bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Comparison between Urine and Cervical Samples for HPV DNA Detection and Typing in Young Women in Colombia
Authors: Cómbita Alba Lucía , Gheit Tarik , González Paula , Puerto Devi , Murillo Raúl Hernando , Montoya Luisa , Vorsters Alex , Van Keer Severien , Van Damme Pierre , Tommasino Massimo , Hernández-Suárez Gustavo , Sánchez Laura , Herrero Rolando , Wiesner Carolina
Published: March 2024

Abstract
Urine sampling for HPV DNA detection has been proposed as an effective method for monitoring the impact of HPV vaccination programs; however, conflicting results have been reported. The goal of this study was to evaluate the performance of optimized urine HPV DNA testing in women aged 19 to 25 years. Optimization process included the use of first void urine, immediate mixing of urine with DNA preservative, and the concentration of all HPV DNA, including cell-free DNA fragments. Urine and cervical samples were collected from 535 young women attending cervical screening at health centers from two Colombian cities. HPV DNA detection and genotyping was performed using an HPV type-specific multiplex genotyping assay, which combines multiplex polymerase chain reaction with bead-based Luminex technology. Concordance between HPV DNA detection in urine and cervical samples was determined using kappa statistics and McNemar tests. The accuracy of HPV DNA testing in urine samples was evaluated measuring sensitivity and specificity using as reference the results obtained from cervical samples. Statistical analysis was performed using STATA11.2 software. The findings revealed an overall HPV prevalence of 60.00% in cervical samples and 64.72% in urine samples, HPV-16 being the most frequent HPV type detected in both specimens. Moreover, our results indicate that detection of HPV DNA in first void urine provides similar results to those obtained with cervical samples and can be used to monitor HPV vaccination trials and programs as evidenced by the substantial concordance found for the detection of the four vaccine types. Cancer Prev Res; 9(9); 766–71. ©2016 AACR.
Data from Circulating Receptor Activator of Nuclear Factor-κB (RANK), RANK ligand (RANKL), and Mammographic Density in Premenopausal Women
Authors: Toriola Adetunji T. , Appleton Catherine M. , Zong Xiaoyu , Luo Jingqin , Weilbaecher Katherine , Tamimi Rulla M. , Colditz Graham A.
Published: March 2024

Abstract
The receptor activator of nuclear factor-κB (RANK) pathway plays essential roles in breast development. Mammographic density is a strong risk factor for breast cancer, especially in premenopausal women. We, therefore, investigated the associations of circulating RANK and soluble RANK ligand (sRANKL) with mammographic density in premenopausal women. Mammographic density was measured as volumetric percent density in 365 cancer-free premenopausal women (mean age, 47.5 years) attending screening mammogram at the Washington University School of Medicine (St. Louis, MO). We used linear regression models adjusted for confounders, to compare the least-square means of volumetric percent density across tertiles of circulating RANK and sRANKL. Furthermore, because RANKL levels in mammary tissue are modulated by progesterone, we stratified analyses by progesterone levels. The mean volumetric percent density increased across tertiles of circulating RANK from 8.6% in tertile 1, to 8.8% in tertile 2, and 9.5% in tertile 3 (Ptrend = 0.02). For sRANKL, the mean volumetric percent density was 8.5% in tertile 1, 9.4% in tertile 2, and 9.0% in tertile 3 (Ptrend = 0.30). However, when restricted to women with higher progesterone levels, the mean volumetric percent density increased from 9.1% in sRANKL tertile 1 to 9.5% in tertile 2, and 10.1% in tertile 3 (Ptrend = 0.01). Circulating RANK was positively associated with volumetric percent density, while circulating sRANKL was positively associated with volumetric percent density among women with higher progesterone levels. These findings support the inhibition of RANKL signaling as a pathway to reduce mammographic density and possibly breast cancer incidence in high-risk women with dense breasts.
Data from Saliva and Lung Microbiome Associations with Electronic Cigarette Use and Smoking
Authors: Ying Kevin L. , Brasky Theodore M. , Freudenheim Jo L. , McElroy Joseph P. , Nickerson Quentin A. , Song Min-Ae , Weng Daniel Y. , Wewers Mark D. , Whiteman Noah B. , Mathe Ewy A. , Shields Peter G.
Published: March 2024

Abstract
The microbiome has increasingly been linked to cancer. Little is known about the lung and oral cavity microbiomes in smokers, and even less for electronic cigarette (EC) users, compared with never-smokers. In a cross-sectional study (n = 28) of smokers, EC users, and never-smokers, bronchoalveolar lavage and saliva samples underwent metatranscriptome profiling to examine associations with lung and oral microbiomes. Pairwise comparisons assessed differentially abundant bacteria species. Total bacterial load was similar between groups, with no differences in bacterial diversity across lung microbiomes. In lungs, 44 bacteria species differed significantly (FDR < 0.1) between smokers/never-smokers, with most decreased in smokers. Twelve species differed between smokers/EC users, all decreased in smokers of which Neisseria sp. KEM232 and Curvibacter sp. AEP1-3 were observed. Among the top five decreased species in both comparisons, Neisseria elongata, Neisseria sicca, and Haemophilus parainfluenzae were observed. In the oral microbiome, 152 species were differentially abundant for smokers/never-smokers, and 17 between smokers/electronic cigarette users, but only 21 species were differentially abundant in both the lung and oral cavity. EC use is not associated with changes in the lung microbiome compared with never-smokers, indicating EC toxicity does not affect microbiota. Statistically different bacteria in smokers compared with EC users and never-smokers were almost all decreased, potentially due to toxic effects of cigarette smoke. The low numbers of overlapping oral and lung microbes suggest that the oral microbiome is not a surrogate for analyzing smoking-related effects in the lung.
Prevention Relevance:
The microbiome affects cancer and other disease risk. The effects of e-cig usage on the lung microbiome are essentially unknown. Given the importance of lung microbiome dysbiosis populated by oral species which have been observed to drive lung cancer progression, it is important to study effects of e-cig use on microbiome.
Data from Association Between Aspirin Use and Gastric Adenocarcinoma: A Prospective Cohort Study
Authors: Kwon Sohee , Ma Wenjie , Drew David A. , Klempner Samuel J. , Leonardo Brianna M. , Flynn Jacqueline J. , Cao Yin , Giovannucci Edward L. , Bao Ying , Fuchs Charles S. , Song Mingyang , Chan Andrew T.
Published: March 2024

Abstract
Prospective data examining the association of aspirin use, according to dose and duration, with long-term risk of gastric adenocarcinoma in non-Asian cohorts are lacking. We evaluated the association between aspirin use and risk of gastric adenocarcinoma in two large prospective U.S. cohort studies, the Nurses' Health Study and the Health Professionals Follow-up Study. Cox proportional hazards regression models were used to calculate multivariable adjusted HRs and 95% confidence intervals (CI). Among the 159,116 participants, we documented 316 gastric adenocarcinoma cases (176 women, 140 men) over 34 years encompassing 4.5 million person-years. Among women, regular aspirin use (at least two times or more per week) was significantly associated with lower risk of gastric adenocarcinoma (multivariable HR, 0.52; 95% CI, 0.37–0.73) compared with nonregular use. However, regular aspirin use was not associated with gastric adenocarcinoma risk among men (multivariable HR, 1.08; 95% CI, 0.77–1.52; Pheterogeneity for sex = 0.003). Among women, the lower risk of gastric adenocarcinoma was more apparent with increasing duration of aspirin use (Ptrend < 0.001) and more than five tablets per week (multivariable HR, 0.51; 95% CI, 0.31–0.84). Regular, long-term aspirin use was associated with lower risk of gastric adenocarcinoma among women, but not men. The benefit appeared after at least 10 years of use and was maximized at higher doses among women. The heterogeneity by sex in the association of aspirin use with risk of gastric adenocarcinoma requires further investigation.
Prevention Relevance:
Novel prevention is urgently needed to reduce incidence and mortality of gastric cancer. We found that regular aspirin use was associated with lower risk of gastric adenocarcinoma among women, but not men. The benefit appeared after at least 10 years of use and was maximized at higher doses among women.

See related Spotlight, p. 213
Data from Cancer Prevention with Resistant Starch in Lynch Syndrome Patients in the CAPP2-Randomized Placebo Controlled Trial: Planned 10-Year Follow-up
Authors: Mathers John C. , Elliott Faye , Macrae Finlay , Mecklin Jukka-Pekka , Möslein Gabriela , McRonald Fiona E. , Bertario Lucio , Evans D. Gareth , Gerdes Anne-Marie , Ho Judy W.C. , Lindblom Annika , Morrison Patrick J. , Rashbass Jem , Ramesar Raj S. , Seppälä Toni T. , Thomas Huw J.W. , Sheth Harsh J. , Pylvänäinen Kirsi , Reed Lynn , Borthwick Gillian M. , Bishop D. Timothy , Burn John
Published: March 2024

Abstract
The CAPP2 trial investigated the long-term effects of aspirin and resistant starch on cancer incidence in patients with Lynch syndrome (LS). Participants with LS were randomized double-blind to 30 g resistant starch (RS) daily or placebo for up to 4 years. We present long-term cancer outcomes based on the planned 10-year follow-up from recruitment, supplemented by National Cancer Registry data to 20 years in England, Wales, and Finland. Overall, 463 participants received RS and 455 participants received placebo. After up to 20 years follow-up, there was no difference in colorectal cancer incidence (n = 52 diagnosed with colorectal cancer among those randomized to RS against n = 53 on placebo) but fewer participants had non-colorectal LS cancers in those randomized to RS (n = 27) compared with placebo (n = 48); intention-to-treat (ITT) analysis [HR, 0.54; 95% confidence interval (CI), 0.33–0.86; P = 0.010]. In ITT analysis, allowing for multiple primary cancer diagnoses among participants by calculating incidence rate ratios (IRR) confirmed the protective effect of RS against non–colorectal cancer LS cancers (IRR, 0.52; 95% CI, 0.32–0.84; P = 0.0075). These effects are particularly pronounced for cancers of the upper GI tract; 5 diagnoses in those on RS versus 21 diagnoses on placebo. The reduction in non–colorectal cancer LS cancers was detectable in the first 10 years and continued in the next decade. For colorectal cancer, ITT analysis showed no effect of RS on colorectal cancer risk (HR, 0.92; 95% CI, 0.62–1.34; P = 0.63). There was no interaction between aspirin and RS treatments. In conclusion, 30 g daily RS appears to have a substantial protective effect against non–colorectal cancer cancers for patients with LS.
Prevention Relevance:
Regular bowel screening and aspirin reduce colorectal cancer among patients with LS but extracolonic cancers are difficult to detect and manage. This study suggests that RS reduces morbidity associated with extracolonic cancers.

See related Spotlight, p. 557
Data from Obesity-associated Breast Inflammation among Hispanic/Latina Breast Cancer Patients
Authors: Greenlee Heather , Shi Zaixing , Hibshoosh Hanina , Giri Dilip D. , Ahmed Aqeel , Williams Samantha , Falcone Domenick J. , Winston Lisle A. , Zhou Xi K. , Hudis Clifford A. , Hershman Dawn L. , Dannenberg Andrew J. , Iyengar Neil M.
Published: March 2024

Abstract
Breast white adipose tissue inflammation (BWATi) is associated with obesity and higher breast cancer risk among non-Hispanic white women. Obesity is prevalent in Hispanic/Latina patients with breast cancer, and the occurrence of BWATi in this population is not well-characterized. The association between BWATi and body mass index (BMI) was evaluated in Hispanic/Latina patients with breast cancer who underwent mastectomy. BWATi was defined as the presence of crown-like structures of the breast (CLS-B), detected by CD68 IHC in nontumor breast tissue. BWATi severity was quantified as number of CLS-B/cm2. Adipocyte diameter was measured using hematoxylin and eosin-stained breast tissue sections. Preoperative BMI (within 1 week prior to mastectomy) was categorized as normal (18.5–<25.0 kg/m2), overweight (25.0–<30.0 kg/m2), class I obesity (30.0–<35.0 kg/m2), and class II–III obesity (35.0 kg/m2 or above). Patient charts were abstracted to record clinicopathologic features and liver function tests <90 days before mastectomy. The study included 91 women (mean age 69 years; range 36–96 years). Prevalence of BWATi increased with BMI (24% in normal weight, 34% in overweight, 57% in class I obesity, and 65% in class II–III obesity; Ptrend <0.01). Severe BWATi (>0.27 CLS-B/cm2) was associated with higher BMI (Ptrend = 0.046) and greater adipocyte diameter (P = 0.04). Adjusting for BMI, neoadjuvant chemotherapy, and elevated alanine aminotransferase were associated with severe BWATi, and current smoking was associated with mild BWATi (all P < 0.05). BWATi was associated with higher BMI in Hispanic/Latina patients with breast cancer, consistent with previously described associations in other populations.
Data from Withaferin A Inhibits Fatty Acid Synthesis in Rat Mammary Tumors
Authors: Singh Krishna B. , Hahm Eun-Ryeong , Kim Su-Hyeong , Singh Shivendra V.
Published: March 2024

Abstract
Withaferin A (WA), which is a small molecule derived from a medicinal plant (Withania somnifera), inhibits growth of human breast cancer xenografts and mammary tumor development in rodent models without any toxicity. However, the mechanism underlying inhibition of mammary cancer development by WA administration is not fully understood. Herein, we demonstrate that the fatty acid synthesis pathway is a novel target of WA in mammary tumors. Treatment of MCF-7 and MDA-MB-231 cells with WA resulted in suppression of fatty acid metabolizing enzymes, including ATP-citrate lyase (ACLY), acetyl-CoA carboxylase 1 (ACC1), fatty acid synthase (FASN), and carnitine palmitoyltransferase 1A (CPT1A). Expression of FASN and CPT1A was significantly higher in N-methyl-N-nitrosourea–induced mammary tumors in rats when compared with normal mammary tissues. WA-mediated inhibition of mammary tumor development in rats was associated with a statistically significant decrease in expression of ACC1 and FASN and suppression of plasma and/or mammary tumor levels of total free fatty acids and phospholipids. WA administration also resulted in a significant increase in percentage of natural killer cells in the spleen. The protein level of sterol regulatory element binding protein 1 (SREBP1) was decreased in MDA-MB-231 cells after WA treatment. Overexpression of SREBP1 in MDA-MB-231 cells conferred partial but significant protection against WA-mediated downregulation of ACLY and ACC1. In conclusion, circulating and/or mammary tumor levels of fatty acid synthesis enzymes and total free fatty acids may serve as biomarkers of WA efficacy in future clinical trials.
Prevention Relevance:
The present study shows that breast cancer prevention by WA in rats is associated with suppression of fatty acid synthesis.
Data from Genome-wide DNA Methylation Events in TMPRSS2–ERG Fusion-Negative Prostate Cancers Implicate an EZH2-Dependent Mechanism with miR-26a Hypermethylation
Authors: Börno Stefan T. , Fischer Axel , Kerick Martin , Fälth Maria , Laible Mark , Brase Jan C. , Kuner Ruprecht , Dahl Andreas , Grimm Christina , Sayanjali Behnam , Isau Melanie , Röhr Christina , Wunderlich Andrea , Timmermann Bernd , Claus Rainer , Plass Christoph , Graefen Markus , Simon Ronald , Demichelis Francesca , Rubin Mark A. , Sauter Guido , Schlomm Thorsten , Sültmann Holger , Lehrach Hans , Schweiger Michal R.
Published: March 2024

Abstract
Prostate cancer is the second most common cancer among men worldwide. Alterations in the DNA methylation pattern can be one of the leading causes for prostate cancer formation. This study is the first high-throughput sequencing study investigating genome-wide DNA methylation patterns in a large cohort of 51 tumor and 53 benign prostate samples using methylated DNA immunoprecipitation sequencing. Comparative analyses identified more than 147,000 cancer-associated epigenetic alterations. In addition, global methylation patterns show significant differences based on the TMPRSS2–ERG rearrangement status. We propose the hypermethylation of miR-26a as an alternative pathway of ERG rearrangement-independent EZH2 activation. The observed increase in differential methylation events in fusion–negative tumors can explain the tumorigenic process in the absence of genomic rearrangements.

Significance: In contrast to TMPRSS2–ERG-rearranged tumors, the pathomechanism for gene fusion–negative tumors is completely unclear. Using a sequencing-based approach, our work uncovers significant global epigenetic alterations in TMPRSS2–ERG gene fusion–negative tumors and provides a mechanistic explanation for the tumor formation process. Cancer Discov; 2(11); 1024–35. ©2012 AACR.

Read the Commentary on this article by Alumkal and Herman, p. 979.

This article is featured in Highlights of This Issue, p. 961
Data from Dual Roles of PARP-1 Promote Cancer Growth and Progression
Authors: Schiewer Matthew J. , Goodwin Jonathan F. , Han Sumin , Brenner J. Chad , Augello Michael A. , Dean Jeffry L. , Liu Fengzhi , Planck Jamie L. , Ravindranathan Preethi , Chinnaiyan Arul M. , McCue Peter , Gomella Leonard G. , Raj Ganesh V. , Dicker Adam P. , Brody Jonathan R. , Pascal John M. , Centenera Margaret M. , Butler Lisa M. , Tilley Wayne D. , Feng Felix Y. , Knudsen Karen E.
Published: March 2024

Abstract
PARP-1 is an abundant nuclear enzyme that modifies substrates by poly(ADP-ribose)-ylation. PARP-1 has well-described functions in DNA damage repair and also functions as a context-specific regulator of transcription factors. With multiple models, data show that PARP-1 elicits protumorigenic effects in androgen receptor (AR)–positive prostate cancer cells, in both the presence and absence of genotoxic insult. Mechanistically, PARP-1 is recruited to sites of AR function, therein promoting AR occupancy and AR function. It was further confirmed in genetically defined systems that PARP-1 supports AR transcriptional function, and that in models of advanced prostate cancer, PARP-1 enzymatic activity is enhanced, further linking PARP-1 to AR activity and disease progression. In vivo analyses show that PARP-1 activity is required for AR function in xenograft tumors, as well as tumor cell growth in vivo and generation and maintenance of castration resistance. Finally, in a novel explant system of primary human tumors, targeting PARP-1 potently suppresses tumor cell proliferation. Collectively, these studies identify novel functions of PARP-1 in promoting disease progression, and ultimately suggest that the dual functions of PARP-1 can be targeted in human prostate cancer to suppress tumor growth and progression to castration resistance.

Significance: These studies introduce a paradigm shift with regard to PARP-1 function in human malignancy, and suggest that the dual functions of PARP-1 in DNA damage repair and transcription factor regulation can be leveraged to suppress pathways critical for promalignant phenotypes in prostate cancer cells by modulation of the DNA damage response and hormone signaling pathways. The combined studies highlight the importance of dual PARP-1 function in malignancy and provide the basis for therapeutic targeting. Cancer Discov; 2(12); 1134–49. ©2012 AACR.

This article is highlighted in the In This Issue feature, p. 1065
Data from Cancer-Stimulated Mesenchymal Stem Cells Create a Carcinoma Stem Cell Niche via Prostaglandin E2 Signaling
Authors: Li Hua-Jung , Reinhardt Ferenc , Herschman Harvey R. , Weinberg Robert A.
Published: March 2024

Abstract
Mesenchymal cells of the tumor-associated stroma are critical determinants of carcinoma cell behavior. We focus here on interactions of carcinoma cells with mesenchymal stem cells (MSC), which are recruited to the tumor stroma and, once present, are able to influence the phenotype of the carcinoma cells. We find that carcinoma cell–derived interleukin-1 (IL-1) induces prostaglandin E2 (PGE2) secretion by MSCs. The resulting PGE2 operates in an autocrine manner, cooperating with ongoing paracrine IL-1 signaling, to induce expression of a group of cytokines by the MSCs. The PGE2 and cytokines then proceed to act in a paracrine fashion on the carcinoma cells to induce activation of β-catenin signaling and formation of cancer stem cells. These observations indicate that MSCs and derived cell types create a cancer stem cell niche to enable tumor progression via release of PGE2 and cytokines.

Significance: Although PGE2 has been implicated time and again in fostering tumorigenesis, its effects on carcinoma cells that contribute specifically to tumor formation are poorly understood. Here we show that tumor cells are able to elicit a strong induction of the COX-2/microsomal prostaglandin-E synthase-1 (mPGES-1)/PGE2 axis in MSCs recruited to the tumor-associated stroma by releasing IL-1, which in turn elicits a mesenchymal/stem cell–like phenotype in the carcinoma cells. Cancer Discov; 2(9); 840–55. ©2012 AACR.

Read the Commentary on this article by Räsänen and Herlyn, p. 775.

This article is highlighted in the In This Issue feature, p. 753.
Data from MicroRNAs Reprogram Normal Fibroblasts into Cancer-Associated Fibroblasts in Ovarian Cancer
Authors: Mitra Anirban K. , Zillhardt Marion , Hua Youjia , Tiwari Payal , Murmann Andrea E. , Peter Marcus E. , Lengyel Ernst
Published: March 2024

Abstract
Cancer-associated fibroblasts (CAF) are a major constituent of the tumor stroma, but little is known about how cancer cells transform normal fibroblasts into CAFs. microRNAs (miRNA) are small noncoding RNA molecules that negatively regulate gene expression at a posttranscriptional level. Although it is clearly established that miRNAs are deregulated in human cancers, it is not known whether miRNA expression in resident fibroblasts is affected by their interaction with cancer cells. We found that in ovarian CAFs, miR-31 and miR-214 were downregulated, whereas miR-155 was upregulated when compared with normal or tumor-adjacent fibroblasts. Mimicking this deregulation by transfecting miRNAs and miRNA inhibitors induced a functional conversion of normal fibroblasts into CAFs, and the reverse experiment resulted in the reversion of CAFs into normal fibroblasts. The miRNA-reprogrammed normal fibroblasts and patient-derived CAFs shared a large number of upregulated genes highly enriched in chemokines, which are known to be important for CAF function. The most highly upregulated chemokine, CCL5, (C-C motif ligand 5) was found to be a direct target of miR-214. These results indicate that ovarian cancer cells reprogram fibroblasts to become CAFs through the action of miRNAs. Targeting these miRNAs in stromal cells could have therapeutic benefit.

Significance: The mechanism by which quiescent fibroblasts are converted into CAFs is unclear. The present study identifies a set of 3 miRNAs that reprogram normal fibroblasts to CAFs. These miRNAs may represent novel therapeutic targets in the tumor microenvironment. Cancer Discov; 2(12); 1100–8. ©2012 AACR.

Read the Commentary on this article by Chou and Werb, p. 1078

This article is highlighted in the In This Issue feature, p. 1065
Data from A Bioluminescent Transposon Reporter-Trap Identifies Tumor-Specific Microenvironment-Induced Promoters in Salmonella for Conditional Bacterial-Based Tumor Therapy
Authors: Flentie Kelly , Kocher Brandon , Gammon Seth T. , Novack Deborah V. , McKinney Jeffrey S. , Piwnica-Worms David
Published: March 2024

Abstract
Salmonella specifically localize to malignant tumors in vivo, a trait potentially exploitable as a delivery system for cancer therapeutics. To characterize mechanisms and genetic responses of Salmonella during interaction with living neoplastic cells, we custom-designed a promoterless transposon reporter containing bacterial luciferase. Analysis of a library containing 7,400 independent Salmonella transposon insertion mutants in coculture with melanoma or colon carcinoma cells identified five bacterial genes specifically activated by cancer cells: adiY, yohJ, STM1787, STM1791, and STM1793. Experiments linked acidic pH, a common characteristic of the tumor microenvironment, to a strong, specific, and reversible stimulus for activation of these Salmonella genes in vitro and in vivo. Indeed, a Salmonella reporter strain encoding a luciferase transgene regulated by the STM1787 promoter, which contains a tusp motif, showed tumor-induced bioluminescence in vivo. Furthermore, Salmonella expressing Shiga toxin from the STM1787 promoter provided potent and selective antitumor activity in vitro and in vivo, showing the potential for a conditional bacterial-based tumor-specific therapeutic.

Significance: Salmonella, which often encounter acidic environments during classical host infection, may co-opt evolutionarily conserved pathways for tumor colonization in response to the acidic tumor microenvironment. We identified specific promoter sequences that provide a platform for targeted Salmonella-based tumor therapy in vivo. Cancer Discov; 2(7); 624–37. ©2012 AACR.

Read the Commentary on this article by Hoffman, p. 588.

This article is highlighted in the In This Issue feature, p. 569.
Data from Ovarian Cancer Spheroids Use Myosin-Generated Force to Clear the Mesothelium
Authors: Iwanicki Marcin P. , Davidowitz Rachel A. , Ng Mei Rosa , Besser Achim , Muranen Taru , Merritt Melissa , Danuser Gaudenz , Ince Tan , Brugge Joan S.
Published: March 2024

Abstract
Dissemination of ovarian tumors involves the implantation of cancer spheroids into the mesothelial monolayer on the walls of peritoneal and pleural cavity organs. Biopsies of tumors attached to peritoneal organs show that mesothelial cells are not present under tumor masses. We have developed a live, image-based in vitro model in which interactions between tumor spheroids and mesothelial cells can be monitored in real time to provide spatial and temporal understanding of mesothelial clearance. In this article, we provide evidence that ovarian cancer spheroids use integrin- and talin-dependent activation of myosin and traction force to promote displacement of mesothelial cells from underneath a tumor cell spheroid. These results suggest that ovarian tumor cell clusters gain access to the submesothelial environment by exerting force on the mesothelial cells lining target organs, driving migration and clearance of the mesothelial cells.

Significance: This study uses time-lapse video microscopy to decipher cellular events associated with ovarian tumor cell intercalation of mesothelial cell layers. Ovarian cancer clusters were found to use actomyosin-generated force to physically displace mesothelial cells and gain access to the submesothelial environment. Blockade of force-conducting molecules, including α5 integrin, talin I, and nonmuscle myosin II, in cancer cells abrogated mesothelial displacement from underneath attached cancer spheroids. Cancer Discovery; 1(2); 144–57. ©2011 AACR.

Read the Commentary on this article by Kenny et al., p. 100

This article is highlighted in the In This Issue feature, p. 91
Data from The Transcription Factor ZNF217 Is a Prognostic Biomarker and Therapeutic Target during Breast Cancer Progression
Authors: Littlepage Laurie E. , Adler Adam S. , Kouros-Mehr Hosein , Huang Guiqing , Chou Jonathan , Krig Sheryl R. , Griffith Obi L. , Korkola James E. , Qu Kun , Lawson Devon A. , Xue Qing , Sternlicht Mark D. , Dijkgraaf Gerrit J.P. , Yaswen Paul , Rugo Hope S. , Sweeney Colleen A. , Collins Colin C. , Gray Joe W. , Chang Howard Y. , Werb Zena
Published: March 2024

Abstract
The transcription factor ZNF217 is a candidate oncogene in the amplicon on chromosome 20q13 that occurs in 20% to 30% of primary human breast cancers and that correlates with poor prognosis. We show that Znf217 overexpression drives aberrant differentiation and signaling events, promotes increased self-renewal capacity, mesenchymal marker expression, motility, and metastasis, and represses an adult tissue stem cell gene signature downregulated in cancers. By in silico screening, we identified candidate therapeutics that at low concentrations inhibit growth of cancer cells expressing high ZNF217. We show that the nucleoside analogue triciribine inhibits ZNF217-induced tumor growth and chemotherapy resistance and inhibits signaling events [e.g., phospho-AKT, phospho-mitogen-activated protein kinase (MAPK)] in vivo. Our data suggest that ZNF217 is a biomarker of poor prognosis and a therapeutic target in patients with breast cancer and that triciribine may be part of a personalized treatment strategy in patients overexpressing ZNF217. Because ZNF217 is amplified in numerous cancers, these results have implications for other cancers.

Significance: This study finds that ZNF217 is a poor prognostic indicator and therapeutic target in patients with breast cancer and may be a strong biomarker of triciribine treatment efficacy in patients. Because previous clinical trials for triciribine did not include biomarkers of treatment efficacy, this study provides a rationale for revisiting triciribine in the clinical setting as a therapy for patients with breast cancer who overexpress ZNF217. Cancer Discov; 2(7); 638–51. ©2012 AACR.

This article is highlighted in the In This Issue feature, p. 569.
Data from Differential Sensitivity of Glioma- versus Lung Cancer–Specific EGFR Mutations to EGFR Kinase Inhibitors
Authors: Vivanco Igor , Robins H. Ian , Rohle Daniel , Campos Carl , Grommes Christian , Nghiemphu Phioanh Leia , Kubek Sara , Oldrini Barbara , Chheda Milan G. , Yannuzzi Nicolas , Tao Hui , Zhu Shaojun , Iwanami Akio , Kuga Daisuke , Dang Julie , Pedraza Alicia , Brennan Cameron W. , Heguy Adriana , Liau Linda M. , Lieberman Frank , Yung W. K. Alfred , Gilbert Mark R. , Reardon David A. , Drappatz Jan , Wen Patrick Y. , Lamborn Kathleen R. , Chang Susan M. , Prados Michael D. , Fine Howard A. , Horvath Steve , Wu Nian , Lassman Andrew B. , DeAngelis Lisa M. , Yong William H. , Kuhn John G. , Mischel Paul S. , Mehta Minesh P. , Cloughesy Timothy F. , Mellinghoff Ingo K.
Published: March 2024

Abstract
Activation of the epidermal growth factor receptor (EGFR) in glioblastoma (GBM) occurs through mutations or deletions in the extracellular (EC) domain. Unlike lung cancers with EGFR kinase domain (KD) mutations, GBMs respond poorly to the EGFR inhibitor erlotinib. Using RNAi, we show that GBM cells carrying EGFR EC mutations display EGFR addiction. In contrast to KD mutants found in lung cancer, glioma-specific EGFR EC mutants are poorly inhibited by EGFR inhibitors that target the active kinase conformation (e.g., erlotinib). Inhibitors that bind to the inactive EGFR conformation, however, potently inhibit EGFR EC mutants and induce cell death in EGFR-mutant GBM cells. Our results provide first evidence for single kinase addiction in GBM and suggest that the disappointing clinical activity of first-generation EGFR inhibitors in GBM versus lung cancer may be attributed to the different conformational requirements of mutant EGFR in these 2 cancer types.

Significance: Approximately 40% of human glioblastomas harbor oncogenic EGFR alterations, but attempts to therapeutically target EGFR with first-generation EGFR kinase inhibitors have failed. Here, we demonstrate selective sensitivity of glioma-specific EGFR mutants to ATP-site competitive EGFR kinase inhibitors that target the inactive conformation of the catalytic domain. Cancer Discov; 2(5); 458–71. ©2012 AACR.

Read the Commentary on this article by Park and Lemmon, p. 398.

This article is highlighted in the In This Issue feature, p. 377.
Data from De-Repression of PDGFRβ Transcription Promotes Acquired Resistance to EGFR Tyrosine Kinase Inhibitors in Glioblastoma Patients
Authors: Akhavan David , Pourzia Alexandra L. , Nourian Alex A. , Williams Kevin J. , Nathanson David , Babic Ivan , Villa Genaro R. , Tanaka Kazuhiro , Nael Ali , Yang Huijun , Dang Julie , Vinters Harry V. , Yong William H. , Flagg Mitchell , Tamanoi Fuyuhiko , Sasayama Takashi , James C. David , Kornblum Harley I. , Cloughesy Tim F. , Cavenee Webster K. , Bensinger Steven J. , Mischel Paul S.
Published: March 2024

Abstract
Acquired resistance to tyrosine kinase inhibitors (TKI) represents a major challenge for personalized cancer therapy. Multiple genetic mechanisms of acquired TKI resistance have been identified in several types of human cancer. However, the possibility that cancer cells may also evade treatment by co-opting physiologically regulated receptors has not been addressed. Here, we show the first example of this alternate mechanism in brain tumors by showing that EGF receptor (EGFR)-mutant glioblastomas (GBMs) evade EGFR TKIs by transcriptionally de-repressing platelet-derived growth factor receptor β (PDGFRβ). Mechanistic studies show that EGFRvIII signaling actively suppresses PDGFRβ transcription in an mTORC1- and extracellular signal–regulated kinase-dependent manner. Genetic or pharmacologic inhibition of oncogenic EGFR renders GBMs dependent on the consequently de-repressed PDGFRβ signaling for growth and survival. Importantly, combined inhibition of EGFR and PDGFRβ signaling potently suppresses tumor growth in vivo. These data identify a novel, nongenetic TKI resistance mechanism in brain tumors and provide compelling rationale for combination therapy.

Significance: These results provide the first clinical and biologic evidence for receptor tyrosine kinase (RTK) “switching” as a mechanism of resistance to EGFR inhibitors in GBM and provide a molecular explanation of how tumors can become “addicted” to a nonamplified, nonmutated, physiologically regulated RTK to evade targeted treatment. Cancer Discov; 3(5); 534–47. ©2013 AACR.

This article is highlighted in the In This Issue feature, p. 471
Data from Forced Mitotic Entry of S-Phase Cells as a Therapeutic Strategy Induced by Inhibition of WEE1
Authors: Aarts Marieke , Sharpe Rachel , Garcia-Murillas Isaac , Gevensleben Heidrun , Hurd Melissa S. , Shumway Stuart D. , Toniatti Carlo , Ashworth Alan , Turner Nicholas C.
Published: March 2024

Abstract
Inhibition of the protein kinase WEE1 synergizes with chemotherapy in preclinical models and WEE1 inhibitors are being explored as potential cancer therapies. Here, we investigate the mechanism that underlies this synergy. We show that WEE1 inhibition forces S-phase–arrested cells directly into mitosis without completing DNA synthesis, resulting in highly abnormal mitoses characterized by dispersed chromosomes and disorganized bipolar spindles, ultimately resulting in mitotic exit with gross micronuclei formation and apoptosis. This mechanism of cell death is shared by CHK1 inhibitors, and combined WEE1 and CHK1 inhibition forces mitotic entry from S-phase in the absence of chemotherapy. We show that p53/p21 inactivation combined with high expression of mitotic cyclins and EZH2 predispose to mitotic entry during S-phase with cells reliant on WEE1 to prevent premature cyclin-dependent kinase (CDK)1 activation. These features are characteristic of aggressive breast, and other, cancers for which WEE1 inhibitor combinations represent a promising targeted therapy.

Significance: Here, we describe a novel mechanism of inducing cancer cell death by WEE1 inhibition, forcing mitotic entry directly from S-phase. This mechanism represents a potential therapeutic approach for aggressive breast cancers, and in particular triple-negative and basal-like breast cancers, as WEE1 inhibition specifically targets the features inherent in these cancers: frequent TP53 mutation and high expression of mitotic cyclins and the polycomb protein EZH2. Cancer Discov; 2(6); 524–39. © 2012 AACR.

This article is highlighted in the In This Issue feature, p. 473
Data from C-Raf Is Required for the Initiation of Lung Cancer by K-RasG12D
Authors: Karreth Florian A. , Frese Kristopher K. , DeNicola Gina M. , Baccarini Manuela , Tuveson David A.
Published: March 2024

Abstract
The Ras/Raf/MEK/ERK (extracellular signal–regulated kinase) pathway is primarily responsible for mitogenesis in metazoans, and mutational activation of this pathway is common in cancer. A variety of selective chemical inhibitors directed against the mitogen-activated protein kinase pathway are now available for clinical investigation and thus the determination of the importance of each of the kinases in oncogenesis is paramount. We investigated the role of two Raf kinases, B-Raf and C-Raf, in Ras oncogenesis, and found that although B-Raf and C-Raf have overlapping functions in primary mesenchymal cells, C-Raf but not B-Raf is required for the proliferative effects of K-RasG12D in primary epithelial cells. Furthermore, in a lung cancer mouse model, C-Raf is essential for tumor initiation by oncogenic K-RasG12D, whereas B-Raf is dispensable for this process. Our findings reveal that K-RasG12D elicits its oncogenic effects primarily through C-Raf and suggest that selective C-Raf inhibition could be explored as a therapeutic strategy for K-Ras–dependent cancers.

Significance: Ras is one of the most prevalent oncogenes in human cancer; however, it is considered “undruggable.” Therefore, increasing our understanding of the importance of Ras effectors, including the Raf/MEK/ERK pathway, will create novel avenues for therapeutic intervention. Cancer Discovery; 1(2); 128–36. © 2011 AACR.

Read the Commentary on this article by Rebocho and Marais, p. 98

This article is highlighted in the In This Issue feature, p. 91
Data from Autophagy Sustains Mitochondrial Glutamine Metabolism and Growth of BrafV600E–Driven Lung Tumors
Authors: Strohecker Anne M. , Guo Jessie Yanxiang , Karsli-Uzunbas Gizem , Price Sandy M. , Chen Guanghua Jim , Mathew Robin , McMahon Martin , White Eileen
Published: March 2024

Abstract
Autophagic elimination of defective mitochondria suppresses oxidative stress and preserves mitochondrial function. Here, the essential autophagy gene Atg7 was deleted in a mouse model of BrafV600E-induced lung cancer in the presence or absence of the tumor suppressor Trp53. Atg7 deletion initially induced oxidative stress and accelerated tumor cell proliferation in a manner indistinguishable from Nrf2 ablation. Compound deletion of Atg7 and Nrf2 had no additive effect, suggesting that both genes modulate tumorigenesis by regulating oxidative stress and revealing a potential mechanism of autophagy-mediated tumor suppression. At later stages of tumorigenesis, Atg7 deficiency resulted in an accumulation of defective mitochondria, proliferative defects, reduced tumor burden, conversion of adenomas and adenocarcinomas to oncocytomas, and increased mouse life span. Autophagy-defective tumor-derived cell lines were impaired in their ability to respire and survive starvation and were glutamine-dependent, suggesting that autophagy-supplied substrates from protein degradation sustains BrafV600E tumor growth and metabolism.

Significance: The essential autophagy gene Atg7 functions to promote BrafV600E-driven lung tumorigenesis by preserving mitochondrial glutamine metabolism. This suggests that inhibiting autophagy is a novel approach to treating BrafV600E-driven cancers. Cancer Discov; 3(11); 1272–85. ©2013 AACR.

See related commentary by Chen and Guan, p. 1225

This article is highlighted in the In This Issue feature, p. 1207
Data from CD36 Repression Activates a Multicellular Stromal Program Shared by High Mammographic Density and Tumor Tissues
Authors: DeFilippis Rosa Anna , Chang Hang , Dumont Nancy , Rabban Joseph T. , Chen Yunn-Yi , Fontenay Gerald V. , Berman Hal K. , Gauthier Mona L. , Zhao Jianxin , Hu Donglei , Marx James J. , Tjoe Judy A. , Ziv Elad , Febbraio Maria , Kerlikowske Karla , Parvin Bahram , Tlsty Thea D.
Published: March 2024

Abstract
Although high mammographic density is considered one of the strongest risk factors for invasive breast cancer, the genes involved in modulating this clinical feature are unknown. Tissues of high mammographic density share key histologic features with stromal components within malignant lesions of tumor tissues, specifically low adipocyte and high extracellular matrix (ECM) content. We show that CD36, a transmembrane receptor that coordinately modulates multiple protumorigenic phenotypes, including adipocyte differentiation, angiogenesis, cell–ECM interactions, and immune signaling, is greatly repressed in multiple cell types of disease-free stroma associated with high mammographic density and tumor stroma. Using both in vitro and in vivo assays, we show that CD36 repression is necessary and sufficient to recapitulate the above-mentioned phenotypes observed in high mammographic density and tumor tissues. Consistent with a functional role for this coordinated program in tumorigenesis, we observe that clinical outcomes are strongly associated with CD36 expression.

Significance: CD36 simultaneously controls adipocyte content and matrix accumulation and is coordinately repressed in multiple cell types within tumor and high mammographic density stroma, suggesting that activation of this stromal program is an early event in tumorigenesis. Levels of CD36 and extent of mammographic density are both modifiable factors that provide potential for intervention. Cancer Discov; 2(9); 826–39. ©2012 AACR.

Read the Commentary on this article by DeClerck, p. 772.

This article is highlighted in the In This Issue feature, p. 753.
Data from Histone H3.3 Mutations Drive Pediatric Glioblastoma through Upregulation of MYCN
Authors: Bjerke Lynn , Mackay Alan , Nandhabalan Meera , Burford Anna , Jury Alexa , Popov Sergey , Bax Dorine A. , Carvalho Diana , Taylor Kathryn R. , Vinci Maria , Bajrami Ilirjana , McGonnell Imelda M. , Lord Christopher J. , Reis Rui M. , Hargrave Darren , Ashworth Alan , Workman Paul , Jones Chris
Published: March 2024

Abstract
Children and young adults with glioblastoma (GBM) have a median survival rate of only 12 to 15 months, and these GBMs are clinically and biologically distinct from histologically similar cancers in older adults. They are defined by highly specific mutations in the gene encoding the histone H3.3 variant H3F3A, occurring either at or close to key residues marked by methylation for regulation of transcription—K27 and G34. Here, we show that the cerebral hemisphere-specific G34 mutation drives a distinct expression signature through differential genomic binding of the K36 trimethylation mark (H3K36me3). The transcriptional program induced recapitulates that of the developing forebrain, and involves numerous markers of stem-cell maintenance, cell-fate decisions, and self-renewal. Critically, H3F3A G34 mutations cause profound upregulation of MYCN, a potent oncogene that is causative of GBMs when expressed in the correct developmental context. This driving aberration is selectively targetable in this patient population through inhibiting kinases responsible for stabilization of the protein.

Significance: We provide the mechanistic explanation for how the first histone gene mutation in human disease biology acts to deliver MYCN, a potent tumorigenic initiator, into a stem-cell compartment of the developing forebrain, selectively giving rise to incurable cerebral hemispheric GBM. Using synthetic lethal approaches to these mutant tumor cells provides a rational way to develop novel and highly selective treatment strategies. Cancer Discov; 3(5); 512–19. ©2013 AACR.

See related commentary by Huang and Weiss, p. 484

This article is highlighted in the In This Issue feature, p. 471
Data from Restricted Expression of miR-30c-2-3p and miR-30a-3p in Clear Cell Renal Cell Carcinomas Enhances HIF2α Activity
Authors: Mathew Lijoy K. , Lee Samuel S. , Skuli Nicolas , Rao Shilpa , Keith Brian , Nathanson Katherine L. , Lal Priti , Simon M. Celeste
Published: March 2024

Abstract
Inactivation of the von-Hippel Lindau (VHL) tumor suppressor gene occurs in 90% of human clear cell renal cell carcinomas (ccRCC) and leads to the stable expression of the hypoxia-inducible factors HIF1α and HIF2α. The constitutive expression of HIF1α in a majority of VHL-deficient tumors is counterintuitive, given that HIF1α functions as a tumor suppressor in ccRCC, whereas HIF2α clearly enhances tumor growth. We demonstrate here that miR-30c-2-3p and miR-30a-3p specifically bind and inhibit expression of HIF2A transcripts, and that the locus encoding miR-30c-2-3p and miR-30a-3p is selectively repressed in “H1H2” VHL-deficient tumors expressing both HIF1α and HIF2α proteins. Inhibiting miR-30a-3p expression increases HIF2α levels in H1H2 ccRCC cells and promotes cellular proliferation, angiogenesis, and xenograft tumor growth. Our results indicate that miR-30c-2-3p and miR-30a-3p repression enhances HIF2α expression and suggests a mechanism whereby the tumor-suppressive effects of constitutive HIF1α expression are attenuated in VHL-deficient H1H2 tumors.

Significance: HIF1α is constitutively expressed in a majority of VHL-deficient ccRCCs, despite its tumor suppressor activity in these malignancies. This study demonstrates that repression of miR-30c-2-3p/miR-30a-3p increases HIF2α levels to promote tumor growth, thereby ameliorating the inhibitory effects of HIF1α in ccRCCs. Cancer Discov; 4(1); 53–60. ©2013 AACR.

See related commentary by Moch and Lukamowicz-Rajska, p. 22

This article is highlighted in the In This Issue feature, p. 1
Data from Inflammation-Induced NFATc1–STAT3 Transcription Complex Promotes Pancreatic Cancer Initiation by KrasG12D
Authors: Baumgart Sandra , Chen Nai-Ming , Siveke Jens T. , König Alexander , Zhang Jin-San , Singh Shiv K. , Wolf Elmar , Bartkuhn Marek , Esposito Irene , Heßmann Elisabeth , Reinecke Johanna , Nikorowitsch Julius , Brunner Marius , Singh Garima , Fernandez-Zapico Martin E. , Smyrk Thomas , Bamlet William R. , Eilers Martin , Neesse Albrecht , Gress Thomas M. , Billadeau Daniel D. , Tuveson David , Urrutia Raul , Ellenrieder Volker
Published: March 2024

Abstract
Cancer-associated inflammation is a molecular key feature in pancreatic ductal adenocarcinoma. Oncogenic KRAS in conjunction with persistent inflammation is known to accelerate carcinogenesis, although the underlying mechanisms remain poorly understood. Here, we outline a novel pathway whereby the transcription factors NFATc1 and STAT3 cooperate in pancreatic epithelial cells to promote KrasG12D-driven carcinogenesis. NFATc1 activation is induced by inflammation and itself accelerates inflammation-induced carcinogenesis in KrasG12D mice, whereas genetic or pharmacologic ablation of NFATc1 attenuates this effect. Mechanistically, NFATc1 complexes with STAT3 for enhancer–promoter communications at jointly regulated genes involved in oncogenesis, for example, Cyclin, EGFR and WNT family members. The NFATc1–STAT3 cooperativity is operative in pancreatitis-mediated carcinogenesis as well as in established human pancreatic cancer. Together, these studies unravel new mechanisms of inflammatory-driven pancreatic carcinogenesis and suggest beneficial effects of chemopreventive strategies using drugs that are currently available for targeting these factors in clinical trials.

Significance: Our study points to the existence of an oncogenic NFATc1–STAT3 cooperativity that mechanistically links inflammation with pancreatic cancer initiation and progression. Because NFATc1–STAT3 nucleoprotein complexes control the expression of gene networks at the intersection of inflammation and cancer, our study has significant relevance for potentially managing pancreatic cancer and other inflammatory-driven malignancies. Cancer Discov; 4(6); 688–701. ©2014 AACR.

This article is highlighted in the In This Issue feature, p. 621