bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Pathobiological Pseudohypoxia as a Putative Mechanism Underlying Myelodysplastic Syndromes
Authors: Hayashi Yoshihiro , Zhang Yue , Yokota Asumi , Yan Xiaomei , Liu Jinqin , Choi Kwangmin , Li Bing , Sashida Goro , Peng Yanyan , Xu Zefeng , Huang Rui , Zhang Lulu , Freudiger George M. , Wang Jingya , Dong Yunzhu , Zhou Yile , Wang Jieyu , Wu Lingyun , Bu Jiachen , Chen Aili , Zhao Xinghui , Sun Xiujuan , Chetal Kashish , Olsson Andre , Watanabe Miki , Romick-Rosendale Lindsey E. , Harada Hironori , Shih Lee-Yung , Tse William , Bridges James P. , Caligiuri Michael A. , Huang Taosheng , Zheng Yi , Witte David P. , Wang Qian-fei , Qu Cheng-Kui , Salomonis Nathan , Grimes H. Leighton , Nimer Stephen D. , Xiao Zhijian , Huang Gang
Published: March 2024

Abstract
Myelodysplastic syndromes (MDS) are heterogeneous hematopoietic disorders that are incurable with conventional therapy. Their incidence is increasing with global population aging. Although many genetic, epigenetic, splicing, and metabolic aberrations have been identified in patients with MDS, their clinical features are quite similar. Here, we show that hypoxia-independent activation of hypoxia-inducible factor 1α (HIF1A) signaling is both necessary and sufficient to induce dysplastic and cytopenic MDS phenotypes. The HIF1A transcriptional signature is generally activated in MDS patient bone marrow stem/progenitors. Major MDS-associated mutations (Dnmt3a, Tet2, Asxl1, Runx1, and Mll1) activate the HIF1A signature. Although inducible activation of HIF1A signaling in hematopoietic cells is sufficient to induce MDS phenotypes, both genetic and chemical inhibition of HIF1A signaling rescues MDS phenotypes in a mouse model of MDS. These findings reveal HIF1A as a central pathobiologic mediator of MDS and as an effective therapeutic target for a broad spectrum of patients with MDS.

Significance: We showed that dysregulation of HIF1A signaling could generate the clinically relevant diversity of MDS phenotypes by functioning as a signaling funnel for MDS driver mutations. This could resolve the disconnection between genotypes and phenotypes and provide a new clue as to how a variety of driver mutations cause common MDS phenotypes. Cancer Discov; 8(11); 1438–57. ©2018 AACR.

See related commentary by Chen and Steidl, p. 1355.

This article is highlighted in the In This Issue feature, p. 1333
Data from PTEN Methylation by NSD2 Controls Cellular Sensitivity to DNA Damage
Authors: Zhang Jinfang , Lee Yu-Ru , Dang Fabin , Gan Wenjian , Menon Archita Venugopal , Katon Jesse M. , Hsu Chih-Hung , Asara John M. , Tibarewal Priyanka , Leslie Nicholas R. , Shi Yang , Pandolfi Pier Paolo , Wei Wenyi
Published: March 2024

Abstract
The function of PTEN in the cytoplasm largely depends on its lipid-phosphatase activity, though which it antagonizes the PI3K–AKT oncogenic pathway. However, molecular mechanisms underlying the role of PTEN in the nucleus remain largely elusive. Here, we report that DNA double-strand breaks (DSB) promote PTEN interaction with MDC1 upon ATM-dependent phosphorylation of T/S398-PTEN. Importantly, DNA DSBs enhance NSD2 (MMSET/WHSC1)-mediated dimethylation of PTEN at K349, which is recognized by the tudor domain of 53BP1 to recruit PTEN to DNA-damage sites, governing efficient repair of DSBs partly through dephosphorylation of γH2AX. Of note, inhibiting NSD2-mediated methylation of PTEN, either through expressing methylation-deficient PTEN mutants or through inhibiting NSD2, sensitizes cancer cells to combinatorial treatment with a PI3K inhibitor and DNA-damaging agents in both cell culture and in vivo xenograft models. Therefore, our study provides a novel molecular mechanism for PTEN regulation of DSB repair in a methylation- and protein phosphatase–dependent manner.
Significance:
NSD2-mediated dimethylation of PTEN is recognized by the 53BP1 tudor domain to facilitate PTEN recruitment into DNA-damage sites, governing efficient repair of DNA DSBs. Importantly, inhibiting PTEN methylation sensitizes cancer cells to combinatorial treatment with a PI3K inhibitor combined with DNA-damaging agents in both cell culture and in vivo xenograft models.

This article is highlighted in the In This Issue feature, p. 1143
Data from A Preexisting Rare PIK3CAE545K Subpopulation Confers Clinical Resistance to MEK plus CDK4/6 Inhibition in NRAS Melanoma and Is Dependent on S6K1 Signaling
Authors: Romano Gabriele , Chen Pei-Ling , Song Ping , McQuade Jennifer L. , Liang Roger J. , Liu Mingguang , Roh Whijae , Duose Dzifa Y. , Carapeto Fernando C.L. , Li Jun , Teh Jessica L.F. , Aplin Andrew E. , Chen Merry , Zhang Jianhua , Lazar Alexander J. , Davies Michael A. , Futreal P. Andrew , Amaria Rodabe N. , Zhang David Y. , Wargo Jennifer A. , Kwong Lawrence N.
Published: March 2024

Abstract
Combined MEK and CDK4/6 inhibition (MEKi + CDK4i) has shown promising clinical outcomes in patients with NRAS-mutant melanoma. Here, we interrogated longitudinal biopsies from a patient who initially responded to MEKi + CDK4i therapy but subsequently developed resistance. Whole-exome sequencing and functional validation identified an acquired PIK3CAE545K mutation as conferring drug resistance. We demonstrate that PIK3CAE545K preexisted in a rare subpopulation that was missed by both clinical and research testing, but was revealed upon multiregion sampling due to PIK3CAE545K being nonuniformly distributed. This resistant population rapidly expanded after the initiation of MEKi + CDK4i therapy and persisted in all successive samples even after immune checkpoint therapy and distant metastasis. Functional studies identified activated S6K1 as both a key marker and specific therapeutic vulnerability downstream of PIK3CAE545K-induced resistance. These results demonstrate that difficult-to-detect preexisting resistance mutations may exist more often than previously appreciated and also posit S6K1 as a common downstream therapeutic nexus for the MAPK, CDK4/6, and PI3K pathways.

Significance: We report the first characterization of clinical acquired resistance to MEKi + CDK4i, identifying a rare preexisting PIK3CAE545K subpopulation that expands upon therapy and exhibits drug resistance. We suggest that single-region pretreatment biopsy is insufficient to detect rare, spatially segregated drug-resistant subclones. Inhibition of S6K1 is able to resensitize PIK3CAE545K-expressing NRAS-mutant melanoma cells to MEKi + CDK4i. Cancer Discov; 8(5); 556–67. ©2018 AACR.

See related commentary by Sullivan, p. 532.

See related article by Teh et al., p. 568.

This article is highlighted in the In This Issue feature, p. 517
Data from Acetyl-CoA Metabolism Supports Multistep Pancreatic Tumorigenesis
Authors: Carrer Alessandro , Trefely Sophie , Zhao Steven , Campbell Sydney L. , Norgard Robert J. , Schultz Kollin C. , Sidoli Simone , Parris Joshua L.D. , Affronti Hayley C. , Sivanand Sharanya , Egolf Shaun , Sela Yogev , Trizzino Marco , Gardini Alessandro , Garcia Benjamin A. , Snyder Nathaniel W. , Stanger Ben Z. , Wellen Kathryn E.
Published: March 2024

Abstract
Pancreatic ductal adenocarcinoma (PDA) has a poor prognosis, and new strategies for prevention and treatment are urgently needed. We previously reported that histone H4 acetylation is elevated in pancreatic acinar cells harboring Kras mutations prior to the appearance of premalignant lesions. Because acetyl-CoA abundance regulates global histone acetylation, we hypothesized that altered acetyl-CoA metabolism might contribute to metabolic or epigenetic alterations that promote tumorigenesis. We found that acetyl-CoA abundance is elevated in KRAS-mutant acinar cells and that its use in the mevalonate pathway supports acinar-to-ductal metaplasia (ADM). Pancreas-specific loss of the acetyl-CoA–producing enzyme ATP-citrate lyase (ACLY) accordingly suppresses ADM and tumor formation. In PDA cells, growth factors promote AKT–ACLY signaling and histone acetylation, and both cell proliferation and tumor growth can be suppressed by concurrent BET inhibition and statin treatment. Thus, KRAS-driven metabolic alterations promote acinar cell plasticity and tumor development, and targeting acetyl-CoA–dependent processes exerts anticancer effects.
Significance:
Pancreatic cancer is among the deadliest of human malignancies. We identify a key role for the metabolic enzyme ACLY, which produces acetyl-CoA, in pancreatic carcinogenesis. The data suggest that acetyl-CoA use for histone acetylation and in the mevalonate pathway facilitates cell plasticity and proliferation, suggesting potential to target these pathways.

See related commentary by Halbrook et al., p. 326.

This article is highlighted in the In This Issue feature, p. 305
Data from Recurrent Tumor Cell–Intrinsic and –Extrinsic Alterations during MAPKi-Induced Melanoma Regression and Early Adaptation
Authors: Song Chunying , Piva Marco , Sun Lu , Hong Aayoung , Moriceau Gatien , Kong Xiangju , Zhang Hong , Lomeli Shirley , Qian Jin , Yu Clarissa C. , Damoiseaux Robert , Kelley Mark C. , Dahlman Kimberley B. , Scumpia Philip O. , Sosman Jeffrey A. , Johnson Douglas B. , Ribas Antoni , Hugo Willy , Lo Roger S.
Published: March 2024

Abstract
Treatment of advanced BRAFV600-mutant melanoma using a BRAF inhibitor or its combination with a MEK inhibitor typically elicits partial responses. We compared the transcriptomes of patient-derived tumors regressing on MAPK inhibitor (MAPKi) therapy against MAPKi-induced temporal transcriptomic states in human melanoma cell lines or murine melanoma in immune-competent mice. Despite heterogeneous dynamics of clinical tumor regression, residual tumors displayed highly recurrent transcriptomic alterations and enriched processes, which were also observed in MAPKi-selected cell lines (implying tumor cell–intrinsic reprogramming) or in bulk mouse tumors (and the CD45-negative or CD45-positive fractions, implying tumor cell–intrinsic or stromal/immune alterations, respectively). Tumor cell–intrinsic reprogramming attenuated MAPK dependency, while enhancing mesenchymal, angiogenic, and IFN-inflammatory features and growth/survival dependence on multi-RTKs and PD-L2. In the immune compartment, PD-L2 upregulation in CD11c+ immunocytes drove the loss of T-cell inflammation and promoted BRAFi resistance. Thus, residual melanoma early on MAPKi therapy already displays potentially exploitable adaptive transcriptomic, epigenomic, immune-regulomic alterations.

Significance: Incomplete MAPKi-induced melanoma regression results in transcriptome/methylome-wide reprogramming and MAPK-redundant escape. Although regressing/residual melanoma is highly T cell–inflamed, stromal adaptations, many of which are tumor cell–driven, could suppress/eliminate intratumoral T cells, reversing tumor regression. This catalog of recurrent alterations helps identify adaptations such as PD-L2 operative tumor cell intrinsically and/or extrinsically early on therapy. Cancer Discov; 7(11); 1248–65. ©2017 AACR.

See related commentary by Haq, p. 1216.

This article is highlighted in the In This Issue feature, p. 1201
Data from The Mechanism of Anti–PD-L1 Antibody Efficacy against PD-L1–Negative Tumors Identifies NK Cells Expressing PD-L1 as a Cytolytic Effector
Authors: Dong Wenjuan , Wu Xiaojin , Ma Shoubao , Wang Yufeng , Nalin Ansel P. , Zhu Zheng , Zhang Jianying , Benson Don M. , He Kai , Caligiuri Michael A. , Yu Jianhua
Published: March 2024

Abstract
Blockade of PD-L1 expression on tumor cells via anti–PD-L1 monoclonal antibody (mAb) has shown great promise for successful cancer treatment by overcoming T-cell exhaustion; however, the function of PD-L1 on natural killer (NK) cells and the effects of anti–PD-L1 mAb on PD-L1+ NK cells remain unknown. Moreover, patients with PD-L1− tumors can respond favorably to anti–PD-L1 mAb therapy for unclear reasons. Here, we show that some tumors can induce PD-L1 on NK cells via AKT signaling, resulting in enhanced NK-cell function and preventing cell exhaustion. Anti–PD-L1 mAb directly acts on PD-L1+ NK cells against PD-L1− tumors via a p38 pathway. Combination therapy with anti–PD-L1 mAb and NK cell–activating cytokines significantly improves the therapeutic efficacy of human NK cells against PD-L1− human leukemia when compared with monotherapy. Our discovery of a PD-1–independent mechanism of antitumor efficacy via the activation of PD-L1+ NK cells with anti–PD-L1 mAb offers new insights into NK-cell activation and provides a potential explanation as to why some patients lacking PD-L1 expression on tumor cells still respond to anti–PD-L1 mAb therapy.
Significance:
Targeting PD-L1 expressed on PD-L1+ tumors with anti–PD-L1 mAb successfully overcomes T-cell exhaustion to control cancer, yet patients with PD-L1− tumors can respond to anti–PD-L1 mAb. Here, we show that anti–PD-L1 mAb activates PD-L1+ NK cells to control growth of PD-L1− tumors in vivo, and does so independent of PD-1.

This article is highlighted in the In This Issue feature, p. 1325
Data from Early Detection of Molecular Residual Disease in Localized Lung Cancer by Circulating Tumor DNA Profiling
Authors: Chaudhuri Aadel A. , Chabon Jacob J. , Lovejoy Alexander F. , Newman Aaron M. , Stehr Henning , Azad Tej D. , Khodadoust Michael S. , Esfahani Mohammad Shahrokh , Liu Chih Long , Zhou Li , Scherer Florian , Kurtz David M. , Say Carmen , Carter Justin N. , Merriott David J. , Dudley Jonathan C. , Binkley Michael S. , Modlin Leslie , Padda Sukhmani K. , Gensheimer Michael F. , West Robert B. , Shrager Joseph B. , Neal Joel W. , Wakelee Heather A. , Loo Billy W. , Alizadeh Ash A. , Diehn Maximilian
Published: March 2024

Abstract
Identifying molecular residual disease (MRD) after treatment of localized lung cancer could facilitate early intervention and personalization of adjuvant therapies. Here, we apply cancer personalized profiling by deep sequencing (CAPP-seq) circulating tumor DNA (ctDNA) analysis to 255 samples from 40 patients treated with curative intent for stage I–III lung cancer and 54 healthy adults. In 94% of evaluable patients experiencing recurrence, ctDNA was detectable in the first posttreatment blood sample, indicating reliable identification of MRD. Posttreatment ctDNA detection preceded radiographic progression in 72% of patients by a median of 5.2 months, and 53% of patients harbored ctDNA mutation profiles associated with favorable responses to tyrosine kinase inhibitors or immune checkpoint blockade. Collectively, these results indicate that ctDNA MRD in patients with lung cancer can be accurately detected using CAPP-seq and may allow personalized adjuvant treatment while disease burden is lowest.

Significance: This study shows that ctDNA analysis can robustly identify posttreatment MRD in patients with localized lung cancer, identifying residual/recurrent disease earlier than standard-of-care radiologic imaging, and thus could facilitate personalized adjuvant treatment at early time points when disease burden is lowest. Cancer Discov; 7(12); 1394–403. ©2017 AACR.

See related commentary by Comino-Mendez and Turner, p. 1368.

This article is highlighted in the In This Issue feature, p. 1355
Data from ER Translocation of the MAPK Pathway Drives Therapy Resistance in BRAF-Mutant Melanoma
Authors: Ojha Rani , Leli Nektaria M. , Onorati Angelique , Piao Shengfu , Verginadis Ioannis I. , Tameire Feven , Rebecca Vito W. , Chude Cynthia I. , Murugan Sengottuvelan , Fennelly Colin , Noguera-Ortega Estela , Chu Charleen T. , Liu Shujing , Xu Xiaowei , Krepler Clemens , Xiao Min , Xu Wei , Wei Zhi , Frederick Dennie T. , Boland Genevieve , Mitchell Tara C. , Karakousis Giorgos C. , Schuchter Lynn M. , Flaherty Keith T. , Zhang Gao , Herlyn Meenhard , Koumenis Constantinos , Amaravadi Ravi K.
Published: March 2024

Abstract
Resistance to BRAF and MEK inhibitors (BRAFi + MEKi) in BRAF-mutant tumors occurs through heterogeneous mechanisms, including ERK reactivation and autophagy. Little is known about the mechanisms by which ERK reactivation or autophagy is induced by BRAFi + MEKi. Here, we report that in BRAF-mutant melanoma cells, BRAFi + MEKi induced SEC61-dependent endoplasmic reticulum (ER) translocation of the MAPK pathway via GRP78 and KSR2. Inhibition of ER translocation prevented ERK reactivation and autophagy. Following ER translocation, ERK exited the ER and was rephosphorylated by PERK. Reactivated ERK phosphorylated ATF4, which activated cytoprotective autophagy. Upregulation of GRP78 and phosphorylation of ATF4 were detected in tumors of patients resistant to BRAFi + MEKi. ER translocation of the MAPK pathway was demonstrated in therapy-resistant patient-derived xenografts. Expression of a dominant-negative ATF4 mutant conferred sensitivity to BRAFi + MEKi in vivo. This mechanism reconciles two major targeted therapy resistance pathways and identifies druggable targets, whose inhibition would likely enhance the response to BRAFi + MEKi.
Significance:
ERK reactivation and autophagy are considered distinct resistance pathways to BRAF + MEK inhibition (BRAFi + MEKi) in BRAFV600E cancers. Here, we report BRAFi + MEKi–induced ER translocation of the MAPK pathway is necessary for ERK reactivation, which drives autophagy. The ER translocation mechanism is a major druggable driver of resistance to targeted therapy.

This article is highlighted in the In This Issue feature, p. 305
Data from Suppression of Tumor Invasion and Metastasis by Concurrent Inhibition of c-Met and VEGF Signaling in Pancreatic Neuroendocrine Tumors
Authors: Sennino Barbara , Ishiguro-Oonuma Toshina , Wei Ying , Naylor Ryan M. , Williamson Casey W. , Bhagwandin Vikash , Tabruyn Sebastien P. , You Weon-Kyoo , Chapman Harold A. , Christensen James G. , Aftab Dana T. , McDonald Donald M.
Published: March 2024

Abstract
Invasion and metastasis increase after the inhibition of VEGF signaling in some preclinical tumor models. In the present study we asked whether selective VEGF inhibition is sufficient to increase invasion and metastasis and whether selective c-Met inhibition is sufficient to block this effect. Treatment of pancreatic neuroendocrine tumors in RIP-Tag2 mice with a neutralizing anti-VEGF antibody reduced tumor burden but increased tumor hypoxia, hypoxia-inducible factor-1α, and c-Met activation and also increased invasion and metastasis. However, invasion and metastasis were reduced by concurrent inhibition of c-Met by PF-04217903 or PF-02341066 (crizotinib). A similar benefit was found in orthotopic Panc-1 pancreatic carcinomas treated with sunitinib plus PF-04217903 and in RIP-Tag2 tumors treated with XL184 (cabozantinib), which simultaneously blocks VEGF and c-Met signaling. These findings document that invasion and metastasis are promoted by selective inhibition of VEGF signaling and can be reduced by the concurrent inhibition of c-Met.

Significance: This report examines the mechanism of increased tumor aggressiveness after anti-VEGF therapy and presents evidence for roles of vascular pruning, hypoxia, and c-Met activation. The results show that simultaneous inhibition of c-Met and VEGF signaling not only slows tumor growth but also reduces invasion and metastasis. Cancer Discovery; 2(3); 270–87. ©2012 AACR.

Read the Commentary on this article by Lynn and Brekken, p. 211

This article is highlighted in the In This Issue feature, p. 193
Data from Acquisition of the Recurrent Gly101Val Mutation in BCL2 Confers Resistance to Venetoclax in Patients with Progressive Chronic Lymphocytic Leukemia
Authors: Blombery Piers , Anderson Mary Ann , Gong Jia-nan , Thijssen Rachel , Birkinshaw Richard W. , Thompson Ella R. , Teh Charis E. , Nguyen Tamia , Xu Zhen , Flensburg Christoffer , Lew Thomas E. , Majewski Ian J. , Gray Daniel H.D. , Westerman David A. , Tam Constantine S. , Seymour John F. , Czabotar Peter E. , Huang David C.S. , Roberts Andrew W.
Published: March 2024

Abstract
The BCL2 inhibitor venetoclax induces high rates of durable remission in patients with previously treated chronic lymphocytic leukemia (CLL). However, despite continuous daily treatment, leukemia recurs in most patients. To investigate the mechanisms of secondary resistance, we analyzed paired pre-venetoclax and progression samples from 15 patients with CLL progression enrolled on venetoclax clinical trials. The novel Gly101Val mutation in BCL2 was identified at progression in 7 patients, but not at study entry. It was first detectable after 19 to 42 months of therapy, and its emergence anticipated clinical disease progression by many months. Gly101Val reduces the affinity of BCL2 for venetoclax by ∼180-fold in surface plasmon resonance assays, thereby preventing the drug from displacing proapoptotic mediators from BCL2 in cells and conferring acquired resistance in cell lines and primary patient cells. This mutation provides new insights into the pathobiology of venetoclax resistance and provides a potential biomarker of impending clinical relapse.
Significance:
Why CLL recurs in patients who achieve remission with the BCL2 inhibitor venetoclax has been unknown. We provide the first description of an acquired point mutation in BCL2 arising recurrently and exclusively in venetoclax-treated patients. The mutation reduces venetoclax binding and is sufficient to confer resistance.

See related commentary by Thangavadivel and Byrd, p. 320.

This article is highlighted in the In This Issue feature, p. 305
Data from Somatic Tissue Engineering in Mouse Models Reveals an Actionable Role for WNT Pathway Alterations in Prostate Cancer Metastasis
Authors: Leibold Josef , Ruscetti Marcus , Cao Zhen , Ho Yu-Jui , Baslan Timour , Zou Min , Abida Wassim , Feucht Judith , Han Teng , Barriga Francisco M. , Tsanov Kaloyan M. , Zamechek Leah , Kulick Amanda , Amor Corina , Tian Sha , Rybczyk Katarzyna , Salgado Nelson R. , Sánchez-Rivera Francisco J. , Watson Philip A. , de Stanchina Elisa , Wilkinson John E. , Dow Lukas E. , Abate-Shen Cory , Sawyers Charles L. , Lowe Scott W.
Published: March 2024

Abstract
To study genetic factors influencing the progression and therapeutic responses of advanced prostate cancer, we developed a fast and flexible system that introduces genetic alterations relevant to human disease directly into the prostate glands of mice using tissue electroporation. These electroporation-based genetically engineered mouse models (EPO-GEMM) recapitulate features of traditional germline models and, by modeling genetic factors linked to late-stage human disease, can produce tumors that are metastatic and castration-resistant. A subset of tumors with Trp53 alterations acquired spontaneous WNT pathway alterations, which are also associated with metastatic prostate cancer in humans. Using the EPO-GEMM approach and an orthogonal organoid-based model, we show that WNT pathway activation drives metastatic disease that is sensitive to pharmacologic WNT pathway inhibition. Thus, by leveraging EPO-GEMMs, we reveal a functional role for WNT signaling in driving prostate cancer metastasis and validate the WNT pathway as therapeutic target in metastatic prostate cancer.
Significance:
Our understanding of the factors driving metastatic prostate cancer is limited by the paucity of models of late-stage disease. Here, we develop EPO-GEMMs of prostate cancer and use them to identify and validate the WNT pathway as an actionable driver of aggressive metastatic disease.

This article is highlighted in the In This Issue feature, p. 890
Data from Type I Interferon Regulates a Coordinated Gene Network to Enhance Cytotoxic T Cell–Mediated Tumor Killing
Authors: Fan Jun-Bao , Miyauchi Sayuri , Xu Hui-Zhong , Liu Dan , Kim Leo J.Y. , Burkart Christoph , Cheng Hua , Arimoto Kei-ichiro , Yan Ming , Zhou Yu , Győrffy Balázs , Knobeloch Klaus-Peter , Rich Jeremy N. , Cang Hu , Fu Xiang-Dong , Zhang Dong-Er
Published: March 2024

Abstract
Type I interferons (IFN), which activate many IFN-stimulated genes (ISG), are known to regulate tumorigenesis. However, little is known regarding how various ISGs coordinate with one another in developing antitumor effects. Here, we report that the ISG UBA7 is a tumor suppressor in breast cancer. UBA7 encodes an enzyme that catalyzes the covalent conjugation of the ubiquitin-like protein product of another ISG (ISG15) to cellular proteins in a process known as “ISGylation.” ISGylation of other ISGs, including STAT1 and STAT2, synergistically facilitates production of chemokine-receptor ligands to attract cytotoxic T cells. These gene-activation events are further linked to clustering and nuclear relocalization of STAT1/2 within IFN-induced promyelocytic leukemia (PML) bodies. Importantly, this coordinated ISG–ISGylation network plays a central role in suppressing murine breast cancer growth and metastasis, which parallels improved survival in patients with breast cancer. These findings reveal a cooperative IFN-inducible gene network in orchestrating a tumor-suppressive microenvironment.
Significance:
We report a highly cooperative ISG network, in which UBA7-mediated ISGylation facilitates clustering of transcription factors and activates an antitumor gene-expression program. These findings provide mechanistic insights into immune evasion in breast cancer associated with UBA7 loss, emphasizing the importance of a functional ISG–ISGylation network in tumor suppression.

This article is highlighted in the In This Issue feature, p. 327
Data from PRMT5 Inhibition Modulates E2F1 Methylation and Gene-Regulatory Networks Leading to Therapeutic Efficacy in JAK2V617F-Mutant MPN
Authors: Pastore Friederike , Bhagwat Neha , Pastore Alessandro , Radzisheuskaya Aliaksandra , Karzai Abdul , Krishnan Aishwarya , Li Bing , Bowman Robert L. , Xiao Wenbin , Viny Aaron D. , Zouak Anouar , Park Young C. , Cordner Keith B. , Braunstein Stephanie , Maag Jesper L. , Grego Alexander , Mehta Jaanvi , Wang Min , Lin Hong , Durham Benjamin H. , Koche Richard P. , Rampal Raajit K. , Helin Kristian , Scherle Peggy , Vaddi Kris , Levine Ross L.
Published: March 2024

Abstract
We investigated the role of PRMT5 in myeloproliferative neoplasm (MPN) pathogenesis and aimed to elucidate key PRMT5 targets contributing to MPN maintenance. PRMT5 is overexpressed in primary MPN cells, and PRMT5 inhibition potently reduced MPN cell proliferation ex vivo. PRMT5 inhibition was efficacious at reversing elevated hematocrit, leukocytosis, and splenomegaly in a model of JAK2V617F+ polycythemia vera and leukocyte and platelet counts, hepatosplenomegaly, and fibrosis in the MPLW515L model of myelofibrosis. Dual targeting of JAK and PRMT5 was superior to JAK or PRMT5 inhibitor monotherapy, further decreasing elevated counts and extramedullary hematopoiesis in vivo. PRMT5 inhibition reduced expression of E2F targets and altered the methylation status of E2F1 leading to attenuated DNA damage repair, cell-cycle arrest, and increased apoptosis. Our data link PRMT5 to E2F1 regulatory function and MPN cell survival and provide a strong mechanistic rationale for clinical trials of PRMT5 inhibitors in MPN.
Significance:
Expression of PRMT5 and E2F targets is increased in JAK2V617F+ MPN. Pharmacologic inhibition of PRMT5 alters the methylation status of E2F1 and shows efficacy in JAK2V617F/MPLW515L MPN models and primary samples. PRMT5 represents a potential novel therapeutic target for MPN, which is now being clinically evaluated.

This article is highlighted in the In This Issue feature, p. 1611
Data from Characteristics and Outcome of AKT1E17K-Mutant Breast Cancer Defined through AACR Project GENIE, a Clinicogenomic Registry
Authors: Smyth Lillian M. , Zhou Qin , Nguyen Bastien , Yu Celeste , Lepisto Eva M. , Arnedos Monica , Hasset Michael J. , Lenoue-Newton Michele L. , Blauvelt Natalie , Dogan Semih , Micheel Christine M. , Wathoo Chetna , Horlings Hugo , Hudecek Jan , Gross Benjamin E. , Kundra Ritika , Sweeney Shawn M. , Gao JianJiong , Schultz Nikolaus , Zarski Andrew , Gardos Stuart M. , Lee Jocelyn , Sheffler-Collins Seth , Park Ben H. , Sawyers Charles L. , André Fabrice , Levy Mia , Meric-Bernstam Funda , Bedard Philippe L. , Iasonos Alexia , Schrag Deborah , Hyman David M.
Published: March 2024

Abstract
AKT inhibitors have promising activity in AKT1E17K-mutant estrogen receptor (ER)–positive metastatic breast cancer, but the natural history of this rare genomic subtype remains unknown. Utilizing AACR Project GENIE, an international clinicogenomic data-sharing consortium, we conducted a comparative analysis of clinical outcomes of patients with matched AKT1E17K-mutant (n = 153) and AKT1–wild-type (n = 302) metastatic breast cancer. AKT1-mutant cases had similar adjusted overall survival (OS) compared with AKT1–wild-type controls (median OS, 24.1 vs. 29.9, respectively; P = 0.98). AKT1-mutant cases enjoyed longer durations on mTOR inhibitor therapy, an observation previously unrecognized in pivotal clinical trials due to the rarity of this alteration. Other baseline clinicopathologic features, as well as durations on other classes of therapy, were broadly similar. In summary, we demonstrate the feasibility of using a novel and publicly accessible clincogenomic registry to define outcomes in a rare genomically defined cancer subtype, an approach with broad applicability to precision oncology.
Significance:
We delineate the natural history of a rare genomically distinct cancer, AKT1E17K-mutant ER-positive breast cancer, using a publicly accessible registry of real-world patient data, thereby illustrating the potential to inform drug registration through synthetic control data.

See related commentary by Castellanos and Baxi, p. 490.
Data from A Mutation in Histone H2B Represents a New Class of Oncogenic Driver
Authors: Bennett Richard L. , Bele Aditya , Small Eliza C. , Will Christine M. , Nabet Behnam , Oyer Jon A. , Huang Xiaoxiao , Ghosh Rajarshi P. , Grzybowski Adrian T. , Yu Tao , Zhang Qiao , Riva Alberto , Lele Tanmay P. , Schatz George C. , Kelleher Neil L. , Ruthenburg Alexander J. , Liphardt Jan , Licht Jonathan D.
Published: March 2024

Abstract
By examination of the cancer genomics database, we identified a new set of mutations in core histones that frequently recur in cancer patient samples and are predicted to disrupt nucleosome stability. In support of this idea, we characterized a glutamate to lysine mutation of histone H2B at amino acid 76 (H2B-E76K), found particularly in bladder and head and neck cancers, that disrupts the interaction between H2B and H4. Although H2B-E76K forms dimers with H2A, it does not form stable histone octamers with H3 and H4 in vitro, and when reconstituted with DNA forms unstable nucleosomes with increased sensitivity to nuclease. Expression of the equivalent H2B mutant in yeast restricted growth at high temperature and led to defective nucleosome-mediated gene repression. Significantly, H2B-E76K expression in the normal mammary epithelial cell line MCF10A increased cellular proliferation, cooperated with mutant PIK3CA to promote colony formation, and caused a significant drift in gene expression and fundamental changes in chromatin accessibility, particularly at gene regulatory elements. Taken together, these data demonstrate that mutations in the globular domains of core histones may give rise to an oncogenic program due to nucleosome dysfunction and deregulation of gene expression.
Significance:
Mutations in the core histones frequently occur in cancer and represent a new mechanism of epigenetic dysfunction that involves destabilization of the nucleosome, deregulation of chromatin accessibility, and alteration of gene expression to drive cellular transformation.

See related commentary by Sarthy and Henikoff, p. 1346.

This article is highlighted in the In This Issue feature, p. 1325
Data from CDK7 Inhibition Suppresses Castration-Resistant Prostate Cancer through MED1 Inactivation
Authors: Rasool Reyaz ur , Natesan Ramakrishnan , Deng Qu , Aras Shweta , Lal Priti , Sander Effron Samuel , Mitchell-Velasquez Erick , Posimo Jessica M. , Carskadon Shannon , Baca Sylvan C. , Pomerantz Mark M. , Siddiqui Javed , Schwartz Lauren E. , Lee Daniel J. , Palanisamy Nallasivam , Narla Goutham , Den Robert B. , Freedman Matthew L. , Brady Donita C. , Asangani Irfan A.
Published: March 2024

Abstract
Metastatic castration-resistant prostate cancer (CRPC) is a fatal disease, primarily resulting from the transcriptional addiction driven by androgen receptor (AR). First-line CRPC treatments typically target AR signaling, but are rapidly bypassed, resulting in only a modest survival benefit with antiandrogens. Therapeutic approaches that more effectively block the AR-transcriptional axis are urgently needed. Here, we investigated the molecular mechanism underlying the association between the transcriptional coactivator MED1 and AR as a vulnerability in AR-driven CRPC. MED1 undergoes CDK7-dependent phosphorylation at T1457 and physically engages AR at superenhancer sites, and is essential for AR-mediated transcription. In addition, a CDK7-specific inhibitor, THZ1, blunts AR-dependent neoplastic growth by blocking AR/MED1 corecruitment genome-wide, as well as reverses the hyperphosphorylated MED1-associated enzalutamide-resistant phenotype. In vivo, THZ1 induces tumor regression of AR-amplified human CRPC in a xenograft mouse model. Together, we demonstrate that CDK7 inhibition selectively targets MED1-mediated, AR-dependent oncogenic transcriptional amplification, thus representing a potential new approach for the treatment of CRPC.
Significance:
Potent inhibition of AR signaling is critical to treat CRPC. This study uncovers a driver role for CDK7 in regulating AR-mediated transcription through phosphorylation of MED1, thus revealing a therapeutically targetable potential vulnerability in AR-addicted CRPC.

See related commentary by Russo et al., p. 1490.

This article is highlighted in the In This Issue feature, p. 1469
Data from Limited Environmental Serine and Glycine Confer Brain Metastasis Sensitivity to PHGDH Inhibition
Authors: Ngo Bryan , Kim Eugenie , Osorio-Vasquez Victoria , Doll Sophia , Bustraan Sophia , Liang Roger J. , Luengo Alba , Davidson Shawn M. , Ali Ahmed , Ferraro Gino B. , Fischer Grant M. , Eskandari Roozbeh , Kang Diane S. , Ni Jing , Plasger Ariana , Rajasekhar Vinagolu K. , Kastenhuber Edward R. , Bacha Sarah , Sriram Roshan K. , Stein Benjamin D. , Bakhoum Samuel F. , Snuderl Matija , Cotzia Paolo , Healey John H. , Mainolfi Nello , Suri Vipin , Friedman Adam , Manfredi Mark , Sabatini David M. , Jones Drew R. , Yu Min , Zhao Jean J. , Jain Rakesh K. , Keshari Kayvan R. , Davies Michael A. , Vander Heiden Matthew G. , Hernando Eva , Mann Matthias , Cantley Lewis C. , Pacold Michael E.
Published: March 2024

Abstract
A hallmark of metastasis is the adaptation of tumor cells to new environments. Metabolic constraints imposed by the serine and glycine–limited brain environment restrict metastatic tumor growth. How brain metastases overcome these growth-prohibitive conditions is poorly understood. Here, we demonstrate that 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the rate-limiting step of glucose-derived serine synthesis, is a major determinant of brain metastasis in multiple human cancer types and preclinical models. Enhanced serine synthesis proved important for nucleotide production and cell proliferation in highly aggressive brain metastatic cells. In vivo, genetic suppression and pharmacologic inhibition of PHGDH attenuated brain metastasis, but not extracranial tumor growth, and improved overall survival in mice. These results reveal that extracellular amino acid availability determines serine synthesis pathway dependence, and suggest that PHGDH inhibitors may be useful in the treatment of brain metastasis.
Significance:
Using proteomics, metabolomics, and multiple brain metastasis models, we demonstrate that the nutrient-limited environment of the brain potentiates brain metastasis susceptibility to serine synthesis inhibition. These findings underscore the importance of studying cancer metabolism in physiologically relevant contexts, and provide a rationale for using PHGDH inhibitors to treat brain metastasis.

This article is highlighted in the In This Issue feature, p. 1241
Data from Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression
Authors: Francescone Ralph , Barbosa Vendramini-Costa Débora , Franco-Barraza Janusz , Wagner Jessica , Muir Alexander , Lau Allison N. , Gabitova Linara , Pazina Tatiana , Gupta Sapna , Luong Tiffany , Rollins Dustin , Malik Ruchi , Thapa Roshan J. , Restifo Diana , Zhou Yan , Cai Kathy Q. , Hensley Harvey H. , Tan Yinfei , Kruger Warren D. , Devarajan Karthik , Balachandran Siddharth , Klein-Szanto Andres J. , Wang Huamin , El-Deiry Wafik S. , Vander Heiden Matthew G. , Peri Suraj , Campbell Kerry S. , Astsaturov Igor , Cukierman Edna
Published: March 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a poor 5-year survival rate and lacks effective therapeutics. Therefore, it is of paramount importance to identify new targets. Using multiplex data from patient tissue, three-dimensional coculturing in vitro assays, and orthotopic murine models, we identified Netrin G1 (NetG1) as a promoter of PDAC tumorigenesis. We found that NetG1+ cancer-associated fibroblasts (CAF) support PDAC survival, through a NetG1-mediated effect on glutamate/glutamine metabolism. Also, NetG1+ CAFs are intrinsically immunosuppressive and inhibit natural killer cell–mediated killing of tumor cells. These protumor functions are controlled by a signaling circuit downstream of NetG1, which is comprised of AKT/4E-BP1, p38/FRA1, vesicular glutamate transporter 1, and glutamine synthetase. Finally, blocking NetG1 with a neutralizing antibody stunts in vivo tumorigenesis, suggesting NetG1 as potential target in PDAC.
Significance:
This study demonstrates the feasibility of targeting a fibroblastic protein, NetG1, which can limit PDAC tumorigenesis in vivo by reverting the protumorigenic properties of CAFs. Moreover, inhibition of metabolic proteins in CAFs altered their immunosuppressive capacity, linking metabolism with immunomodulatory function.

See related commentary by Sherman, p. 230.

This article is highlighted in the In This Issue feature, p. 211
Data from Radiotherapy and Immunotherapy Promote Tumoral Lipid Oxidation and Ferroptosis via Synergistic Repression of SLC7A11
Authors: Lang Xueting , Green Michael D. , Wang Weimin , Yu Jiali , Choi Jae Eun , Jiang Long , Liao Peng , Zhou Jiajia , Zhang Qiang , Dow Ania , Saripalli Anjali L. , Kryczek Ilona , Wei Shuang , Szeliga Wojciech , Vatan Linda , Stone Everett M. , Georgiou George , Cieslik Marcin , Wahl Daniel R. , Morgan Meredith A. , Chinnaiyan Arul M. , Lawrence Theodore S. , Zou Weiping
Published: March 2024

Abstract
A challenge in oncology is to rationally and effectively integrate immunotherapy with traditional modalities, including radiotherapy. Here, we demonstrate that radiotherapy induces tumor-cell ferroptosis. Ferroptosis agonists augment and ferroptosis antagonists limit radiotherapy efficacy in tumor models. Immunotherapy sensitizes tumors to radiotherapy by promoting tumor-cell ferroptosis. Mechanistically, IFNγ derived from immunotherapy-activated CD8+ T cells and radiotherapy-activated ATM independently, yet synergistically, suppresses SLC7A11, a unit of the glutamate–cystine antiporter xc−, resulting in reduced cystine uptake, enhanced tumor lipid oxidation and ferroptosis, and improved tumor control. Thus, ferroptosis is an unappreciated mechanism and focus for the development of effective combinatorial cancer therapy.
Significance:
This article describes ferroptosis as a previously unappreciated mechanism of action for radiotherapy. Further, it shows that ferroptosis is a novel point of synergy between immunotherapy and radiotherapy. Finally, it nominates SLC7A11, a critical regulator of ferroptosis, as a mechanistic determinant of synergy between radiotherapy and immunotherapy.

This article is highlighted in the In This Issue feature, p. 1631
Data from A TLR3 Ligand Reestablishes Chemotherapeutic Responses in the Context of FPR1 Deficiency
Authors: Le Naour Julie , Liu Peng , Zhao Liwei , Adjemian Sandy , Sztupinszki Zsofia , Taieb Julien , Mulot Claire , Silvin Aymeric , Dutertre Charles-Antoine , Ginhoux Florent , Sauvat Allan , Cerrato Giulia , Castoldi Francesca , Martins Isabelle , Stoll Gautier , Paillet Juliette , Mangane Khady , Richter Cornelia , Kepp Oliver , Maiuri Maria Chiara , Pietrocola Federico , Vandenabeele Peter , André Fabrice , Delaloge Suzette , Szallasi Zoltan , Laurent-Puig Pierre , Zucman-Rossi Jessica , Zitvogel Laurence , Pol Jonathan G. , Vacchelli Erika , Kroemer Guido
Published: March 2024

Abstract
For anthracycline-based chemotherapy to be immunogenic, dying cancer cells must release annexin A1 (ANXA1) that subsequently interacts with the pattern recognition receptor, formyl peptide receptor 1 (FPR1), on the surface of dendritic cells (DC). Approximately 30% of individuals bear loss-of-function alleles of FPR1, calling for strategies to ameliorate their anticancer immune response. Here, we show that immunotherapy with a ligand of Toll-like receptor-3, polyinosinic:polycytidylic acid (pIC), restores the deficient response to chemotherapy of tumors lacking ANXA1 developing in immunocompetent mice or those of normal cancers growing in FPR1-deficient mice. This effect was accompanied by improved DC- and T-lymphocyte–mediated anticancer immunity. Of note, carcinogen-induced breast cancers precociously developed in FPR1-deficient mice as compared with wild-type controls. A similar tendency for earlier cancer development was found in patients carrying the loss-of-function allele of FPR1. These findings have potential implications for the clinical management of FPR1-deficient patients.
Significance:
The loss-of-function variant rs867228 in FPR1, harbored by approximately 30% of the world population, is associated with the precocious manifestation of breast, colorectal, esophageal, and head and neck carcinomas. pIC restores deficient chemotherapeutic responses in mice lacking Fpr1, suggesting a personalized strategy for compensating for the FPR1 defect.

This article is highlighted in the In This Issue feature, p. 211
Data from Induction of APOBEC3 Exacerbates DNA Replication Stress and Chromosomal Instability in Early Breast and Lung Cancer Evolution
Authors: Venkatesan Subramanian , Angelova Mihaela , Puttick Clare , Zhai Haoran , Caswell Deborah R. , Lu Wei-Ting , Dietzen Michelle , Galanos Panagiotis , Evangelou Konstantinos , Bellelli Roberto , Lim Emilia L. , Watkins Thomas B.K. , Rowan Andrew , Teixeira Vitor H. , Zhao Yue , Chen Haiquan , Ngo Bryan , Zalmas Lykourgos-Panagiotis , Al Bakir Maise , Hobor Sebastijan , Grönroos Eva , Pennycuick Adam , Nigro Ersilia , Campbell Brittany B. , Brown William L. , Akarca Ayse U. , Marafioti Teresa , Wu Mary Y. , Howell Michael , Boulton Simon J. , Bertoli Cosetta , Fenton Tim R. , de Bruin Robertus A.M. , Maya-Mendoza Apolinar , Santoni-Rugiu Eric , Hynds Robert E. , Gorgoulis Vassilis G. , Jamal-Hanjani Mariam , McGranahan Nicholas , Harris Reuben S. , Janes Sam M. , Bartkova Jirina , Bakhoum Samuel F. , Bartek Jiri , Kanu Nnennaya , Swanton Charles
Published: March 2024

Abstract
APOBEC3 enzymes are cytosine deaminases implicated in cancer. Precisely when APOBEC3 expression is induced during cancer development remains to be defined. Here we show that specific APOBEC3 genes are upregulated in breast ductal carcinoma in situ, and in preinvasive lung cancer lesions coincident with cellular proliferation. We observe evidence of APOBEC3-mediated subclonal mutagenesis propagated from TRACERx preinvasive to invasive non–small cell lung cancer (NSCLC) lesions. We find that APOBEC3B exacerbates DNA replication stress and chromosomal instability through incomplete replication of genomic DNA, manifested by accumulation of mitotic ultrafine bridges and 53BP1 nuclear bodies in the G1 phase of the cell cycle. Analysis of TRACERx NSCLC clinical samples and mouse lung cancer models revealed APOBEC3B expression driving replication stress and chromosome missegregation. We propose that APOBEC3 is functionally implicated in the onset of chromosomal instability and somatic mutational heterogeneity in preinvasive disease, providing fuel for selection early in cancer evolution.
Significance:
This study reveals the dynamics and drivers of APOBEC3 gene expression in preinvasive disease and the exacerbation of cellular diversity by APOBEC3B through DNA replication stress to promote chromosomal instability early in cancer evolution.

This article is highlighted in the In This Issue feature, p. 2355
Data from Calnexin Impairs the Antitumor Immunity of CD4+ and CD8+ T Cells
Authors: Chen Yichen , Ma Da , Wang Xi , Fang Juan , Liu Xiangqi , Song Jingjing , Li Xinye , Ren Xianyue , Li Qiusheng , Li Qunxing , Wen Shuqiong , Luo Liqun , Xia Juan , Cui Jun , Zeng Gucheng , Chen Lieping , Cheng Bin , Wang Zhi
Published: March 2024

Abstract
Elucidation of the mechanisms of T-cell–mediated antitumor responses will provide information for the rational design and development of cancer immunotherapies. Here, we found that calnexin, an endoplasmic reticulum (ER) chaperone protein, is significantly upregulated in oral squamous cell carcinoma (OSCC). Upregulation of its membranous expression on OSCC cells is associated with inhibited T-cell infiltration in tumor tissues and correlates with poor survival of patients with OSCC. We found that calnexin inhibits the proliferation of CD4+ and CD8+ T cells isolated from the whole blood of healthy donors and patients with OSCC and inhibits the secretion of IFNγ, TNFα, and IL2 from these cells. Furthermore, in a melanoma model, knockdown of calnexin enhanced the infiltration and effector functions of T cells in the tumor microenvironment and conferred better control of tumor growth, whereas treatment with a recombinant calnexin protein impaired the infiltration and effector functions of T cells and promoted tumor growth. We also found that calnexin enhanced the expression of PD-1 on CD4+ and CD8+ T cells by restraining the DNA methylation status of a CpG island in the PD-1 promoter. Thus, this work uncovers a mechanism by which T-cell antitumor responses are regulated by calnexin in tumor cells and suggests that calnexin might serve as a potential target for the improvement of antitumor immunotherapy.
Data from Increased Frequency of ICOS+ CD4 T Cells as a Pharmacodynamic Biomarker for Anti-CTLA-4 Therapy
Authors: Ng Tang Derek , Shen Yu , Sun Jingjing , Wen Sijin , Wolchok Jedd D. , Yuan Jianda , Allison James P. , Sharma Padmanee
Published: March 2024

Abstract
Pharmacodynamic biomarkers can play an important role in understanding whether a therapeutic agent has “hit its target” to impact biologic function. A pharmacodynamic biomarker for anti-CTLA-4 therapy remains to be elucidated. We previously reported that anti-CTLA-4 therapy increases the frequency of CD4 T cells expressing the inducible costimulator (ICOS) molecule. To determine whether the frequency of ICOS+ CD4 T cells could be used as a pharmacodynamic biomarker for anti-CTLA-4 therapy, we carried out flow cytometric studies and statistical analyses on data from 56 individuals, which included 10 healthy donors, 36 patients who received anti-CTLA-4 monoclonal antibody (mAb), and 10 patients who received treatment with a different immunomodulatory agent (gp100 DNA vaccine). After treatment with anti-CTLA-4 mAb (ipilimumab; Bristol-Myers Squibb), we detected a statistically significant increase in the frequency of ICOS+ CD4 T-cells. After two doses of anti-CTLA-4 therapy, the assay was found to have an estimated specificity of 96% [95% confidence interval (CI), 88–100] and sensitivity of 71% (95% CI, 54–85), with positive expression defined as a frequency that is more than the upper bound of 95% CI among baseline samples from all subjects. Our data suggest that an increased frequency of ICOS+ CD4 T cells measured by flow cytometry can be used as a reproducible pharmacodynamic biomarker to indicate biologic activity in the setting of anti-CTLA-4 therapy, which should enable appropriate immune monitoring to determine whether patients receiving anti-CTLA-4 monotherapy or combination treatment strategies are having an adequate biologic response. Cancer Immunol Res; 1(4); 229–34. ©2013 AACR.