bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Nrf2 Mutagenic Activation Drives Hepatocarcinogenesis
Authors: Ngo Hoang Kieu Chi , Kim Do-Hee , Cha Young-Nam , Na Hye-Kyung , Surh Young-Joon
Published: March 2024

Abstract
Nrf2, a master regulator of oxidative stress, is considered a prominent target for prevention of hepatocellular carcinoma (HCC), one of the leading causes of cancer-related deaths worldwide. Here we report that Nrf2-deficient mice resisted diethylnitrosamine (DEN)-induced hepatocarcinogenesis without affecting P450-mediated metabolic activation of DEN. Nrf2 expression, nuclear translocation, and transcriptional activity were enhanced in liver tumors. Overactivated Nrf2 was required for hepatoma growth in DEN-induced HCC. Following DEN treatment, Nrf2 genetic disruption reduced expression of pentose phosphate pathway-related enzymes, the depletion of which has been associated with an amelioration of HCC incidence. Conversely, enhanced Nrf2 activity was attributable to alterations in the ability to bind its endogenous inhibitor Keap1. Our findings provide a mechanistic rationale for Nrf2 blockade to prevent and possibly treat liver cancer. Cancer Res; 77(18); 4797–808. ©2017 AACR.
Data from Androgen-Dependent Repression of ERRγ Reprograms Metabolism in Prostate Cancer
Authors: Audet-Walsh Étienne , Yee Tracey , McGuirk Shawn , Vernier Mathieu , Ouellet Carlo , St-Pierre Julie , Giguère Vincent
Published: March 2024

Abstract
How androgen signaling contributes to the oncometabolic state of prostate cancer remains unclear. Here, we show how the estrogen-related receptor γ (ERRγ) negatively controls mitochondrial respiration in prostate cancer cells. Sustained treatment of prostate cancer cells with androgens increased the activity of several metabolic pathways, including aerobic glycolysis, mitochondrial respiration, and lipid synthesis. An analysis of the intersection of gene expression, binding events, and motif analyses after androgen exposure identified a metabolic gene expression signature associated with the action of ERRγ. This metabolic state paralleled the loss of ERRγ expression. It occurred in both androgen-dependent and castration-resistant prostate cancer and was associated with cell proliferation. Clinically, we observed an inverse relationship between ERRγ expression and disease severity. These results illuminate a mechanism in which androgen-dependent repression of ERRγ reprograms prostate cancer cell metabolism to favor mitochondrial activity and cell proliferation. Furthermore, they rationalize strategies to reactivate ERRγ signaling as a generalized therapeutic approach to manage prostate cancer. Cancer Res; 77(2); 378–89. ©2016 AACR.
Data from Preclinical Characterization of BET Family Bromodomain Inhibitor ABBV-075 Suggests Combination Therapeutic Strategies
Authors: Bui Mai H. , Lin Xiaoyu , Albert Daniel H. , Li Leiming , Lam Lloyd T. , Faivre Emily J. , Warder Scott E. , Huang Xiaoli , Wilcox Denise , Donawho Cherrie K. , Sheppard George S. , Wang Le , Fidanze Steve , Pratt John K. , Liu Dachun , Hasvold Lisa , Uziel Tamar , Lu Xin , Kohlhapp Fred , Fang Guowei , Elmore Steven W. , Rosenberg Saul H. , McDaniel Keith F. , Kati Warren M. , Shen Yu
Published: March 2024

Abstract
ABBV-075 is a potent and selective BET family bromodomain inhibitor that recently entered phase I clinical trials. Comprehensive preclinical characterization of ABBV-075 demonstrated broad activity across cell lines and tumor models, representing a variety of hematologic malignancies and solid tumor indications. In most cancer cell lines derived from solid tumors, ABBV-075 triggers prominent G1 cell-cycle arrest without extensive apoptosis. In this study, we show that ABBV-075 efficiently triggers apoptosis in acute myeloid leukemia (AML), non-Hodgkin lymphoma, and multiple myeloma cells. Apoptosis induced by ABBV-075 was mediated in part by modulation of the intrinsic apoptotic pathway, exhibiting synergy with the BCL-2 inhibitor venetoclax in preclinical models of AML. In germinal center diffuse large B-cell lymphoma, BCL-2 levels or venetoclax sensitivity predicted the apoptotic response to ABBV-075 treatment. In vivo combination studies uncovered surprising benefits of low doses of ABBV-075 coupled with bortezomib and azacitidine treatment, despite the lack of in vitro synergy between ABBV-075 and these agents. The in vitro/in vivo activities of ABBV-075 described here may serve as a useful reference to guide the development of ABBV-075 and other BET family inhibitors for cancer therapy. Cancer Res; 77(11); 2976–89. ©2017 AACR.
Data from Functionally Null RAD51D Missense Mutation Associates Strongly with Ovarian Carcinoma
Authors: Rivera Barbara , Di Iorio Massimo , Frankum Jessica , Nadaf Javad , Fahiminiya Somayyeh , Arcand Suzanna L. , Burk David L. , Grapton Damien , Tomiak Eva , Hastings Valerie , Hamel Nancy , Wagener Rabea , Aleynikova Olga , Giroux Sylvie , Hamdan Fadi F. , Dionne-Laporte Alexandre , Zogopoulos George , Rousseau Francois , Berghuis Albert M. , Provencher Diane , Rouleau Guy A. , Michaud Jacques L. , Mes-Masson Anne-Marie , Majewski Jacek , Bens Susanne , Siebert Reiner , Narod Steven A. , Akbari Mohammad R. , Lord Christopher J. , Tonin Patricia N. , Orthwein Alexandre , Foulkes William D.
Published: March 2024

Abstract
RAD51D is a key player in DNA repair by homologous recombination (HR), and RAD51D truncating variant carriers have an increased risk for ovarian cancer. However, the contribution of nontruncating RAD51D variants to cancer predisposition remains uncertain. Using deep sequencing and case–control genotyping studies, we show that in French Canadians, the missense RAD51D variant c.620C>T;p.S207L is highly prevalent and is associated with a significantly increased risk for ovarian high-grade serous carcinoma (HGSC; 3.8% cases vs. 0.2% controls). The frequency of the p.S207L variant did not significantly differ from that of controls in breast, endometrial, pancreas, or colorectal adenocarcinomas. Functionally, we show that this mutation impairs HR by disrupting the RAD51D–XRCC2 interaction and confers PARP inhibitor sensitivity. These results highlight the importance of a functional RAD51D–XRCC2 interaction to promote HR and prevent the development of HGSC. This study identifies c.620C>T;p.S207L as the first bona fide pathogenic RAD51D missense cancer susceptibility allele and supports the use of targeted PARP-inhibitor therapies in ovarian cancer patients carrying deleterious missense RAD51D variants. Cancer Res; 77(16); 4517–29. ©2017 AACR.
Data from Risk of Second Malignancies in Solid Organ Transplant Recipients Who Develop Keratinocyte Cancers
Authors: Zamoiski Rachel D. , Yanik Elizabeth , Gibson Todd M. , Cahoon Elizabeth K. , Madeleine Margaret M. , Lynch Charles F. , Gustafson Sally , Goodman Marc T. , Skeans Melissa , Israni Ajay K. , Engels Eric A. , Morton Lindsay M.
Published: March 2024

Abstract
Solid organ transplant recipients have increased risk for developing keratinocyte cancers, including cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), in part as a result of immunosuppressive medications administered to prevent graft rejection. In the general population, keratinocyte cancers are associated with increased risks of subsequent malignancy, however, the risk in organ transplant populations has not been evaluated. We addressed this question by linking the U.S. Scientific Registry of Transplant Recipients, which includes data on keratinocyte cancer occurrence, with 15 state cancer registries. Risk of developing malignancies after keratinocyte cancer was assessed among 118,440 Caucasian solid organ transplant recipients using multivariate Cox regression models. Cutaneous SCC occurrence (n = 6,169) was associated with 1.44-fold increased risk [95% confidence interval (CI), 1.31–1.59] for developing later malignancies. Risks were particularly elevated for non-cutaneous SCC, including those of the oral cavity/pharynx (HR, 5.60; 95% CI, 4.18–7.50) and lung (HR, 1.66; 95% CI, 1.16–2.31). Cutaneous SCC was also associated with increased risk of human papillomavirus-related cancers, including anal cancer (HR, 2.77; 95% CI, 1.29–5.96) and female genital cancers (HR, 3.43; 95% CI, 1.44–8.19). In contrast, BCC (n = 3,669) was not associated with overall risk of later malignancy (HR, 0.98; 95% CI, 0.87–1.12), including any SCC. Our results suggest that transplant recipients with cutaneous SCC, but not BCC, have an increased risk of developing other SCC. These findings somewhat differ from those for the general population and suggest a shared etiology for cutaneous SCC and other SCC in the setting of immunosuppression. Cutaneous SCC occurrence after transplantation could serve as a marker for elevated malignancy risk. Cancer Res; 77(15); 4196–203. ©2017 AACR.
Data from Cytosine Deaminase APOBEC3A Sensitizes Leukemia Cells to Inhibition of the DNA Replication Checkpoint
Authors: Green Abby M. , Budagyan Konstantin , Hayer Katharina E. , Reed Morgann A. , Savani Milan R. , Wertheim Gerald B. , Weitzman Matthew D.
Published: March 2024

Abstract
Mutational signatures in cancer genomes have implicated the APOBEC3 cytosine deaminases in oncogenesis, possibly offering a therapeutic vulnerability. Elevated APOBEC3B expression has been detected in solid tumors, but expression of APOBEC3A (A3A) in cancer has not been described to date. Here, we report that A3A is highly expressed in subsets of pediatric and adult acute myelogenous leukemia (AML). We modeled A3A expression in the THP1 AML cell line by introducing an inducible A3A gene. A3A expression caused ATR-dependent phosphorylation of Chk1 and cell-cycle arrest, consistent with replication checkpoint activation. Further, replication checkpoint blockade via small-molecule inhibition of ATR kinase in cells expressing A3A led to apoptosis and cell death. Although DNA damage checkpoints are broadly activated in response to A3A activity, synthetic lethality was specific to ATR signaling via Chk1 and did not occur with ATM inhibition. Our findings identify elevation of A3A expression in AML cells, enabling apoptotic sensitivity to inhibitors of the DNA replication checkpoint and suggesting it as a candidate biomarker for ATR inhibitor therapy. Cancer Res; 77(17); 4579–88. ©2017 AACR.
Data from Acetylation of Mastermind-like 1 by p300 Drives the Recruitment of NACK to Initiate Notch-Dependent Transcription
Authors: Jin Ke , Zhou Wen , Han Xiaoqing , Wang Zhiqiang , Li Bin , Jeffries Shawn , Tao Wensi , Robbins David J. , Capobianco Anthony J.
Published: March 2024

Abstract
Although it has long been appreciated that p300 acts as a critical Notch coactivator, the mechanistic details of p300 in Notch-mediated transcription remain unclear. We previously demonstrated that PEAK1-related kinase activating pseudokinase 1 (NACK), also known as SGK223, is a critical coactivator of Notch signaling and binds to the Notch1 ternary complex. Herein we report that p300 and CBP acetylate Mastermind-like 1 (Maml1) on amino acid residues K188 and K189 to recruit NACK to the Notch1 ternary complex, which results in the recruitment of RNA polymerase II to initiate transcription. NACK is recruited to the ternary complexes containing Maml1 and Maml3, but not Maml2. Simultaneous inhibition of p300/CBP and Notch has a synergistic effect in esophageal adenocarcinoma. In summary, this study provides a deeper mechanistic understanding of the assembly of the Notch transcriptional complex and provides rationale and proof of concept for a combinatorial therapeutic attack on Notch-dependent cancers. Cancer Res; 77(16); 4228–37. ©2017 AACR.
Data from Epstein–Barr Virus-Induced VEGF and GM-CSF Drive Nasopharyngeal Carcinoma Metastasis via Recruitment and Activation of Macrophages
Authors: Huang Di , Song Shi-Jian , Wu Zi-Zhao , Wu Wei , Cui Xiu-Ying , Chen Jia-Ning , Zeng Mu-Sheng , Su Shi-Cheng
Published: March 2024

Abstract
Chronic inflammation induced by persistent microbial infection plays an essential role in tumor progression. Although it is well documented that Epstein–Barr virus (EBV) infection is closely associated with nasopharyngeal carcinoma (NPC), how EBV-induced inflammation promotes NPC progression remains largely unknown. Here, we report that tumor infiltration of tumor-associated macrophages (TAM) and expression of CCL18, the cytokine preferentially secreted by TAM, closely correlate with serum EBV infection titers and tumor progression in two cohorts of NPC patients. In vitro, compared with EBV− NPC cell lines, EBV+ NPC cell lines exhibited superior capacity to attract monocytes and skew them to differentiate to a TAM-like phenotype. Cytokine profiling analysis revealed that NPC cells with active EBV replications recruited monocytes by VEGF and induced TAM by GM-CSF in an NF-κB–dependent manner. Reciprocally, TAM induced epithelial–mesenchymal transition and furthered NF-κB activation of tumor cells by CCL18. In humanized mice, NPC cells with active EBV replications exhibited increased metastasis, and neutralization of CCL18, GM-CSF, and VEGF significantly reduced metastasis. Collectively, our work defines a feed-forward loop between tumor cells and macrophages in NPC, which shows how metastatic potential can evolve concurrently with virus-induced chronic inflammation. Cancer Res; 77(13); 3591–604. ©2017 AACR.
Data from Monitoring the Vascular Response and Resistance to Sunitinib in Renal Cell Carcinoma In Vivo with Susceptibility Contrast MRI
Authors: Robinson Simon P. , Boult Jessica K.R. , Vasudev Naveen S. , Reynolds Andrew R.
Published: March 2024

Abstract
Antiangiogenic therapy is efficacious in metastatic renal cell carcinoma (mRCC). However, the ability of antiangiogenic drugs to delay tumor progression and extend survival is limited, due to either innate or acquired drug resistance. Furthermore, there are currently no validated biomarkers that predict which mRCC patients will benefit from antiangiogenic therapy. Here, we exploit susceptibility contrast MRI (SC-MRI) using intravascular ultrasmall superparamagnetic iron oxide particles to quantify and evaluate tumor fractional blood volume (fBV) as a noninvasive imaging biomarker of response to the antiangiogenic drug sunitinib. We also interrogate the vascular phenotype of RCC xenografts exhibiting acquired resistance to sunitinib. SC-MRI of 786-0 xenografts prior to and 2 weeks after daily treatment with 40 mg/kg sunitinib revealed a 71% (P < 0.01) reduction in fBV in the absence of any change in tumor volume. This response was associated with significantly lower microvessel density (P < 0.01) and lower uptake of the perfusion marker Hoechst 33342 (P < 0.05). The average pretreatment tumor fBV was negatively correlated (R2 = 0.92, P < 0.0001) with sunitinib-induced changes in tumor fBV across the cohort. SC-MRI also revealed suppressed fBV in tumors that acquired resistance to sunitinib. In conclusion, SC-MRI enabled monitoring of the antiangiogenic response of 786-0 RCC xenografts to sunitinib, which revealed that pretreatment tumor fBV was found to be a predictive biomarker of subsequent reduction in tumor blood volume in response to sunitinib, and acquired resistance to sunitinib was not associated with a parallel increase in tumor blood volume. Cancer Res; 77(15); 4127–34. ©2017 AACR.
Data from NEMO, a Transcriptional Target of Estrogen and Progesterone, Is Linked to Tumor Suppressor PML in Breast Cancer
Authors: Elsarraj Hanan S. , Valdez Kelli E. , Hong Yan , Grimm Sandra L. , Ricci Lawrence R. , Fan Fang , Tawfik Ossama , May Lisa , Cusick Therese , Inciardi Marc , Redick Mark , Gatewood Jason , Winblad Onalisa , Hilsenbeck Susan , Edwards Dean P. , Hagan Christy R. , Godwin Andrew K. , Fabian Carol , Behbod Fariba
Published: March 2024

Abstract
The beneficial versus detrimental roles of estrogen plus progesterone (E+P) in breast cancer remains controversial. Here we report a beneficial mechanism of E+P treatment in breast cancer cells driven by transcriptional upregulation of the NFκB modulator NEMO, which in turn promotes expression of the tumor suppressor protein promyelocytic leukemia (PML). E+P treatment of patient-derived epithelial cells derived from ductal carcinoma in situ (DCIS) increased secretion of the proinflammatory cytokine IL6. Mechanistic investigations indicated that IL6 upregulation occurred as a result of transcriptional upregulation of NEMO, the gene that harbored estrogen receptor (ER) binding sites within its promoter. Accordingly, E+P treatment of breast cancer cells increased ER binding to the NEMO promoter, thereby increasing NEMO expression, NFκB activation, and IL6 secretion. In two mouse xenograft models of DCIS, we found that RNAi-mediated silencing of NEMO increased tumor invasion and progression. This seemingly paradoxical result was linked to NEMO-mediated regulation of NFκB and IL6 secretion, increased phosphorylation of STAT3 on Ser727, and increased expression of PML, a STAT3 transcriptional target. In identifying NEMO as a pivotal transcriptional target of E+P signaling in breast cancer cells, our work offers a mechanistic explanation for the paradoxical antitumorigenic roles of E+P in breast cancer by showing how it upregulates the tumor suppressor protein PML. Cancer Res; 77(14); 3802–13. ©2017 AACR.
Data from Early Effector T Lymphocytes Coexpress Multiple Inhibitory Receptors in Primary Non–Small Cell Lung Cancer
Authors: Tassi Elena , Grazia Giulia , Vegetti Claudia , Bersani Ilaria , Bertolini Giulia , Molla Alessandra , Baldassari Paola , Andriani Francesca , Roz Luca , Sozzi Gabriella , Pastorino Ugo , Mortarini Roberta , Anichini Andrea
Published: March 2024

Abstract
Clinical efficacy of PD-1/PD-L1 targeting relies upon the reactivation of tumor-specific but functionally impaired PD-1+ T cells present before therapy. Thus, analyzing early-stage primary tumors may reveal the presence of T cells that are not yet functionally impaired. In this study, we report that activated (HLA-DR+) T cells with an effector memory (TEM) profile are enriched in such lesions. Tumor-infiltrating lymphocytes coexpressed PD-1 with the inhibitory receptors TIM-3, CTLA-4, LAG-3, and TIGIT, but also displayed a recently activated, nonexhausted phenotype. We also identified a subset of CD8+PD-1+FOXP3+ T lymphocytes at the earliest phase of functional differentiation after priming, termed “early effector cells” (EEC), which also exhibited an activated nonexhausted phenotype, but was less differentiated and associated with coexpression of multiple inhibitory receptors. In response to autologous tumor, EECs upregulated CD107a, produced IL2 and IFNγ, and were competent for differentiation. The identification of EECs marked by inhibitory receptor expression at tumor sites will enable investigations of early stages of adaptive antitumor immunity, as well as support the rationale for administering immunotherapy in early-stage non–small cell lung cancer. Cancer Res; 77(4); 851–61. ©2016 AACR.
Data from Therapeutic Targeting of the CBP/p300 Bromodomain Blocks the Growth of Castration-Resistant Prostate Cancer
Authors: Jin Lingyan , Garcia Jesse , Chan Emily , de la Cruz Cecile , Segal Ehud , Merchant Mark , Kharbanda Samir , Raisner Ryan , Haverty Peter M. , Modrusan Zora , Ly Justin , Choo Edna , Kaufman Susan , Beresini Maureen H. , Romero F. Anthony , Magnuson Steven , Gascoigne Karen E.
Published: March 2024

Abstract
Resistance invariably develops to antiandrogen therapies used to treat newly diagnosed prostate cancers, but effective treatments for castration-resistant disease remain elusive. Here, we report that the transcriptional coactivator CBP/p300 is required to maintain the growth of castration-resistant prostate cancer. To exploit this vulnerability, we developed a novel small-molecule inhibitor of the CBP/p300 bromodomain that blocks prostate cancer growth in vitro and in vivo. Molecular dissection of the consequences of drug treatment revealed a critical role for CBP/p300 in histone acetylation required for the transcriptional activity of the androgen receptor and its target gene expression. Our findings offer a preclinical proof of concept for small-molecule therapies to target the CBP/p300 bromodomain as a strategy to treat castration-resistant prostate cancer. Cancer Res; 77(20); 5564–75. ©2017 AACR.
Data from Heme-oxygenase-1 Production by Intestinal CX3CR1+ Macrophages Helps to Resolve Inflammation and Prevents Carcinogenesis
Authors: Marelli Giulia , Erreni Marco , Anselmo Achille , Taverniti Valentina , Guglielmetti Simone , Mantovani Alberto , Allavena Paola
Published: March 2024

Abstract
CX3CR1+ macrophages in the intestinal lamina propria contribute to gut homeostasis through the immunomodulatory interleukin IL10, but there is little knowledge on how these cells or the CX3CR1 receptor may affect colorectal carcinogenesis. In this study, we show that CX3CR1-deficient mice fail to resolve gut inflammation despite high production of IL10 and have increased colitis and adenomatous polyps in chemical and genetic models of colon carcinogenesis. Mechanistically, CX3CL1-mediated engagement of the CX3CR1 receptor induced upregulation of heme-oxygenase-1 (HMOX-1), an antioxidant and anti-inflammatory enzyme. CX3CR1-deficient mice exhibited significantly lower expression of HMOX-1 in their adenomatous colon tissues. Combining LPS and CX3CL1 displayed a strong synergistic effect in vitro, but HMOX-1 levels were significantly lower in KO macrophages. Cohousing of wild-type and CX3CR1−/− mice during the AOM/DSS treatment attenuated disease severity in CX3CR1−/− mice, indicating the importance of the microbiome, but did not fully reinstate HMOX-1 levels and did not abolish polyp formation. In contrast, pharmacologic induction of HMOX-1 in vivo by cobalt protoporphyrin-IX treatment eradicated intestinal inflammation and fully protected KO mice from carcinogenesis. Taken together, our results establish an essential role for the receptor CX3CR1 in gut macrophages in resolving inflammation in the intestine, where it helps protects against colitis-associated cancer by regulating HMOX-1 expression. Cancer Res; 77(16); 4472–85. ©2017 AACR.
Data from Loss of Igf2 Gene Imprinting in Murine Prostate Promotes Widespread Neoplastic Growth
Authors: Damaschke Nathan A. , Yang Bing , Bhusari Sachin , Avilla Mele , Zhong Weixiong , Blute Michael L. , Huang Wei , Jarrard David F.
Published: March 2024

Abstract
Loss of imprinting (LOI) is an epigenetic event that relaxes an allele-specific restriction on gene expression. One gene that experiences LOI is the paracrine insulin-like growth factor IGF2, which occurs commonly in human prostate tissues during aging and tumorigenesis. However, the relationship between IGF2 LOI and prostate tumorigenesis has not been established functionally. In this study, we created a mouse model with CTCF-binding site mutations at the Igf2-H19 imprint control region that abolishes CTCF insulator activity, resulting in biallelic Igf2 expression that mimics increased levels seen with aging-induced LOI. We found that Igf2 LOI increased the prevalence and severity of prostatic intraepithelial neoplasia (PIN), a premalignant lesion. Engineering Nkx3.1 deficiency into our model increased the frequency of PIN lesions in an additive fashion. Prostates harboring LOI displayed increased MAPK signaling and epithelial proliferation. In human prostate tissue arrays, we documented a positive correlation in benign tissues of IGF2 levels with phospho-ERK and phospho-AKT levels. Overall, our results establish that Igf2 LOI is sufficient on its own to increase rates of neoplastic development in the prostate by upregulating critical cancer-associated signaling pathways. Cancer Res; 77(19); 5236–47. ©2017 AACR.
Data from RNA Editing in Pathogenesis of Cancer
Authors: Baysal Bora E. , Sharma Shraddha , Hashemikhabir Seyedsasan , Janga Sarath Chandra
Published: March 2024

Abstract
Several adenosine or cytidine deaminase enzymes deaminate transcript sequences in a cell type or environment-dependent manner by a programmed process called RNA editing. RNA editing enzymes catalyze A>I or C>U transcript alterations and have the potential to change protein coding sequences. In this brief review, we highlight some recent work that shows aberrant patterns of RNA editing in cancer. Transcriptome sequencing studies reveal increased or decreased global RNA editing levels depending on the tumor type. Altered RNA editing in cancer cells may provide a selective advantage for tumor growth and resistance to apoptosis. RNA editing may promote cancer by dynamically recoding oncogenic genes, regulating oncogenic gene expression by noncoding RNA and miRNA editing, or by transcriptome scale changes in RNA editing levels that may affect innate immune signaling. Although RNA editing markedly increases complexity of the cancer cell transcriptomes, cancer-specific recoding RNA editing events have yet to be discovered. Epitranscriptomic changes by RNA editing in cancer represent a novel mechanism contributing to sequence diversity independently of DNA mutations. Therefore, RNA editing studies should complement genome sequence data to understand the full impact of nucleic acid sequence alterations in cancer. Cancer Res; 77(14); 3733–9. ©2017 AACR.
Data from MET Exon 14 Mutation Encodes an Actionable Therapeutic Target in Lung Adenocarcinoma
Authors: Lu Xinyuan , Peled Nir , Greer John , Wu Wei , Choi Peter , Berger Alice H. , Wong Sergio , Jen Kuang-Yu , Seo Youngho , Hann Byron , Brooks Angela , Meyerson Matthew , Collisson Eric A.
Published: March 2024

Abstract
Targeting somatically activated oncogenes has revolutionized the treatment of non–small cell lung cancer (NSCLC). Mutations in the gene mesenchymal–epithelial transition (MET) near the exon 14 splice sites are recurrent in lung adenocarcinoma and cause exon skipping (METΔ14). Here, we analyzed 4,422 samples from 12 different malignancies to estimate the rate of said exon skipping. METΔ14 mutation and transcript were most common in lung adenocarcinoma. Endogenously expressed levels of METΔ14 transformed human epithelial lung cells in a hepatocyte growth factor–dependent manner. In addition, overexpression of the orthologous mouse allele induced lung adenocarcinoma in a novel, immunocompetent mouse model. Met inhibition showed clinical benefit in this model. In addition, we observed a clinical response to crizotinib in a patient with METΔ14-driven NSCLC, only to observe new missense mutations in the MET activation loop, critical for binding to crizotinib, upon clinical progression. These findings support genomically selected clinical trials directed toward METΔ14 in a fraction of NSCLC patients, confirm second-site mutations for further therapeutic targeting prior to and beyond acquired resistance, and provide an in vivo system for the study of METΔ14 in an immunocompetent host. Cancer Res; 77(16); 4498–505. ©2017 AACR.
Data from A Novel Spectroscopically Determined Pharmacodynamic Biomarker for Skin Toxicity in Cancer Patients Treated with Targeted Agents
Authors: Azan Antoine , Caspers Peter J. , Bakker Schut Tom C. , Roy Séverine , Boutros Céline , Mateus Christine , Routier Emilie , Besse Benjamin , Planchard David , Seck Atmane , Kamsu Kom Nyam , Tomasic Gorana , Koljenović Senada , Noordhoek Hegt Vincent , Texier Matthieu , Lanoy Emilie , Eggermont Alexander M.M. , Paci Angelo , Robert Caroline , Puppels Gerwin J. , Mir Lluis M.
Published: March 2024

Abstract
Raman spectroscopy is a noninvasive and label-free optical technique that provides detailed information about the molecular composition of a sample. In this study, we evaluated the potential of Raman spectroscopy to predict skin toxicity due to tyrosine kinase inhibitors treatment. We acquired Raman spectra of skin of patients undergoing treatment with MEK, EGFR, or BRAF inhibitors, which are known to induce severe skin toxicity; for this pilot study, three patients were included for each inhibitor. Our algorithm, based on partial least squares-discriminant analysis (PLS-DA) and cross-validation by bootstrapping, discriminated to variable degrees spectra from patient suffering and not suffering cutaneous adverse events. For MEK and EGFR inhibitors, discriminative power was more than 90% in the viable epidermis skin layer; whereas for BRAF inhibitors, discriminative power was 71%. There was a 81.5% correlation between blood drug concentration and Raman signature of skin in the case of EGFR inhibitors and viable epidermis skin layer. Our results demonstrate the power of Raman spectroscopy to detect apparition of skin toxicity in patients treated with tyrosine kinase inhibitors at levels not detectable via dermatological inspection and histological evaluation. Cancer Res; 77(2); 557–65. ©2016 AACR.
Data from Targeting Tumor-Associated Fibroblasts for Therapeutic Delivery in Desmoplastic Tumors
Authors: Miao Lei , Liu Qi , Lin C. Michael , Luo Cong , Wang Yuhua , Liu Lina , Yin Weiyan , Hu Shihao , Kim William Y. , Huang Leaf
Published: March 2024

Abstract
The off-target distribution of anticancer nanoparticles to fibroblasts creates a barrier to the effective treatment of desmoplastic tumors. However, we hypothesized that this nanoparticle detriment might be exploited to target the expression of secreted cytotoxic proteins from tumor-associated fibroblasts (TAF) as an anticancer strategy. In addressing this hypothesis, plasmids encoding the secretable TNF-related factor sTRAIL were loaded into lipid-coated protamine DNA complexes and administered by infusion in a murine xenograft model of human desmoplastic bladder carcinoma. Three doses were sufficient to generate approximately 70% of TAFs as sTRAIL-producing cells. sTRAIL triggered apoptosis in tumor cell nests adjacent to TAFs. Furthermore, it reverted residual fibroblasts to a quiescent state due to insufficient activation, further compromising tumor growth and remodeling the microenvironment to favor second-wave nanotherapy. We confirmed the efficacy of this strategy in an orthotopic xenograft model of human pancreatic cancer, where the desmoplastic stroma is well known to be a major barrier to the delivery of therapeutic nanoparticles. Collectively, our results offer a proof of concept for the use of nanoparticles to modify TAFs as an effective strategy to treat desmoplastic cancers. Cancer Res; 77(3); 719–31. ©2016 AACR.
Data from Noncoding Effects of Circular RNA CCDC66 Promote Colon Cancer Growth and Metastasis
Authors: Hsiao Kuei-Yang , Lin Ya-Chi , Gupta Sachin Kumar , Chang Ning , Yen Laising , Sun H. Sunny , Tsai Shaw-Jenq
Published: March 2024

Abstract
Circular RNA (circRNA) is a class of noncoding RNA whose functions remain mostly unknown. Recent studies indicate circRNA may be involved in disease pathogenesis, but direct evidence is scarce. Here, we characterize the functional role of a novel circRNA, circCCDC66, in colorectal cancer. RNA-Seq data from matched normal and tumor colon tissue samples identified numerous circRNAs specifically elevated in cancer cells, several of which were verified by quantitative RT-PCR. CircCCDC66 expression was elevated in polyps and colon cancer and was associated with poor prognosis. Gain-of-function and loss-of-function studies in colorectal cancer cell lines demonstrated that circCCDC66 controlled multiple pathological processes, including cell proliferation, migration, invasion, and anchorage-independent growth. In-depth characterization revealed that circCCDC66 exerts its function via regulation of a subset of oncogenes, and knockdown of circCCDC66 inhibited tumor growth and cancer invasion in xenograft and orthotopic mouse models, respectively. Taken together, these findings highlight a novel oncogenic function of circRNA in cancer progression and metastasis. Cancer Res; 77(9); 2339–50. ©2017 AACR.
Data from Cervical Cancer Growth Is Regulated by a c-ABL–PLK1 Signaling Axis
Authors: Yang Xu , Chen Gang , Li Wei , Peng Changmin , Zhu Yue , Yang Xiaoming , Li Teng , Cao Cheng , Pei Huadong
Published: March 2024

Abstract
The nonreceptor tyrosine kinase c-ABL controls cell growth but its contributions in solid tumors are not fully understood. Here we report that the Polo-like kinase PLK1, an essential mitotic kinase regulator, is an important downstream effector of c-ABL in regulating the growth of cervical cancer. c-ABL interacted with and phosphorylated PLK1. Phosphorylation of PLK1 by c-ABL inhibited PLK1 ubiquitination and degradation and enhanced its activity, leading to cell-cycle progression and tumor growth. Both c-ABL and PLK1 were overexpressed in cervical carcinoma. Notably, PLK1 tyrosine phosphorylation correlated with patient survival in cervical cancer. In a murine xenograft model of human cervical cancer, combination treatment with c-ABL and PLK1 inhibitors yielded additive effects on tumor growth inhibition. Our findings highlight the c-ABL–PLK1 axis as a novel prognostic marker and treatment target for human cervical cancers. Cancer Res; 77(5); 1142–54. ©2016 AACR.
Data from Intrinsic Subtypes and Gene Expression Profiles in Primary and Metastatic Breast Cancer
Authors: Cejalvo Juan M. , Martínez de Dueñas Eduardo , Galván Patricia , García-Recio Susana , Burgués Gasión Octavio , Paré Laia , Antolín Silvia , Martinello Rosella , Blancas Isabel , Adamo Barbara , Guerrero-Zotano Ángel , Muñoz Montserrat , Nucíforo Paolo , Vidal María , Pérez Ramón M. , Chacón López-Muniz José I. , Caballero Rosalía , Peg Vicente , Carrasco Eva , Rojo Federico , Perou Charles M. , Cortés Javier , Adamo Vincenzo , Albanell Joan , Gomis Roger R. , Lluch Ana , Prat Aleix
Published: March 2024

Abstract
Biological changes that occur during metastatic progression of breast cancer are still incompletely characterized. In this study, we compared intrinsic molecular subtypes and gene expression in 123 paired primary and metastatic tissues from breast cancer patients. Intrinsic subtype was identified using a PAM50 classifier and χ2 tests determined the differences in variable distribution. The rate of subtype conversion was 0% in basal-like tumors, 23.1% in HER2-enriched (HER2-E) tumors, 30.0% in luminal B tumors, and 55.3% in luminal A tumors. In 40.2% of cases, luminal A tumors converted to luminal B tumors, whereas in 14.3% of cases luminal A and B tumors converted to HER2-E tumors. We identified 47 genes that were expressed differentially in metastatic versus primary disease. Metastatic tumors were enriched for proliferation-related and migration-related genes and diminished for luminal-related genes. Expression of proliferation-related genes were better at predicting overall survival in metastatic disease (OSmet) when analyzed in metastatic tissue rather than primary tissue. In contrast, a basal-like gene expression signature was better at predicting OSmet in primary disease compared with metastatic tissue. We observed correlations between time to tumor relapse and the magnitude of changes of proliferation, luminal B, or HER2-E signatures in metastatic versus primary disease. Although the intrinsic subtype was largely maintained during metastatic progression, luminal/HER2-negative tumors acquired a luminal B or HER2-E profile during metastatic progression, likely reflecting tumor evolution or acquisition of estrogen independence. Overall, our analysis revealed the value of stratifying gene expression by both cancer subtype and tissue type, providing clinicians more refined tools to evaluate prognosis and treatment. Cancer Res; 77(9); 2213–21. ©2017 AACR.
Data from Krüppel-like Transcription Factor KLF10 Suppresses TGFβ-Induced Epithelial-to-Mesenchymal Transition via a Negative Feedback Mechanism
Authors: Mishra Vivek Kumar , Subramaniam Malayannan , Kari Vijayalakshmi , Pitel Kevin S. , Baumgart Simon J. , Naylor Ryan M. , Nagarajan Sankari , Wegwitz Florian , Ellenrieder Volker , Hawse John R. , Johnsen Steven A.
Published: March 2024

Abstract
TGFβ–SMAD signaling exerts a contextual effect that suppresses malignant growth early in epithelial tumorigenesis but promotes metastasis at later stages. Longstanding challenges in resolving this functional dichotomy may uncover new strategies to treat advanced carcinomas. The Krüppel-like transcription factor, KLF10, is a pivotal effector of TGFβ/SMAD signaling that mediates antiproliferative effects of TGFβ. In this study, we show how KLF10 opposes the prometastatic effects of TGFβ by limiting its ability to induce epithelial-to-mesenchymal transition (EMT). KLF10 depletion accentuated induction of EMT as assessed by multiple metrics. KLF10 occupied GC-rich sequences in the promoter region of the EMT-promoting transcription factor SLUG/SNAI2, repressing its transcription by recruiting HDAC1 and licensing the removal of activating histone acetylation marks. In clinical specimens of lung adenocarcinoma, low KLF10 expression associated with decreased patient survival, consistent with a pivotal role for KLF10 in distinguishing the antiproliferative versus prometastatic functions of TGFβ. Our results establish that KLF10 functions to suppress TGFβ-induced EMT, establishing a molecular basis for the dichotomy of TGFβ function during tumor progression. Cancer Res; 77(9); 2387–400. ©2017 AACR.
Data from FGF19 Protects Hepatocellular Carcinoma Cells against Endoplasmic Reticulum Stress via Activation of FGFR4–GSK3β–Nrf2 Signaling
Authors: Teng Yong , Zhao Huakan , Gao Lixia , Zhang Wenfa , Shull Austin Y. , Shay Chloe
Published: March 2024

Abstract
The tumor microenvironment induces endoplasmic reticulum (ER) stress in tumor cells, an event that can promote progression, but it is unknown how tumor cells adapt to this stress. In this study, we show that the fibroblast growth factor FGF19, a gene frequently amplified in hepatocellular carcinoma (HCC), facilitates a survival response to ER stress. Levels of FGF19 expression were increased in stressed HCC cells in culture and in a mouse xenograft model. Induction of ER stress required the transcription factor ATF4, which directly bound the FGF19 promoter. In cells where ER stress was induced, FGF19 overexpression promoted HCC cell survival and increased resistance to apoptosis, whereas FGF19 silencing counteracted these effects. Mechanistic investigations implicated glycogen synthase kinase-3β (GSK3β) in regulating nuclear accumulation of the stress-regulated transcription factor Nrf2 activated by FGF19. Our findings show how FGF19 provides a cytoprotective role against ER stress by activating a FGFR4–GSK3β–Nrf2 signaling cascade, with implications for targeting this signaling node as a candidate therapeutic regimen for HCC management. Cancer Res; 77(22); 6215–25. ©2017 AACR.
Data from Cathepsin B Is Dispensable for Cellular Processing of Cathepsin B-Cleavable Antibody–Drug Conjugates
Authors: Caculitan Niña G. , dela Cruz Chuh Josefa , Ma Yong , Zhang Donglu , Kozak Katherine R. , Liu Yichin , Pillow Thomas H. , Sadowsky Jack , Cheung Tommy K. , Phung Qui , Haley Benjamin , Lee Byoung-Chul , Akita Robert W. , Sliwkowski Mark X. , Polson Andrew G.
Published: March 2024

Abstract
Antibody–drug conjugates (ADC) are designed to selectively bind to tumor antigens via the antibody and release their cytotoxic payload upon internalization. Controllable payload release through judicious design of the linker has been an early technological milestone. Here, we examine the effect of the protease-cleavable valine-citrulline [VC(S)] linker on ADC efficacy. The VC(S) linker was designed to be cleaved by cathepsin B, a lysosomal cysteine protease. Surprisingly, suppression of cathepsin B expression via CRISPR-Cas9 gene deletion or shRNA knockdown had no effect on the efficacy of ADCs with VC(S) linkers armed with a monomethyl auristatin E (MMAE) payload. Mass spectrometry studies of payload release suggested that other cysteine cathepsins can cleave the VC(S) linker. Also, ADCs with a nonprotease-cleavable enantiomer, the VC(R) isomer, mediated effective cell killing with a cysteine-VC(R)-MMAE catabolite generated by lysosomal catabolism. Based on these observations, we altered the payload to a pyrrolo[2,1-c][1,4]benzodiazepine dimer (PBD) conjugate that requires linker cleavage in order to bind its DNA target. Unlike the VC-MMAE ADCs, the VC(S)-PBD ADC is at least 20-fold more cytotoxic than the VC(R)-PBD ADC. Our findings reveal that the VC(S) linker has multiple paths to produce active catabolites and that antibody and intracellular targets are more critical to ADC efficacy. These results suggest that protease-cleavable linkers are unlikely to increase the therapeutic index of ADCs and that resistance based on linker processing is improbable. Cancer Res; 77(24); 7027–37. ©2017 AACR.
Data from Genetic and Environmental Determinants of Immune Response to Cutaneous Melanoma
Authors: Poźniak Joanna , Nsengimana Jérémie , Laye Jonathan P. , O’Shea Sally J. , Diaz Joey Mark S. , Droop Alastair P. , Filia Anastasia , Harland Mark , Davies John R. , Mell Tracey , Randerson-Moor Juliette A. , Muralidhar Sathya , Hogan Sabrina A. , Freiberger Sandra Nicole , Levesque Mitchell P. , Cook Graham P. , Bishop D. Timothy , Newton-Bishop Julia
Published: March 2024

Abstract
The immune response to melanoma improves the survival in untreated patients and predicts the response to immune checkpoint blockade. Here, we report genetic and environmental predictors of the immune response in a large primary cutaneous melanoma cohort. Bioinformatic analysis of 703 tumor transcriptomes was used to infer immune cell infiltration and to categorize tumors into immune subgroups, which were then investigated for association with biological pathways, clinicopathologic factors, and copy number alterations. Three subgroups, with “low”, “intermediate”, and “high” immune signals, were identified in primary tumors and replicated in metastatic tumors. Genes in the low subgroup were enriched for cell-cycle and metabolic pathways, whereas genes in the high subgroup were enriched for IFN and NF-κB signaling. We identified high MYC expression partially driven by amplification, HLA-B downregulation, and deletion of IFNγ and NF-κB pathway genes as the regulators of immune suppression. Furthermore, we showed that cigarette smoking, a globally detrimental environmental factor, modulates immunity, reducing the survival primarily in patients with a strong immune response. Together, these analyses identify a set of factors that can be easily assessed that may serve as predictors of response to immunotherapy in patients with melanoma.
Significance:
These findings identify novel genetic and environmental modulators of the immune response against primary cutaneous melanoma and predict their impact on patient survival.

See related commentary by Anichini, p. 2457
Data from Breast Cancer Risk and Insulin Resistance: Post Genome-Wide Gene–Environment Interaction Study Using a Random Survival Forest
Authors: Jung Su Yon , Papp Jeanette C. , Sobel Eric M. , Yu Herbert , Zhang Zuo-Feng
Published: March 2024

Abstract
Obesity–insulin connections have been considered potential risk factors for postmenopausal breast cancer, and the association between insulin resistance (IR) genotypes and phenotypes can be modified by obesity-lifestyle factors, affecting breast cancer risk. In this study, we explored the role of IR in those pathways at the genome-wide level. We identified IR-genetic factors and selected lifestyles to generate risk profiles for postmenopausal breast cancer. Using large-scale cohort data from postmenopausal women in the Women's Health Initiative Database for Genotypes and Phenotypes Study, our previous genome-wide association gene–behavior interaction study identified 58 loci for associations with IR phenotypes (homeostatic model assessment–IR, hyperglycemia, and hyperinsulinemia). We evaluated those single-nucleotide polymorphisms (SNP) and additional 31 lifestyles in relation to breast cancer risk by conducting a two-stage multimodal random survival forest analysis. We identified the most predictive genetic and lifestyle variables in overall and subgroup analyses [stratified by body mass index (BMI), exercise, and dietary fat intake]. Two SNPs (LINC00460 rs17254590 and MKLN1 rs117911989), exogenous factors related to lifetime cumulative exposure to estrogen, BMI, and dietary alcohol consumption were the most common influential factors across the analyses. Individual SNPs did not have significant associations with breast cancer, but SNPs and lifestyles combined synergistically increased the risk of breast cancer in a gene–behavior, dose-dependent manner. These findings may contribute to more accurate predictions of breast cancer and suggest potential intervention strategies for women with specific genetic and lifestyle factors to reduce their breast cancer risk.
Significance:
These findings identify insulin resistance SNPs in combination with lifestyle as synergistic factors for breast cancer risk, suggesting lifestyle changes can prevent breast cancer in women who carry the risk genotypes.
Data from Diabetes Treatments and Risks of Adverse Breast Cancer Outcomes among Early-Stage Breast Cancer Patients: A SEER-Medicare Analysis
Authors: Chen Lu , Chubak Jessica , Boudreau Denise M. , Barlow William E. , Weiss Noel S. , Li Christopher I.
Published: March 2024

Abstract
The widely prescribed diabetes medicine metformin has been reported to lower the risk of incident breast cancer, but it is unclear whether it affects malignant progression after diagnosis. In this study, we conducted a retrospective cohort study using the linked Surveillance, Epidemiology, and End-Results (SEER)-Medicare database. Women were included in the study if they were aged 66 to 80 years, newly diagnosed with stage I or II breast cancer, and enrolled in Medicare Parts A, B, and D during 2007 to 2011. Information on dispensed diabetes-related medications was obtained from Medicare Part D claims data. Our primary outcomes were second breast cancer events (SBCE), breast cancer recurrence, and breast cancer death. Time-varying Cox proportional hazard models were used to estimate HRs and their 95% confidence intervals (CI). Among 14,766 women included in the study, 791 experienced SBCE, 627 had a recurrence, and 237 died from breast cancer. Use of metformin (n = 2,558) was associated with 28% (95% CI, 0.57–0.92), 31% (95% CI, 0.53–0.90), and 49% (95% CI, 0.33–0.78) lower risks of an SBCE, breast cancer recurrence, and breast cancer death. Use of sulfonylureas or insulin was associated with 1.49- (95% CI, 1.00–2.23) and 2.58-fold (95% CI, 1.72–3.90) higher risks of breast cancer death. Further research may be warranted to determine whether metformin is a preferred treatment for diabetes among breast cancer survivors and whether it benefits breast cancer patients without diabetes. Cancer Res; 77(21); 6033–41. ©2017 AACR.