutated oncogene in cancer, yet there is little understanding of how specific KRAS amino acid changes affect tumor initiation, progression, or therapy response. Using high-fidelity CRISPR-based engineering, we created an allelic series of new LSL-Kras mutant mice, reflecting codon 12 and 13 mutations that are highly prevalent in lung (KRASG12C), pancreas (KRASG12R), and colon (KRASG13D) cancers. Induction of each allele in either the murine colon or pancreas revealed striking quantitative and qualitative differences between KRAS mutants in driving the early stages of transformation. Furthermore, using pancreatic organoid models, we show that KRASG13D mutants are sensitive to EGFR inhibition, whereas KRASG12C-mutant organoids are selectively responsive to covalent G12C inhibitors only when EGFR is suppressed. Together, these new mouse strains provide an ideal platform for investigating KRAS biology in vivo and for developing preclinical precision oncology models of KRAS-mutant pancreas, colon, and lung cancers.
Significance:
KRAS is the most frequently mutated oncogene. Here, we describe new preclinical models that mimic tissue-selective KRAS mutations and show that each mutation has distinct cellular consequences in vivo and carries differential sensitivity to targeted therapeutic agents.

See related commentary by Kostyrko and Sweet-Cordero, p. 1626.

This article is highlighted in the In This Issue feature, p. 1611
Data from Myeloid-Derived Suppressor Cell Subsets Drive Glioblastoma Growth in a Sex-Specific Manner
Authors: Bayik Defne , Zhou Yadi , Park Chihyun , Hong Changjin , Vail Daniel , Silver Daniel J. , Lauko Adam , Roversi Gustavo , Watson Dionysios C. , Lo Alice , Alban Tyler J. , McGraw Mary , Sorensen Mia , Grabowski Matthew M. , Otvos Balint , Vogelbaum Michael A. , Horbinski Craig , Kristensen Bjarne Winther , Khalil Ahmad M. , Hwang Tae Hyun , Ahluwalia Manmeet S. , Cheng Feixiong , Lathia Justin D.
Published: March 2024

Abstract
Myeloid-derived suppressor cells (MDSC) that block antitumor immunity are elevated in glioblastoma (GBM) patient blood and tumors. However, the distinct contributions of monocytic (mMDSC) versus granulocytic (gMDSC) subsets have yet to be determined. In mouse models of GBM, we observed that mMDSCs were enriched in the male tumors, whereas gMDSCs were elevated in the blood of females. Depletion of gMDSCs extended survival only in female mice. Using gene-expression signatures coupled with network medicine analysis, we demonstrated in preclinical models that mMDSCs could be targeted with antiproliferative agents in males, whereas gMDSC function could be inhibited by IL1β blockade in females. Analysis of patient data confirmed that proliferating mMDSCs were predominant in male tumors and that a high gMDSC/IL1β gene signature correlated with poor prognosis in female patients. These findings demonstrate that MDSC subsets differentially drive immune suppression in a sex-specific manner and can be leveraged for therapeutic intervention in GBM.
Significance:
Sexual dimorphism at the level of MDSC subset prevalence, localization, and gene-expression profile constitutes a therapeutic opportunity. Our results indicate that chemotherapy can be used to target mMDSCs in males, whereas IL1 pathway inhibitors can provide benefit to females via inhibition of gMDSCs.

See related commentary by Gabrilovich et al., p. 1100.

This article is highlighted in the In This Issue feature, p. 1079
Data from Priority COVID-19 Vaccination for Patients with Cancer while Vaccine Supply Is Limited
Authors: Ribas Antoni , Sengupta Rajarshi , Locke Trevan , Zaidi Sayyed Kaleem , Campbell Katie M. , Carethers John M. , Jaffee Elizabeth M. , Wherry E. John , Soria Jean-Charles , D'Souza Gypsyamber
Published: March 2024

AbstractSummary:
Published series on COVID-19 support the notion that patients with cancer are a particularly vulnerable population. There is a confluence of risk factors between cancer and COVID-19, and cancer care and treatments increase exposure to the virus and may dampen natural immune responses. The available evidence supports the conclusion that patients with cancer, in particular with hematologic malignancies, should be considered among the very high-risk groups for priority COVID-19 vaccination.
Data from Acalabrutinib plus Obinutuzumab in Treatment-Naïve and Relapsed/Refractory Chronic Lymphocytic Leukemia
Authors: Woyach Jennifer A. , Blachly James S. , Rogers Kerry A. , Bhat Seema A. , Jianfar Mojgan , Lozanski Gerard , Weiss David M. , Andersen Barbara L. , Gulrajani Michael , Frigault Melanie M. , Hamdy Ahmed , Izumi Raquel , Munugalavadla Veerendra , Quah Cheng , Wang Min-Hui , Byrd John C.
Published: March 2024

Abstract
Acalabrutinib is a selective irreversible Bruton tyrosine kinase (BTK) inhibitor that does not affect IL2-associated tyrosine kinase or antibody-dependent cellular cytotoxicity, making it an attractive candidate for combination therapy with anti-CD20 antibodies. We investigated acalabrutinib plus obinutuzumab in a phase Ib/II study (NCT02296918) of patients with treatment-naïve or relapsed/refractory chronic lymphocytic leukemia (CLL). Nineteen treatment-naïve and 26 relapsed/refractory patients were treated with acalabrutinib (100 mg twice daily) until progression and obinutuzumab (cycle 1: 100 mg day 1, 900 mg day 2, 1000 mg days 8 and 15; cycles 2–6: 1,000 mg day 1). Grade 3/4 adverse events occurred in 71% of patients. Overall response rates were 95% (treatment-naïve) and 92% (relapsed/refractory). Thirty-two percent of treatment-naïve and 8% of relapsed/refractory patients achieved complete remission. At 36 months, 94% (treatment-naïve) and 88% (relapsed/refractory) were progression free. Acalabrutinib plus obinutuzumab was well tolerated, producing high and durable responses in treatment-naïve and relapsed/refractory CLL.
Significance:
Rituximab plus the less selective BTK inhibitor ibrutinib has not shown benefit in CLL; however, the selective BTK inhibitor acalabrutinib plus the antibody-dependent cellular cytotoxicity–enhanced antibody obinutuzumab yielded durable responses that deepened over time in treatment-naïve and relapsed/refractory CLL, supporting the evaluation of this approach in larger, comparative studies in CLL.

This article is highlighted in the In This Issue feature, p. 327
Data from Tumor Microenvironment Is Critical for the Maintenance of Cellular States Found in Primary Glioblastomas
Authors: Pine Allison R. , Cirigliano Stefano M. , Nicholson James G. , Hu Yang , Linkous Amanda , Miyaguchi Ken , Edwards Lincoln , Singhania Richa , Schwartz Theodore H. , Ramakrishna Rohan , Pisapia David J. , Snuderl Matija , Elemento Olivier , Fine Howard A.
Published: March 2024

Abstract
Glioblastoma (GBM), an incurable tumor, remains difficult to model and more importantly to treat due to its genetic/epigenetic heterogeneity and plasticity across cellular states. The ability of current tumor models to recapitulate the cellular states found in primary tumors remains unexplored. To address this issue, we compared single-cell RNA sequencing of tumor cells from 5 patients across four patient-specific glioblastoma stem cell (GSC)–derived model types, including glioma spheres, tumor organoids, glioblastoma cerebral organoids (GLICO), and patient-derived xenografts. We find that GSCs within the GLICO model are enriched for a neural progenitor–like cell subpopulation and recapitulate the cellular states and their plasticity found in the corresponding primary parental tumors. These data demonstrate how the contribution of a neuroanatomically accurate human microenvironment is critical and sufficient for recapitulating the cellular states found in human primary GBMs, a principle that may likely apply to other tumor models.
Significance:
It has been unclear how well different patient-derived GBM models are able to recreate the full heterogeneity of primary tumors. Here, we provide a complete transcriptomic characterization of the major model types. We show that the microenvironment is crucial for recapitulating GSC cellular states, highlighting the importance of tumor–host cell interactions.

See related commentary by Luo and Weiss, p. 907.

This article is highlighted in the In This Issue feature, p. 890
Data from Single-Cell Transcriptome Analysis Reveals Disease-Defining T-cell Subsets in the Tumor Microenvironment of Classic Hodgkin Lymphoma
Authors: Aoki Tomohiro , Chong Lauren C. , Takata Katsuyoshi , Milne Katy , Hav Monirath , Colombo Anthony , Chavez Elizabeth A. , Nissen Michael , Wang Xuehai , Miyata-Takata Tomoko , Lam Vivian , Viganò Elena , Woolcock Bruce W. , Telenius Adèle , Li Michael Y. , Healy Shannon , Ghesquiere Chanel , Kos Daniel , Goodyear Talia , Veldman Johanna , Zhang Allen W. , Kim Jubin , Saberi Saeed , Ding Jiarui , Farinha Pedro , Weng Andrew P. , Savage Kerry J. , Scott David W. , Krystal Gerald , Nelson Brad H. , Mottok Anja , Merchant Akil , Shah Sohrab P. , Steidl Christian
Published: March 2024

Abstract
Hodgkin lymphoma is characterized by an extensively dominant tumor microenvironment (TME) composed of different types of noncancerous immune cells with rare malignant cells. Characterization of the cellular components and their spatial relationship is crucial to understanding cross-talk and therapeutic targeting in the TME. We performed single-cell RNA sequencing of more than 127,000 cells from 22 Hodgkin lymphoma tissue specimens and 5 reactive lymph nodes, profiling for the first time the phenotype of the Hodgkin lymphoma–specific immune microenvironment at single-cell resolution. Single-cell expression profiling identified a novel Hodgkin lymphoma–associated subset of T cells with prominent expression of the inhibitory receptor LAG3, and functional analyses established this LAG3+ T-cell population as a mediator of immunosuppression. Multiplexed spatial assessment of immune cells in the microenvironment also revealed increased LAG3+ T cells in the direct vicinity of MHC class II–deficient tumor cells. Our findings provide novel insights into TME biology and suggest new approaches to immune-checkpoint targeting in Hodgkin lymphoma.
Significance:
We provide detailed functional and spatial characteristics of immune cells in classic Hodgkin lymphoma at single-cell resolution. Specifically, we identified a regulatory T-cell–like immunosuppressive subset of LAG3+ T cells contributing to the immune-escape phenotype. Our insights aid in the development of novel biomarkers and combination treatment strategies targeting immune checkpoints.

See related commentary by Fisher and Oh, p. 342.

This article is highlighted in the In This Issue feature, p. 327
Data from Mutant BRAF and MEK Inhibitors Regulate the Tumor Immune Microenvironment via Pyroptosis
Authors: Erkes Dan A. , Cai Weijia , Sanchez Ileine M. , Purwin Timothy J. , Rogers Corey , Field Conroy O. , Berger Adam C. , Hartsough Edward J. , Rodeck Ulrich , Alnemri Emad S. , Aplin Andrew E.
Published: March 2024

Abstract
Combinations of BRAF inhibitors and MEK inhibitors (BRAFi + MEKi) are FDA-approved to treat BRAFV600E/K-mutant melanoma. Efficacy of BRAFi + MEKi associates with cancer cell death and alterations in the tumor immune microenvironment; however, the links are poorly understood. We show that BRAFi + MEKi caused durable melanoma regression in an immune-mediated manner. BRAFi + MEKi treatment promoted cleavage of gasdermin E (GSDME) and release of HMGB1, markers of pyroptotic cell death. GSDME-deficient melanoma showed defective HMGB1 release, reduced tumor-associated T cell and activated dendritic cell infiltrates in response to BRAFi + MEKi, and more frequent tumor regrowth after drug removal. Importantly, BRAFi + MEKi–resistant disease lacked pyroptosis markers and showed decreased intratumoral T-cell infiltration but was sensitive to pyroptosis-inducing chemotherapy. These data implicate BRAFi + MEKi–induced pyroptosis in antitumor immune responses and highlight new therapeutic strategies for resistant melanoma.
Significance:
Targeted inhibitors and immune checkpoint agents have advanced the care of patients with melanoma; however, detailed knowledge of the intersection between these two research areas is lacking. We describe a molecular mechanism of targeted inhibitor regulation of an immune-stimulatory form of cell death and provide a proof-of-principle salvage therapy concept for inhibitor-resistant melanoma.

See related commentary by Smalley, p. 176.

This article is highlighted in the In This Issue feature, p. 161
Data from Single-Cell RNA Sequencing Reveals Stromal Evolution into LRRC15+ Myofibroblasts as a Determinant of Patient Response to Cancer Immunotherapy
Authors: Dominguez Claudia X. , Müller Sören , Keerthivasan Shilpa , Koeppen Hartmut , Hung Jeffrey , Gierke Sarah , Breart Beatrice , Foreman Oded , Bainbridge Travis W. , Castiglioni Alessandra , Senbabaoglu Yasin , Modrusan Zora , Liang Yuxin , Junttila Melissa R. , Klijn Christiaan , Bourgon Richard , Turley Shannon J.
Published: March 2024

Abstract
With only a fraction of patients responding to cancer immunotherapy, a better understanding of the entire tumor microenvironment is needed. Using single-cell transcriptomics, we chart the fibroblastic landscape during pancreatic ductal adenocarcinoma (PDAC) progression in animal models. We identify a population of carcinoma-associated fibroblasts (CAF) that are programmed by TGFβ and express the leucine-rich repeat containing 15 (LRRC15) protein. These LRRC15+ CAFs surround tumor islets and are absent from normal pancreatic tissue. The presence of LRRC15+ CAFs in human patients was confirmed in >80,000 single cells from 22 patients with PDAC as well as by using IHC on samples from 70 patients. Furthermore, immunotherapy clinical trials comprising more than 600 patients across six cancer types revealed elevated levels of the LRRC15+ CAF signature correlated with poor response to anti–PD-L1 therapy. This work has important implications for targeting nonimmune elements of the tumor microenvironment to boost responses of patients with cancer to immune checkpoint blockade therapy.
Significance:
This study describes the single-cell landscape of CAFs in pancreatic cancer during in vivo tumor evolution. A TGFβ-driven, LRRC15+ CAF lineage is associated with poor outcome in immunotherapy trial data comprising multiple solid-tumor entities and represents a target for combinatorial therapy.

This article is highlighted in the In This Issue feature, p. 161
Data from HER2-Mediated Internalization of Cytotoxic Agents in ERBB2 Amplified or Mutant Lung Cancers
Authors: Li Bob T. , Michelini Flavia , Misale Sandra , Cocco Emiliano , Baldino Laura , Cai Yanyan , Shifman Sophie , Tu Hai-Yan , Myers Mackenzie L. , Xu Chongrui , Mattar Marissa , Khodos Inna , Little Megan , Qeriqi Besnik , Weitsman Gregory , Wilhem Clare J. , Lalani Alshad S. , Diala Irmina , Freedman Rachel A. , Lin Nancy U. , Solit David B. , Berger Michael F. , Barber Paul R. , Ng Tony , Offin Michael , Isbell James M. , Jones David R. , Yu Helena A. , Thyparambil Sheeno , Liao Wei-Li , Bhalkikar Anuja , Cecchi Fabiola , Hyman David M. , Lewis Jason S. , Buonocore Darren J. , Ho Alan L. , Makker Vicky , Reis-Filho Jorge S. , Razavi Pedram , Arcila Maria E. , Kris Mark G. , Poirier John T. , Shen Ronglai , Tsurutani Junji , Ulaner Gary A. , de Stanchina Elisa , Rosen Neal , Rudin Charles M. , Scaltriti Maurizio
Published: March 2024

Abstract
Amplification of and oncogenic mutations in ERBB2, the gene encoding the HER2 receptor tyrosine kinase, promote receptor hyperactivation and tumor growth. Here we demonstrate that HER2 ubiquitination and internalization, rather than its overexpression, are key mechanisms underlying endocytosis and consequent efficacy of the anti-HER2 antibody–drug conjugates (ADC) ado-trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) in lung cancer cell lines and patient-derived xenograft models. These data translated into a 51% response rate in a clinical trial of T-DM1 in 49 patients with ERBB2-amplified or -mutant lung cancers. We show that cotreatment with irreversible pan-HER inhibitors enhances receptor ubiquitination and consequent ADC internalization and efficacy. We also demonstrate that ADC switching to T-DXd, which harbors a different cytotoxic payload, achieves durable responses in a patient with lung cancer and corresponding xenograft model developing resistance to T-DM1. Our findings may help guide future clinical trials and expand the field of ADC as cancer therapy.
Significance:
T-DM1 is clinically effective in lung cancers with amplification of or mutations in ERBB2. This activity is enhanced by cotreatment with irreversible pan-HER inhibitors, or ADC switching to T-DXd. These results may help address unmet needs of patients with HER2-activated tumors and no approved targeted therapy.

See related commentary by Rolfo and Russo, p. 643.

This article is highlighted in the In This Issue feature, p. 627
Data from Epigenetic Suppression of Transgenic T-cell Receptor Expression via Gamma-Retroviral Vector Methylation in Adoptive Cell Transfer Therapy
Authors: Nowicki Theodore S. , Farrell Colin , Morselli Marco , Rubbi Liudmilla , Campbell Katie M. , Macabali Mignonette H. , Berent-Maoz Beata , Comin-Anduix Begoña , Pellegrini Matteo , Ribas Antoni
Published: March 2024

Abstract
Transgenic T-cell receptor (TCR) adoptive cell therapies recognizing tumor antigens are associated with robust initial response rates, but frequent disease relapse. This usually occurs in the setting of poor long-term persistence of cells expressing the transgenic TCR, generated using murine stem cell virus (MSCV) γ-retroviral vectors. Analysis of clinical transgenic adoptive cell therapy products in vivo revealed that despite strong persistence of the transgenic TCR DNA sequence over time, its expression was profoundly decreased over time at the RNA and protein levels. Patients with the greatest degrees of expression suppression displayed significant increases in DNA methylation over time within the MSCV promoter region, as well as progressive increases in DNA methylation within the entire MSCV vector over time. These increases in vector methylation occurred independently of its integration site within the host genomes. These results have significant implications for the design of future viral vector gene–engineered adoptive cell transfer therapies.
Significance:
Cellular immunotherapies' reliance on retroviral vectors encoding foreign genetic material can be vulnerable to progressive acquisition of DNA methylation and subsequent epigenetic suppression of the transgenic product in TCR adoptive cell therapy. This must be considered in the design of future generations of cellular immunotherapies for cancer.

This article is highlighted in the In This Issue feature, p. 1611