bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Loss of PTEN Promotes Resistance to T Cell–Mediated Immunotherapy
Authors: Peng Weiyi , Chen Jie Qing , Liu Chengwen , Malu Shruti , Creasy Caitlin , Tetzlaff Michael T. , Xu Chunyu , McKenzie Jodi A. , Zhang Chunlei , Liang Xiaoxuan , Williams Leila J. , Deng Wanleng , Chen Guo , Mbofung Rina , Lazar Alexander J. , Torres-Cabala Carlos A. , Cooper Zachary A. , Chen Pei-Ling , Tieu Trang N. , Spranger Stefani , Yu Xiaoxing , Bernatchez Chantale , Forget Marie-Andree , Haymaker Cara , Amaria Rodabe , McQuade Jennifer L. , Glitza Isabella C. , Cascone Tina , Li Haiyan S. , Kwong Lawrence N. , Heffernan Timothy P. , Hu Jianhua , Bassett Roland L. , Bosenberg Marcus W. , Woodman Scott E. , Overwijk Willem W. , Lizée Gregory , Roszik Jason , Gajewski Thomas F. , Wargo Jennifer A. , Gershenwald Jeffrey E. , Radvanyi Laszlo , Davies Michael A. , Hwu Patrick
Published: March 2024

Abstract
T cell–mediated immunotherapies are promising cancer treatments. However, most patients still fail to respond to these therapies. The molecular determinants of immune resistance are poorly understood. We show that loss of PTEN in tumor cells in preclinical models of melanoma inhibits T cell–mediated tumor killing and decreases T-cell trafficking into tumors. In patients, PTEN loss correlates with decreased T-cell infiltration at tumor sites, reduced likelihood of successful T-cell expansion from resected tumors, and inferior outcomes with PD-1 inhibitor therapy. PTEN loss in tumor cells increased the expression of immunosuppressive cytokines, resulting in decreased T-cell infiltration in tumors, and inhibited autophagy, which decreased T cell–mediated cell death. Treatment with a selective PI3Kβ inhibitor improved the efficacy of both anti–PD-1 and anti–CTLA-4 antibodies in murine models. Together, these findings demonstrate that PTEN loss promotes immune resistance and support the rationale to explore combinations of immunotherapies and PI3K–AKT pathway inhibitors.

Significance: This study adds to the growing evidence that oncogenic pathways in tumors can promote resistance to the antitumor immune response. As PTEN loss and PI3K–AKT pathway activation occur in multiple tumor types, the results support the rationale to further evaluate combinatorial strategies targeting the PI3K–AKT pathway to increase the efficacy of immunotherapy. Cancer Discov; 6(2); 202–16. ©2015 AACR.

See related commentary by Rizvi and Chan, p. 128.

This article is highlighted in the In This Issue feature, p. 109
Data from Targeting Chromatin Regulators Inhibits Leukemogenic Gene Expression in NPM1 Mutant Leukemia
Authors: Kühn Michael W.M. , Song Evelyn , Feng Zhaohui , Sinha Amit , Chen Chun-Wei , Deshpande Aniruddha J. , Cusan Monica , Farnoud Noushin , Mupo Annalisa , Grove Carolyn , Koche Richard , Bradner James E. , de Stanchina Elisa , Vassiliou George S. , Hoshii Takayuki , Armstrong Scott A.
Published: March 2024

Abstract
Homeobox (HOX) proteins and the receptor tyrosine kinase FLT3 are frequently highly expressed and mutated in acute myeloid leukemia (AML). Aberrant HOX expression is found in nearly all AMLs that harbor a mutation in the Nucleophosmin (NPM1) gene, and FLT3 is concomitantly mutated in approximately 60% of these cases. Little is known about how mutant NPM1 (NPM1mut) cells maintain aberrant gene expression. Here, we demonstrate that the histone modifiers MLL1 and DOT1L control HOX and FLT3 expression and differentiation in NPM1mut AML. Using a CRISPR/Cas9 genome editing domain screen, we show NPM1mut AML to be exceptionally dependent on the menin binding site in MLL1. Pharmacologic small-molecule inhibition of the menin–MLL1 protein interaction had profound antileukemic activity in human and murine models of NPM1mut AML. Combined pharmacologic inhibition of menin–MLL1 and DOT1L resulted in dramatic suppression of HOX and FLT3 expression, induction of differentiation, and superior activity against NPM1mut leukemia.

Significance: MLL1 and DOT1L are chromatin regulators that control HOX, MEIS1, and FLT3 expression and are therapeutic targets in NPM1mut AML. Combinatorial small-molecule inhibition has synergistic on-target activity and constitutes a novel therapeutic concept for this common AML subtype. Cancer Discov; 6(10); 1166–81. ©2016 AACR.

See related commentary by Hourigan and Aplan, p. 1087.

This article is highlighted in the In This Issue feature, p. 1069
Data from Genomics of Ovarian Cancer Progression Reveals Diverse Metastatic Trajectories Including Intraepithelial Metastasis to the Fallopian Tube
Authors: Eckert Mark A. , Pan Shawn , Hernandez Kyle M. , Loth Rachel M. , Andrade Jorge , Volchenboum Samuel L. , Faber Pieter , Montag Anthony , Lastra Ricardo , Peter Marcus E. , Yamada S. Diane , Lengyel Ernst
Published: March 2024

Abstract
Accumulating evidence has supported the fallopian tube rather than the ovary as the origin for high-grade serous ovarian cancer (HGSOC). To understand the relationship between putative precursor lesions and metastatic tumors, we performed whole-exome sequencing on specimens from eight HGSOC patient progression series consisting of serous tubal intraepithelial carcinomas (STIC), invasive fallopian tube lesions, invasive ovarian lesions, and omental metastases. Integration of copy number and somatic mutations revealed patient-specific patterns with similar mutational signatures and copy-number variation profiles across all anatomic sites, suggesting that genomic instability is an early event in HGSOC. Phylogenetic analyses supported STIC as precursor lesions in half of our patient cohort, but also identified STIC as metastases in 2 patients. Ex vivo assays revealed that HGSOC spheroids can implant in the fallopian tube epithelium and mimic STIC lesions. That STIC may represent metastases calls into question the assumption that STIC are always indicative of primary fallopian tube cancers.

Significance: We find that the putative precursor lesions for HGSOC, STIC, possess most of the genomic aberrations present in advanced cancers. In addition, a proportion of STIC represent intraepithelial metastases to the fallopian tube rather than the origin of HGSOC. Cancer Discov; 6(12); 1342–51. ©2016 AACR.

See related commentary by Swisher et al., p. 1309.

This article is highlighted in the In This Issue feature, p. 1293
Data from Immunogenomics of Hypermutated Glioblastoma: A Patient with Germline POLE Deficiency Treated with Checkpoint Blockade Immunotherapy
Authors: Johanns Tanner M. , Miller Christopher A. , Dorward Ian G. , Tsien Christina , Chang Edward , Perry Arie , Uppaluri Ravindra , Ferguson Cole , Schmidt Robert E. , Dahiya Sonika , Ansstas George , Mardis Elaine R. , Dunn Gavin P.
Published: March 2024

Abstract
We present the case of a patient with a left frontal glioblastoma with primitive neuroectodermal tumor features and hypermutated genotype in the setting of a POLE germline alteration. During standard-of-care chemoradiation, the patient developed a cervical spine metastasis and was subsequently treated with pembrolizumab. Shortly thereafter, the patient developed an additional metastatic spinal lesion. Using whole-exome DNA sequencing and clonal analysis, we report changes in the subclonal architecture throughout treatment. Furthermore, a persistently high neoantigen load was observed within all tumors. Interestingly, following initiation of pembrolizumab, brisk lymphocyte infiltration was observed in the subsequently resected metastatic spinal lesion and an objective radiographic response was noted in a progressive intracranial lesion, suggestive of active central nervous system (CNS) immunosurveillance following checkpoint blockade therapy.

Significance: It is unclear whether hypermutated glioblastomas are susceptible to checkpoint blockade in adults. Herein, we provide proof of principle that glioblastomas with DNA-repair defects treated with checkpoint blockade may result in CNS immune activation, leading to clinically and immunologically significant responses. These patients may represent a genomically stratified group for whom immunotherapy could be considered. Cancer Discov; 6(11); 1230–6. ©2016 AACR.

See related commentary by Snyder and Wolchok, p. 1210.

This article is highlighted in the In This Issue feature, p. 1197
Data from Integrin-α10 Dependency Identifies RAC and RICTOR as Therapeutic Targets in High-Grade Myxofibrosarcoma
Authors: Okada Tomoyo , Lee Ann Y. , Qin Li-Xuan , Agaram Narasimhan , Mimae Takahiro , Shen Yawei , O'Connor Rachael , López-Lago Miguel A. , Craig Amanda , Miller Martin L. , Agius Phaedra , Molinelli Evan , Socci Nicholas D. , Crago Aimee M. , Shima Fumi , Sander Chris , Singer Samuel
Published: March 2024

Abstract
Myxofibrosarcoma is a common mesenchymal malignancy with complex genomics and heterogeneous clinical outcomes. Through gene-expression profiling of 64 primary high-grade myxofibrosarcomas, we defined an expression signature associated with clinical outcome. The gene most significantly associated with disease-specific death and distant metastasis was ITGA10 (integrin-α10). Functional studies revealed that myxofibrosarcoma cells strongly depended on integrin-α10, whereas normal mesenchymal cells did not. Integrin-α10 transmitted its tumor-specific signal via TRIO and RICTOR, two oncoproteins that are frequently co-overexpressed through gene amplification on chromosome 5p. TRIO and RICTOR activated RAC/PAK and AKT/mTOR to promote sarcoma cell survival. Inhibition of these proteins with EHop-016 (RAC inhibitor) and INK128 (mTOR inhibitor) had antitumor effects in tumor-derived cell lines and mouse xenografts, and combining the drugs enhanced the effects. Our results demonstrate the importance of integrin-α10/TRIO/RICTOR signaling for driving myxofibrosarcoma progression and provide the basis for promising targeted treatment strategies for patients with high-risk disease.

Significance: Identifying the molecular pathogenesis for myxofibrosarcoma progression has proven challenging given the highly complex genomic alterations in this tumor type. We found that integrin-α10 promotes tumor cell survival through activation of TRIO–RAC–RICTOR–mTOR signaling, and that inhibitors of RAC and mTOR have antitumor effects in vivo, thus identifying a potential treatment strategy for patients with high-risk myxofibrosarcoma. Cancer Discov; 6(10); 1148–65. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 1069
Data from Infection Exposure Is a Causal Factor in B-cell Precursor Acute Lymphoblastic Leukemia as a Result of Pax5-Inherited Susceptibility
Authors: Martín-Lorenzo Alberto , Hauer Julia , Vicente-Dueñas Carolina , Auer Franziska , González-Herrero Inés , García-Ramírez Idoia , Ginzel Sebastian , Thiele Ralf , Constantinescu Stefan N. , Bartenhagen Christoph , Dugas Martin , Gombert Michael , Schäfer Daniel , Blanco Oscar , Mayado Andrea , Orfao Alberto , Alonso-López Diego , Rivas Javier De Las , Cobaleda César , García-Cenador Maria Begoña , García-Criado Francisco Javier , Sánchez-García Isidro , Borkhardt Arndt
Published: March 2024

Abstract
Earlier in the past century, infections were regarded as the most likely cause of childhood B-cell precursor acute lymphoblastic leukemia (pB-ALL). However, there is a lack of relevant biologic evidence supporting this hypothesis. We present in vivo genetic evidence mechanistically connecting inherited susceptibility to pB-ALL and postnatal infections by showing that pB-ALL was initiated in Pax5 heterozygous mice only when they were exposed to common pathogens. Strikingly, these murine pB-ALLs closely resemble the human disease. Tumor exome sequencing revealed activating somatic, nonsynonymous mutations of Jak3 as a second hit. Transplantation experiments and deep sequencing suggest that inactivating mutations in Pax5 promote leukemogenesis by creating an aberrant progenitor compartment that is susceptible to malignant transformation through accumulation of secondary Jak3 mutations. Thus, treatment of Pax5+/− leukemic cells with specific JAK1/3 inhibitors resulted in increased apoptosis. These results uncover the causal role of infection in pB-ALL development.

Significance: These results demonstrate that delayed infection exposure is a causal factor in pB-ALL. Therefore, these findings have critical implications for the understanding of the pathogenesis of leukemia and for the development of novel therapies for this disease. Cancer Discov; 5(12); 1328–43. ©2015 AACR.

See related commentary by Greaves and Müschen, p. 1244.

This article is highlighted in the In This Issue feature, p. 1225
Data from Mesothelin-Targeted CARs: Driving T Cells to Solid Tumors
Authors: Morello Aurore , Sadelain Michel , Adusumilli Prasad S.
Published: March 2024

Abstract
Chimeric antigen receptors (CAR) are synthetic receptors that target T cells to cell-surface antigens and augment T-cell function and persistence. Mesothelin is a cell-surface antigen implicated in tumor invasion, which is highly expressed in mesothelioma and lung, pancreas, breast, ovarian, and other cancers. Its low-level expression in mesothelia, however, commands thoughtful therapeutic interventions. Encouragingly, recent clinical trials evaluating active immunization or immunoconjugates in patients with pancreatic adenocarcinoma or mesothelioma have shown responses without toxicity. Altogether, these findings and preclinical CAR therapy models using either systemic or regional T-cell delivery argue favorably for mesothelin CAR therapy in multiple solid tumors.

Significance: Recent success obtained with adoptive transfer of CAR T cells targeting CD19 in patients with refractory hematologic malignancies has generated much enthusiasm for T-cell engineering and raises the prospect of implementing similar strategies for solid tumors. Mesothelin is expressed in a wide range and a high percentage of solid tumors, which we review here in detail. Mesothelin CAR therapy has the potential to treat multiple solid malignancies. Cancer Discov; 6(2); 133–46. ©2015 AACR.
Data from Mass Cytometric Functional Profiling of Acute Myeloid Leukemia Defines Cell-Cycle and Immunophenotypic Properties That Correlate with Known Responses to Therapy
Authors: Behbehani Gregory K. , Samusik Nikolay , Bjornson Zach B. , Fantl Wendy J. , Medeiros Bruno C. , Nolan Garry P.
Published: March 2024

Abstract
Acute myeloid leukemia (AML) is characterized by a high relapse rate that has been attributed to the quiescence of leukemia stem cells (LSC), which renders them resistant to chemotherapy. However, this hypothesis is largely supported by indirect evidence and fails to explain the large differences in relapse rates across AML subtypes. To address this, bone marrow aspirates from 41 AML patients and five healthy donors were analyzed by high-dimensional mass cytometry. All patients displayed immunophenotypic and intracellular signaling abnormalities within CD34+CD38lo populations, and several karyotype- and genotype-specific surface marker patterns were identified. The immunophenotypic stem and early progenitor cell populations from patients with clinically favorable core-binding factor AML demonstrated a 5-fold higher fraction of cells in S-phase compared with other AML samples. Conversely, LSCs in less clinically favorable FLT3-ITD AML exhibited dramatic reductions in S-phase fraction. Mass cytometry also allowed direct observation of the in vivo effects of cytotoxic chemotherapy.

Significance: The mechanisms underlying differences in relapse rates across AML subtypes are poorly understood. This study suggests that known chemotherapy sensitivities of common AML subsets are mediated by cell-cycle differences among LSCs and provides a basis for using in vivo functional characterization of AML cells to inform therapy selection. Cancer Discov; 5(9); 988–1003. ©2015 AACR.

See related commentary by Do and Byrd, p. 912.

This article is highlighted in the In This Issue feature, p. 893
Data from Tumor Cell–Independent Estrogen Signaling Drives Disease Progression through Mobilization of Myeloid-Derived Suppressor Cells
Authors: Svoronos Nikolaos , Perales-Puchalt Alfredo , Allegrezza Michael J. , Rutkowski Melanie R. , Payne Kyle K. , Tesone Amelia J. , Nguyen Jenny M. , Curiel Tyler J. , Cadungog Mark G. , Singhal Sunil , Eruslanov Evgeniy B. , Zhang Paul , Tchou Julia , Zhang Rugang , Conejo-Garcia Jose R.
Published: March 2024

Abstract
The role of estrogens in antitumor immunity remains poorly understood. Here, we show that estrogen signaling accelerates the progression of different estrogen-insensitive tumor models by contributing to deregulated myelopoiesis by both driving the mobilization of myeloid-derived suppressor cells (MDSC) and enhancing their intrinsic immunosuppressive activity in vivo. Differences in tumor growth are dependent on blunted antitumor immunity and, correspondingly, disappear in immunodeficient hosts and upon MDSC depletion. Mechanistically, estrogen receptor alpha activates the STAT3 pathway in human and mouse bone marrow myeloid precursors by enhancing JAK2 and SRC activity. Therefore, estrogen signaling is a crucial mechanism underlying pathologic myelopoiesis in cancer. Our work suggests that new antiestrogen drugs that have no agonistic effects may have benefits in a wide range of cancers, independently of the expression of estrogen receptors in tumor cells, and may synergize with immunotherapies to significantly extend survival.

Significance: Ablating estrogenic activity delays malignant progression independently of the tumor cell responsiveness, owing to a decrease in the mobilization and immunosuppressive activity of MDSCs, which boosts T-cell–dependent antitumor immunity. Our results provide a mechanistic rationale to block estrogen signaling with newer antagonists to boost the effectiveness of anticancer immunotherapies. Cancer Discov; 7(1); 72–85. ©2016 AACR.

See related commentary by Welte et al., p. 17.

This article is highlighted in the In This Issue feature, p. 1
Data from TGFβ1-Mediated SMAD3 Enhances PD-1 Expression on Antigen-Specific T Cells in Cancer
Authors: Park Benjamin V. , Freeman Zachary T. , Ghasemzadeh Ali , Chattergoon Michael A. , Rutebemberwa Alleluiah , Steigner Jordana , Winter Matthew E. , Huynh Thanh V. , Sebald Suzanne M. , Lee Se-Jin , Pan Fan , Pardoll Drew M. , Cox Andrea L.
Published: March 2024

Abstract
Programmed death-1 (PD-1) is a coinhibitory receptor that downregulates the activity of tumor-infiltrating lymphocytes (TIL) in cancer and of virus-specific T cells in chronic infection. The molecular mechanisms driving high PD-1 expression on TILs have not been fully investigated. We demonstrate that TGFβ1 enhances antigen-induced PD-1 expression through SMAD3-dependent, SMAD2-independent transcriptional activation in T cells in vitro and in TILs in vivo. The PD-1hi subset seen in CD8+ TILs is absent in Smad3-deficient tumor-specific CD8+ TILs, resulting in enhanced cytokine production by TILs and in draining lymph nodes and antitumor activity. In addition to TGFβ1′s previously known effects on T-cell function, our findings suggest that TGFβ1 mediates T-cell suppression via PD-1 upregulation in the tumor microenvironment (TME). They highlight bidirectional cross-talk between effector TILs and TGFβ-producing cells that upregulates multiple components of the PD-1 signaling pathway to inhibit antitumor immunity.

Significance: Engagement of the coinhibitory receptor PD-1 or its ligand, PD-L1, dramatically inhibits the antitumor function of TILs within the TME. Our findings represent a novel immunosuppressive function of TGFβ and demonstrate that TGFβ1 allows tumors to evade host immune responses in part through enhanced SMAD3-mediated PD-1 expression on TILs. Cancer Discov; 6(12); 1366–81. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 1293
Data from Blastic Plasmacytoid Dendritic Cell Neoplasm Is Dependent on BCL2 and Sensitive to Venetoclax
Authors: Montero Joan , Stephansky Jason , Cai Tianyu , Griffin Gabriel K. , Cabal-Hierro Lucia , Togami Katsuhiro , Hogdal Leah J. , Galinsky Ilene , Morgan Elizabeth A. , Aster Jon C. , Davids Matthew S. , LeBoeuf Nicole R. , Stone Richard M. , Konopleva Marina , Pemmaraju Naveen , Letai Anthony , Lane Andrew A.
Published: March 2024

Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive hematologic malignancy with dismal outcomes for which no standard therapy exists. We found that primary BPDCN cells were dependent on the antiapoptotic protein BCL2 and were uniformly sensitive to the BCL2 inhibitor venetoclax, as measured by direct cytotoxicity, apoptosis assays, and dynamic BH3 profiling. Animals bearing BPDCN patient–derived xenografts had disease responses and improved survival after venetoclax treatment in vivo. Finally, we report on 2 patients with relapsed/refractory BPDCN who received venetoclax off-label and experienced significant disease responses. We propose that venetoclax or other BCL2 inhibitors undergo expedited clinical evaluation in BPDCN, alone or in combination with other therapies. In addition, these data illustrate an example of precision medicine to predict treatment response using ex vivo functional assessment of primary tumor tissue, without requiring a genetic biomarker.

Significance: Therapy for BPDCN is inadequate, and survival in patients with the disease is poor. We used primary tumor cell functional profiling to predict BCL2 antagonist sensitivity as a common feature of BPDCN, and demonstrated in vivo clinical activity of venetoclax in patient-derived xenografts and in 2 patients with relapsed chemotherapy-refractory disease. Cancer Discov; 7(2); 156–64. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 115
Data from Tumor Cell–Driven Extracellular Matrix Remodeling Drives Haptotaxis during Metastatic Progression
Authors: Oudin Madeleine J. , Jonas Oliver , Kosciuk Tatsiana , Broye Liliane C. , Guido Bruna C. , Wyckoff Jeff , Riquelme Daisy , Lamar John M. , Asokan Sreeja B. , Whittaker Charlie , Ma Duanduan , Langer Robert , Cima Michael J. , Wisinski Kari B. , Hynes Richard O. , Lauffenburger Douglas A. , Keely Patricia J. , Bear James E. , Gertler Frank B.
Published: March 2024

Abstract
Fibronectin (FN) is a major component of the tumor microenvironment, but its role in promoting metastasis is incompletely understood. Here, we show that FN gradients elicit directional movement of breast cancer cells, in vitro and in vivo. Haptotaxis on FN gradients requires direct interaction between α5β1 integrin and MENA, an actin regulator, and involves increases in focal complex signaling and tumor cell–mediated extracellular matrix (ECM) remodeling. Compared with MENA, higher levels of the prometastatic MENAINV isoform associate with α5, which enables 3-D haptotaxis of tumor cells toward the high FN concentrations typically present in perivascular space and in the periphery of breast tumor tissue. MENAINV and FN levels were correlated in two breast cancer cohorts, and high levels of MENAINV were significantly associated with increased tumor recurrence as well as decreased patient survival. Our results identify a novel tumor cell–intrinsic mechanism that promotes metastasis through ECM remodeling and ECM-guided directional migration.

Significance: Here, we provide new insight into how tumor cell:ECM interactions generate signals and structures that promote directed tumor cell migration, a critical component of metastasis. Our results identify a tumor cell–intrinsic mechanism driven by the actin regulatory protein MENA that promotes ECM remodeling and haptotaxis along FN gradients. Cancer Discov; 6(5); 516–31. ©2016 AACR.

See related commentary by Santiago-Medina and Yang, p. 474.

This article is highlighted in the In This Issue feature, p. 461
Data from Hif1a Deletion Reveals Pro-Neoplastic Function of B Cells in Pancreatic Neoplasia
Authors: Lee Kyoung Eun , Spata Michelle , Bayne Lauren J. , Buza Elizabeth L. , Durham Amy C. , Allman David , Vonderheide Robert H. , Simon M. Celeste
Published: March 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related deaths worldwide, with an exceedingly low 5-year survival rate. PDAC tumors are characterized by an extensive desmoplastic stromal response and hypovascularity, suggesting that tumor hypoxia could regulate PDAC initiation and/or progression. Using a well-defined, autochthonous KrasG12D-driven murine model, as well as human tumors, we demonstrate that hypoxia and stabilization of hypoxia-inducible factor 1α (HIF1α), a principal mediator of hypoxic adaptation, emerge early during preinvasive stages of PDAC. Surprisingly, pancreas-specific Hif1a deletion drastically accelerated KrasG12D-driven pancreatic neoplasia and was accompanied by significant increases in intrapancreatic B lymphocytes, featuring prominent influx of a rare “B1b” B-cell subtype. Finally, treatment of HIF1α-deficient mice with B cell–depleting αCD20 monoclonal antibodies inhibited progression of pancreatic intraepithelial neoplasia (PanIN). Our data reveal a previously unrecognized role for B cells in promoting pancreatic tumorigenesis and implicate HIF1α as a critical regulator of PDAC development.

Significance: We show here that pancreas-specific Hif1a deletion promotes PDAC initiation, coincident with increased intrapancreatic accumulation of B cells, and that B-cell depletion suppresses pancreatic tumorigenesis. We therefore demonstrate a protective role for HIF1α in pancreatic cancer initiation and uncover a previously unrecognized function of B cells. Cancer Discov; 6(3); 256–69. ©2015 AACR.

See related commentary by Roghanian et al., p. 230.

See related article by Pylayeva-Gupta et al., p. 247.

See related article by Gunderson et al., p. 270.

This article is highlighted in the In This Issue feature, p. 217
Data from Chromosomal Instability Affects the Tumorigenicity of Glioblastoma Tumor-Initiating Cells
Authors: Godek Kristina M. , Venere Monica , Wu Quilian , Mills Kevin D. , Hickey William F. , Rich Jeremy N. , Compton Duane A.
Published: March 2024

Abstract
Tumors are dynamic organs that evolve during disease progression with genetic, epigenetic, and environmental differences among tumor cells serving as the foundation for selection and evolution in tumors. Tumor-initiating cells (TIC) that are responsible for tumorigenesis are a source of functional cellular heterogeneity, whereas chromosomal instability (CIN) is a source of karyotypic genetic diversity. However, the extent that CIN contributes to TIC genetic diversity and its relationship to TIC function remains unclear. Here, we demonstrate that glioblastoma TICs display CIN with lagging chromosomes at anaphase and extensive nonclonal chromosome copy-number variations. Elevating the basal chromosome missegregation rate in TICs decreases both proliferation and the stem-like phenotype of TICs in vitro. Consequently, tumor formation is abolished in an orthotopic mouse model. These results demonstrate that TICs generate genetic heterogeneity within tumors, but that TIC function is impaired if the rate of genetic change is elevated above a tolerable threshold.

Significance: Genetic heterogeneity among TICs may produce advantageous karyotypes that lead to therapy resistance and relapse; however, we found that TICs have an upper tolerable limit for CIN. Thus, increasing the chromosome missegregation rate offers a new therapeutic strategy to eliminate TICs from tumors. Cancer Discov; 6(5); 532–45. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 461
Data from Clinical Response of Carcinomas Harboring the BRD4–NUT Oncoprotein to the Targeted Bromodomain Inhibitor OTX015/MK-8628
Authors: Stathis Anastasios , Zucca Emanuele , Bekradda Mohamed , Gomez-Roca Carlos , Delord Jean-Pierre , de La Motte Rouge Thibault , Uro-Coste Emmanuelle , de Braud Filippo , Pelosi Giuseppe , French Christopher A.
Published: March 2024

Abstract
The antineoplastic, prodifferentiative effects of bromodomain and extra-terminal (BET) bromodomain (BRD) inhibitors were initially discovered in NUT midline carcinoma (NMC), an aggressive subtype of squamous cancer driven by the BRD4–NUT fusion oncoprotein. BRD4–NUT blocks differentiation and maintains tumor growth through a potent chromatin-modifying mechanism. OTX015/MK-8628, a novel oral BET inhibitor, targets BRD2/3/4/T with preclinical activity in NMC and several other tumor types and is currently in clinical development. Antitumor activity was evaluated in four patients with advanced-stage NMC with confirmed BRD4–NUT fusions who were treated with 80 mg OTX015/MK-8628 once daily in a compassionate-use context. Two patients responded rapidly with tumor regression and symptomatic relief, and a third had meaningful disease stabilization with a minor metabolic response. The main side effects were mild to moderate gastrointestinal toxicity and fatigue, and reversible grade 3 thrombocytopenia. This is the first proof-of-concept evidence of clinical activity of a BRD inhibitor in targeting BRD4–NUT.

Significance: We present the first clinical proof-of-concept that targeting BRD4–NUT with a BET inhibitor results in impressive and rapid antitumor activity in NMC. It offers strong potential for future clinical application in this rare patient population as either a single agent or in combination with other agents. Cancer Discov; 6(5); 492–500. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 461
Data from Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK-Rearranged Lung Cancer
Authors: Gainor Justin F. , Dardaei Leila , Yoda Satoshi , Friboulet Luc , Leshchiner Ignaty , Katayama Ryohei , Dagogo-Jack Ibiayi , Gadgeel Shirish , Schultz Katherine , Singh Manrose , Chin Emily , Parks Melissa , Lee Dana , DiCecca Richard H. , Lockerman Elizabeth , Huynh Tiffany , Logan Jennifer , Ritterhouse Lauren L. , Le Long P. , Muniappan Ashok , Digumarthy Subba , Channick Colleen , Keyes Colleen , Getz Gad , Dias-Santagata Dora , Heist Rebecca S. , Lennerz Jochen , Sequist Lecia V. , Benes Cyril H. , Iafrate A. John , Mino-Kenudson Mari , Engelman Jeffrey A. , Shaw Alice T.
Published: March 2024

Abstract
Advanced, anaplastic lymphoma kinase (ALK)–positive lung cancer is currently treated with the first-generation ALK inhibitor crizotinib followed by more potent, second-generation ALK inhibitors (e.g., ceritinib and alectinib) upon progression. Second-generation inhibitors are generally effective even in the absence of crizotinib-resistant ALK mutations, likely reflecting incomplete inhibition of ALK by crizotinib in many cases. Herein, we analyzed 103 repeat biopsies from ALK-positive patients progressing on various ALK inhibitors. We find that each ALK inhibitor is associated with a distinct spectrum of ALK resistance mutations and that the frequency of one mutation, ALKG1202R, increases significantly after treatment with second-generation agents. To investigate strategies to overcome resistance to second-generation ALK inhibitors, we examine the activity of the third-generation ALK inhibitor lorlatinib in a series of ceritinib-resistant, patient-derived cell lines, and observe that the presence of ALK resistance mutations is highly predictive for sensitivity to lorlatinib, whereas those cell lines without ALK mutations are resistant.

Significance: Secondary ALK mutations are a common resistance mechanism to second-generation ALK inhibitors and predict for sensitivity to the third-generation ALK inhibitor lorlatinib. These findings highlight the importance of repeat biopsies and genotyping following disease progression on targeted therapies, particularly second-generation ALK inhibitors. Cancer Discov; 6(10); 1118–33. ©2016 AACR.

See related commentary by Qiao and Lovly, p. 1084.

This article is highlighted in the In This Issue feature, p. 1069
Data from MYC Drives Pten/Trp53-Deficient Proliferation and Metastasis due to IL6 Secretion and AKT Suppression via PHLPP2
Authors: Nowak Dawid G. , Cho Hyejin , Herzka Tali , Watrud Kaitlin , DeMarco Daniel V. , Wang Victoria M.Y. , Senturk Serif , Fellmann Christof , Ding David , Beinortas Tumas , Kleinman David , Chen Muhan , Sordella Raffaella , Wilkinson John E. , Castillo-Martin Mireia , Cordon-Cardo Carlos , Robinson Brian D. , Trotman Lloyd C.
Published: March 2024

Abstract
We have recently recapitulated metastasis of human PTEN/TP53–mutant prostate cancer in the mouse using the RapidCaP system. Surprisingly, we found that this metastasis is driven by MYC, and not AKT, activation. Here, we show that cell–cell communication by IL6 drives the AKT–MYC switch through activation of the AKT-suppressing phosphatase PHLPP2, when PTEN and p53 are lost together, but not separately. IL6 then communicates a downstream program of STAT3-mediated MYC activation, which drives cell proliferation. Similarly, in tissues, peak proliferation in Pten/Trp53–mutant primary and metastatic prostate cancer does not correlate with activated AKT, but with STAT3/MYC activation instead. Mechanistically, MYC strongly activates the AKT phosphatase PHLPP2 in primary cells and prostate cancer metastasis. We show genetically that Phlpp2 is essential for dictating the proliferation of MYC-mediated AKT suppression. Collectively, our data reveal competition between two proto-oncogenes, MYC and AKT, which ensnarls the Phlpp2 gene to facilitate MYC-driven prostate cancer metastasis after loss of Pten and Trp53.

Significance: Our data identify IL6 detection as a potential causal biomarker for MYC-driven metastasis after loss of PTEN and p53. Second, our finding that MYC then must supersede AKT to drive cell proliferation points to MYC inhibition as a critical part of PI3K pathway therapy in lethal prostate cancer. Cancer Discov; 5(6); 636–51. ©2015 AACR.

This article is highlighted in the In This Issue feature, p. 565
Data from Neutrophils Suppress Intraluminal NK Cell–Mediated Tumor Cell Clearance and Enhance Extravasation of Disseminated Carcinoma Cells
Authors: Spiegel Asaf , Brooks Mary W. , Houshyar Samin , Reinhardt Ferenc , Ardolino Michele , Fessler Evelyn , Chen Michelle B. , Krall Jordan A. , DeCock Jasmine , Zervantonakis Ioannis K. , Iannello Alexandre , Iwamoto Yoshiko , Cortez-Retamozo Virna , Kamm Roger D. , Pittet Mikael J. , Raulet David H. , Weinberg Robert A.
Published: March 2024

Abstract
Immune cells promote the initial metastatic dissemination of carcinoma cells from primary tumors. In contrast to their well-studied functions in the initial stages of metastasis, the specific roles of immunocytes in facilitating progression through the critical later steps of the invasion–metastasis cascade remain poorly understood. Here, we define novel functions of neutrophils in promoting intraluminal survival and extravasation at sites of metastatic dissemination. We show that CD11b+/Ly6G+ neutrophils enhance metastasis formation via two distinct mechanisms. First, neutrophils inhibit natural killer cell function, which leads to a significant increase in the intraluminal survival time of tumor cells. Thereafter, neutrophils operate to facilitate extravasation of tumor cells through the secretion of IL1β and matrix metalloproteinases. These results identify neutrophils as key regulators of intraluminal survival and extravasation through their cross-talk with host cells and disseminating carcinoma cells.

Significance: This study provides important insights into the systemic contributions of neutrophils to cancer metastasis by identifying how neutrophils facilitate intermediate steps of the invasion–metastasis cascade. We demonstrate that neutrophils suppress natural killer cell activity and increase extravasation of tumor cells. Cancer Discov; 6(6); 630–49. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 561
Data from Tracking the Genomic Evolution of Esophageal Adenocarcinoma through Neoadjuvant Chemotherapy
Authors: Murugaesu Nirupa , Wilson Gareth A. , Birkbak Nicolai J. , Watkins Thomas B.K. , McGranahan Nicholas , Kumar Sacheen , Abbassi-Ghadi Nima , Salm Max , Mitter Richard , Horswell Stuart , Rowan Andrew , Phillimore Benjamin , Biggs Jennifer , Begum Sharmin , Matthews Nik , Hochhauser Daniel , Hanna George B. , Swanton Charles
Published: March 2024

Abstract
Esophageal adenocarcinomas are associated with a dismal prognosis. Deciphering the evolutionary history of this disease may shed light on therapeutically tractable targets and reveal dynamic mutational processes during the disease course and following neoadjuvant chemotherapy (NAC). We exome sequenced 40 tumor regions from 8 patients with operable esophageal adenocarcinomas, before and after platinum-containing NAC. This revealed the evolutionary genomic landscape of esophageal adenocarcinomas with the presence of heterogeneous driver mutations, parallel evolution, early genome-doubling events, and an association between high intratumor heterogeneity and poor response to NAC. Multiregion sequencing demonstrated a significant reduction in thymine to guanine mutations within a CpTpT context when comparing early and late mutational processes and the presence of a platinum signature with enrichment of cytosine to adenine mutations within a CpC context following NAC. Esophageal adenocarcinomas are characterized by early chromosomal instability leading to amplifications containing targetable oncogenes persisting through chemotherapy, providing a rationale for future therapeutic approaches.

Significance: This work illustrates dynamic mutational processes occurring during esophageal adenocarcinoma evolution and following selective pressures of platinum exposure, emphasizing the iatrogenic impact of therapy on cancer evolution. Identification of amplifications encoding targetable oncogenes maintained through NAC suggests the presence of stable vulnerabilities, unimpeded by cytotoxics, suitable for therapeutic intervention. Cancer Discov; 5(8); 821–31. ©2015 AACR.

See related commentary by Devarakonda and Govindan, p. 796.

This article is highlighted in the In This Issue feature, p. 783
Data from The CREBBP Acetyltransferase Is a Haploinsufficient Tumor Suppressor in B-cell Lymphoma
Authors: Zhang Jiyuan , Vlasevska Sofija , Wells Victoria A. , Nataraj Sarah , Holmes Antony B. , Duval Romain , Meyer Stefanie N. , Mo Tongwei , Basso Katia , Brindle Paul K. , Hussein Shafinaz , Dalla-Favera Riccardo , Pasqualucci Laura
Published: March 2024

Abstract
Inactivating mutations of the CREBBP acetyltransferase are highly frequent in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), the two most common germinal center (GC)–derived cancers. However, the role of CREBBP inactivation in lymphomagenesis remains unclear. Here, we show that CREBBP regulates enhancer/super-enhancer networks with central roles in GC/post-GC cell fate decisions, including genes involved in signal transduction by the B-cell receptor and CD40 receptor, transcriptional control of GC and plasma cell development, and antigen presentation. Consistently, Crebbp-deficient B cells exhibit enhanced response to mitogenic stimuli and perturbed plasma cell differentiation. Although GC-specific loss of Crebbp was insufficient to initiate malignant transformation, compound Crebbp-haploinsufficient/BCL2-transgenic mice, mimicking the genetics of FL and DLBCL, develop clonal lymphomas recapitulating the features of the human diseases. These findings establish CREBBP as a haploinsufficient tumor-suppressor gene in GC B cells and provide insights into the mechanisms by which its loss contributes to lymphomagenesis.

Significance: Loss-of-function mutations of CREBBP are common and early lesions in FL and DLBCL, suggesting a prominent role in lymphoma initiation. Our studies identify the cellular program by which reduced CREBBP dosage facilitates malignant transformation, and have direct implications for targeted lymphoma therapy based on drugs affecting CREBBP-mediated chromatin acetylation. Cancer Discov; 7(3); 322–37. ©2017 AACR.

This article is highlighted in the In This Issue feature, p. 235
Data from SD-101 in Combination with Pembrolizumab in Advanced Melanoma: Results of a Phase Ib, Multicenter Study
Authors: Ribas Antoni , Medina Theresa , Kummar Shivaani , Amin Asim , Kalbasi Anusha , Drabick Joseph J. , Barve Minal , Daniels Gregory A. , Wong Deborah J. , Schmidt Emmett V. , Candia Albert F. , Coffman Robert L. , Leung Abraham C.F. , Janssen Robert S.
Published: March 2024

Abstract
PD-1 inhibitors are approved for treating advanced melanoma, but resistance has been observed. This phase Ib trial evaluated intratumoral SD-101, a synthetic CpG oligonucleotide that stimulates Toll-like receptor 9 (TLR9), in combination with pembrolizumab in patients with unresectable or metastatic malignant melanoma. The most common adverse events related to SD-101 were injection-site reactions and transient, mild-to-moderate “flu-like” symptoms. Among the 9 patients naïve to anti–PD-1 therapy, the overall response rate (ORR) was 78%. The estimated 12-month progression-free survival rate was 88%, and the overall survival rate was 89%. Among 13 patients having prior anti–PD-1 therapy, the ORR was 15%. RNA profiling of tumor biopsies demonstrated increased CD8+ T cells, natural killer cells, cytotoxic cells, dendritic cells, and B cells. The combination of intratumoral SD-101 and pembrolizumab was well tolerated and induced broad immune activation in the tumor microenvironment with durable tumor responses in both peripheral and visceral lesions.

Significance: These early data demonstrate that the combination of pembrolizumab with intratumoral SD-101 is well tolerated and can induce immune activation at the tumor site. Combining an intratumoral TLR9 innate immune stimulant with PD-1 blockade can potentially increase clinical efficacy with minimal additional toxicity relative to PD-1 blockade alone. Cancer Discov; 8(10); 1250–7. ©2018 AACR.

This article is highlighted in the In This Issue feature, p. 1195
Data from Exome Sequencing of African-American Prostate Cancer Reveals Loss-of-Function ERF Mutations
Authors: Huang Franklin W. , Mosquera Juan Miguel , Garofalo Andrea , Oh Coyin , Baco Maria , Amin-Mansour Ali , Rabasha Bokang , Bahl Samira , Mullane Stephanie A. , Robinson Brian D. , Aldubayan Saud , Khani Francesca , Karir Beerinder , Kim Eejung , Chimene-Weiss Jeremy , Hofree Matan , Romanel Alessandro , Osborne Joseph R. , Kim Jong Wook , Azabdaftari Gissou , Woloszynska-Read Anna , Sfanos Karen , De Marzo Angelo M. , Demichelis Francesca , Gabriel Stacey , Van Allen Eliezer M. , Mesirov Jill , Tamayo Pablo , Rubin Mark A. , Powell Isaac J. , Garraway Levi A.
Published: March 2024

Abstract
African-American men have the highest incidence of and mortality from prostate cancer. Whether a biological basis exists for this disparity remains unclear. Exome sequencing (n = 102) and targeted validation (n = 90) of localized primary hormone-naïve prostate cancer in African-American men identified several gene mutations not previously observed in this context, including recurrent loss-of-function mutations in ERF, an ETS transcriptional repressor, in 5% of cases. Analysis of existing prostate cancer cohorts revealed ERF deletions in 3% of primary prostate cancers and mutations or deletions in ERF in 3% to 5% of lethal castration-resistant prostate cancers. Knockdown of ERF confers increased anchorage-independent growth and generates a gene expression signature associated with oncogenic ETS activation and androgen signaling. Together, these results suggest that ERF is a prostate cancer tumor-suppressor gene. More generally, our findings support the application of systematic cancer genomic characterization in settings of broader ancestral diversity to enhance discovery and, eventually, therapeutic applications.

Significance: Systematic genomic sequencing of prostate cancer in African-American men revealed new insights into prostate cancer, including the identification of ERF as a prostate cancer gene; somatic copy-number alteration differences; and uncommon PIK3CA and PTEN alterations. This study highlights the importance of inclusion of underrepresented minorities in cancer sequencing studies. Cancer Discov; 7(9); 973–83. ©2017 AACR.

This article is highlighted in the In This Issue feature, p. 920
Data from Genomic Landscape of Cell-Free DNA in Patients with Colorectal Cancer
Authors: Strickler John H. , Loree Jonathan M. , Ahronian Leanne G. , Parikh Aparna R. , Niedzwiecki Donna , Pereira Allan Andresson Lima , McKinney Matthew , Korn W. Michael , Atreya Chloe E. , Banks Kimberly C. , Nagy Rebecca J. , Meric-Bernstam Funda , Lanman Richard B. , Talasaz AmirAli , Tsigelny Igor F. , Corcoran Ryan B. , Kopetz Scott
Published: March 2024

Abstract
“Liquid biopsy” approaches analyzing cell-free DNA (cfDNA) from the blood of patients with cancer are increasingly utilized in clinical practice. However, it is not yet known whether cfDNA sequencing from large cohorts of patients with cancer can detect genomic alterations at frequencies similar to those observed by direct tumor sequencing, and whether this approach can generate novel insights. Here, we report next-generation sequencing data from cfDNA of 1,397 patients with colorectal cancer. Overall, frequencies of genomic alterations detected in cfDNA were comparable to those observed in three independent tissue-based colorectal cancer sequencing compendia. Our analysis also identified a novel cluster of extracellular domain (ECD) mutations in EGFR, mediating resistance by blocking binding of anti-EGFR antibodies. Patients with EGFR ECD mutations displayed striking tumor heterogeneity, with 91% harboring multiple distinct resistance alterations (range, 1–13; median, 4). These results suggest that cfDNA profiling can effectively define the genomic landscape of cancer and yield important biological insights.

Significance: This study provides one of the first examples of how large-scale genomic profiling of cfDNA from patients with colorectal cancer can detect genomic alterations at frequencies comparable to those observed by direct tumor sequencing. Sequencing of cfDNA also generated insights into tumor heterogeneity and therapeutic resistance and identified novel EGFR ectodomain mutations. Cancer Discov; 8(2); 164–73. ©2017 AACR.

This article is highlighted in the In This Issue feature, p. 127
Data from A Phase Ib Dose-Escalation Study of Encorafenib and Cetuximab with or without Alpelisib in Metastatic BRAF-Mutant Colorectal Cancer
Authors: van Geel Robin M.J.M. , Tabernero Josep , Elez Elena , Bendell Johanna C. , Spreafico Anna , Schuler Martin , Yoshino Takayuki , Delord Jean-Pierre , Yamada Yasuhide , Lolkema Martijn P. , Faris Jason E. , Eskens Ferry A.L.M. , Sharma Sunil , Yaeger Rona , Lenz Heinz-Josef , Wainberg Zev A. , Avsar Emin , Chatterjee Arkendu , Jaeger Savina , Tan Eugene , Maharry Kati , Demuth Tim , Schellens Jan H.M.
Published: March 2024

Abstract
Preclinical evidence suggests that concomitant BRAF and EGFR inhibition leads to sustained suppression of MAPK signaling and suppressed tumor growth in BRAFV600E colorectal cancer models. Patients with refractory BRAFV600-mutant metastatic CRC (mCRC) were treated with a selective RAF kinase inhibitor (encorafenib) plus a monoclonal antibody targeting EGFR (cetuximab), with (n = 28) or without (n = 26) a PI3Kα inhibitor (alpelisib). The primary objective was to determine the maximum tolerated dose (MTD) or a recommended phase II dose. Dose-limiting toxicities were reported in 3 patients receiving dual treatment and 2 patients receiving triple treatment. The MTD was not reached for either group and the phase II doses were selected as 200 mg encorafenib (both groups) and 300 mg alpelisib. Combinations of cetuximab and encorafenib showed promising clinical activity and tolerability in patients with BRAF-mutant mCRC; confirmed overall response rates of 19% and 18% were observed and median progression-free survival was 3.7 and 4.2 months for the dual- and triple-therapy groups, respectively.

Significance: Herein, we demonstrate that dual- (encorafenib plus cetuximab) and triple- (encorafenib plus cetuximab and alpelisib) combination treatments are tolerable and provide promising clinical activity in the difficult-to-treat patient population with BRAF-mutant mCRC. Cancer Discov; 7(6); 610–9. ©2017 AACR.

See related commentary by Sundar et al., p. 558.

This article is highlighted in the In This Issue feature, p. 539