bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from GALNT1-Mediated Glycosylation and Activation of Sonic Hedgehog Signaling Maintains the Self-Renewal and Tumor-Initiating Capacity of Bladder Cancer Stem Cells
Authors: Li Chong , Du Ying , Yang Zhao , He Luyun , Wang Yanying , Hao Lu , Ding Mingxia , Yan Ruping , Wang Jiansong , Fan Zusen
Published: March 2024

Abstract
The existence of bladder cancer stem cells (BCSC) has been suggested to underlie bladder tumor initiation and recurrence. Sonic Hedgehog (SHH) signaling has been implicated in promoting cancer stem cell (CSC) self-renewal and is activated in bladder cancer, but its impact on BCSC maintenance is unclear. In this study, we generated a mAb (BCMab1) against CD44+ human bladder cancer cells that recognizes aberrantly glycosylated integrin α3β1. The combination of BCMab1 with an anti-CD44 antibody identified a BCMab1+CD44+ cell subpopulation as BCSCs with stem cell–like properties. Gene expression analysis revealed that the hedgehog pathway was activated in the BCMab1+CD44+ subpopulation and was required for BCSC self-renewal. Furthermore, the glycotransferase GALNT1 was highly expressed in BCMab1+CD44+ cells and correlated with clinicopathologic features of bladder cancers. Mechanistically, GALNT1 mediated O-linked glycosylation of SHH to promote its activation, which was essential for the self-renewal maintenance of BCSCs and bladder tumorigenesis. Finally, intravesical instillation of GALNT1 siRNA and the SHH inhibitor cyclopamine exerted potent antitumor activity against bladder tumor growth. Taken together, our findings identify a BCSC subpopulation in human bladder tumors that appears to be responsive to the inhibition of GALNT1 and SHH signaling, and thus highlight a potential strategy for preventing the rapid recurrence typical in patients with bladder cancer. Cancer Res; 76(5); 1273–83. ©2015 AACR.
Data from A Small-Molecule Antagonist of HIF2α Is Efficacious in Preclinical Models of Renal Cell Carcinoma
Authors: Wallace Eli M. , Rizzi James P. , Han Guangzhou , Wehn Paul M. , Cao Zhaodan , Du Xinlin , Cheng Tzuling , Czerwinski Robert M. , Dixon Darryl D. , Goggin Barry S. , Grina Jonas A. , Halfmann Megan M. , Maddie Melissa A. , Olive Sarah R. , Schlachter Stephen T. , Tan Huiling , Wang Bin , Wang Keshi , Xie Shanhai , Xu Rui , Yang Hanbiao , Josey John A.
Published: March 2024

Abstract
More than 90% of clear cell renal cell carcinomas (ccRCC) exhibit inactivation of the von Hippel–Lindau (pVHL) tumor suppressor, establishing it as the major underlying cause of this malignancy. pVHL inactivation results in stabilization of the hypoxia-inducible transcription factors, HIF1α and HIF2α, leading to expression of a genetic program essential for the initiation and progression of ccRCC. Herein, we describe the potent, selective, and orally active small-molecule inhibitor PT2385 as a specific antagonist of HIF2α that allosterically blocks its dimerization with the HIF1α/2α transcriptional dimerization partner ARNT/HIF1β. PT2385 inhibited the expression of HIF2α-dependent genes, including VEGF-A, PAI-1, and cyclin D1 in ccRCC cell lines and tumor xenografts. Treatment of tumor-bearing mice with PT2385 caused dramatic tumor regressions, validating HIF2α as a pivotal oncogenic driver in ccRCC. Notably, unlike other anticancer agents that inhibit VEGF receptor signaling, PT2385 exhibited no adverse effect on cardiovascular performance. Thus, PT2385 represents a novel class of therapeutics for the treatment of RCC with potent preclincal efficacy as well as improved tolerability relative to current agents that target the VEGF pathway. Cancer Res; 76(18); 5491–500. ©2016 AACR.
Data from Genomic Loss of DUSP4 Contributes to the Progression of Intraepithelial Neoplasm of Pancreas to Invasive Carcinoma
Authors: Hijiya Naoki , Tsukamoto Yoshiyuki , Nakada Chisato , Tung Nguyen Lam , Kai Tomoki , Matsuura Keiko , Shibata Kohei , Inomata Masafumi , Uchida Tomohisa , Tokunaga Akinori , Amada Kohei , Shirao Kuniaki , Yamada Yasunari , Mori Hiromu , Takeuchi Ichiro , Seto Masao , Aoki Masahiro , Takekawa Mutsuhiro , Moriyama Masatsugu
Published: March 2024

Abstract
The progression from precursor lesions of pancreatic cancer, including pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasm (IPMN), to invasive disease is characterized by stepwise accumulation of genetic alterations. However, it remains unclear whether additional alterations are required for the progression of high-grade neoplasms to invasive pancreatic carcinoma. We compared the genomic profiles of paired noninvasive and invasive carcinoma tissues collected from patients with IPMN. We demonstrate that the frequency of genomic copy-number aberrations significantly increased during the course of invasion, and the loss of 8p11.22-ter was more often associated with invasive tissues. Expression profiling in pancreatic cancer cell lines with and without 8p11.22-ter revealed that DUSP4, an MAPK phosphatase, was significantly downregulated in cells lacking 8p11.22-ter as well as in invasive carcinomas due to genomic loss. Restoration of DUSP4 expression in pancreatic cancer cells significantly suppressed invasiveness and anoikis resistance via ERK inactivation. Accordingly, we found that blockade of ERK signaling by MEK inhibition was effective in an orthotopic xenograft model and significantly extended survival. Collectively, our findings demonstrate a genetic mechanism by which pancreatic precursor lesions progress to invasive carcinomas and highlight DUSP4 as a novel invasion suppressor that can be therapeutically exploited through manipulation of ERK signaling. Cancer Res; 76(9); 2612–25. ©2016 AACR.
Data from DNA-PKcs and PARP1 Bind to Unresected Stalled DNA Replication Forks Where They Recruit XRCC1 to Mediate Repair
Authors: Ying Songmin , Chen Zhihui , Medhurst Annette L. , Neal Jessica A. , Bao Zhengqiang , Mortusewicz Oliver , McGouran Joanna , Song Xinming , Shen Huahao , Hamdy Freddie C. , Kessler Benedikt M. , Meek Katheryn , Helleday Thomas
Published: March 2024

Abstract
A series of critical pathways are responsible for the detection, signaling, and restart of replication forks that encounter blocks during S-phase progression. Small base lesions may obstruct replication fork progression and processing, but the link between repair of small lesions and replication forks is unclear. In this study, we investigated a hypothesized role for DNA-PK, an important enzyme in DNA repair, in cellular responses to DNA replication stress. The enzyme catalytic subunit DNA-PKcs was phosphorylated on S2056 at sites of stalled replication forks in response to short hydroxyurea treatment. Using DNA fiber experiments, we found that catalytically active DNA-PK was required for efficient replication restart of stalled forks. Furthermore, enzymatically active DNA-PK was also required for PARP-dependent recruitment of XRCC1 to stalled replication forks. This activity was enhanced by preventing Mre11-dependent DNA end resection, suggesting that XRCC1 must be recruited early to an unresected stalled fork. We also found that XRCC1 was required for effective restart of a subset of stalled replication forks. Overall, our work suggested that DNA-PK and PARP-dependent recruitment of XRCC1 is necessary to effectively protect, repair, and restart stalled replication forks, providing new insight into how genomic stability is preserved. Cancer Res; 76(5); 1078–88. ©2015 AACR.
Data from Phenotypic and Signaling Consequences of a Novel Aberrantly Spliced Transcript FGF Receptor-3 in Hepatocellular Carcinoma
Authors: Li Ke , Shen Baiyong , Cheng Xi , Ma Ding , Jing Xiaoqian , Liu Xinyu , Yang Weiping , Peng Chenghong , Qiu Weihua
Published: March 2024

Abstract
Fibroblast growth factor receptor 3 (FGFR3) plays important roles in cell proliferation, differentiation, and angiogenesis. FGFR3 is abnormally upregulated in hepatocellular carcinoma (HCC), where it correlates positively with clinicopathologic index, HCC differentiation, and advanced nuclear grade. In this study, we describe an aberrantly spliced transcript of FGFR3, termed FGFR3Δ7-9, was identified as a high frequency even in HCC. FGFR3Δ7-9 lacks exons encoding the immunoglobulin-like III domain and promoted the proliferation, migration, and metastasis of HCC cells both in vitro and in vivo. Coimmunoprecipation and surface plasmon resonance assays demonstrated that the binding affinity of the aberrant FGFR3Δ7-9 receptor to FGFs was significantly higher than wild-type FGFR3IIIc. Furthermore, FGFR3Δ7-9 could be self-activated by homodimerization and autophosphorylation even in the absence of ligand. Finally, FGFR3Δ7-9 more potently induced phosphorylation of the ERK and AKT kinases, leading to abnormal downstream signaling through the ERK and PI3K/AKT/mTOR pathways. FGFR3Δ7-9 also upregulated the metastasis-associated molecules Snail, MMP-9, and downregulated E-cadherin, which associated directly with FGFR3Δ7-9. Thus, as a ligand-dependent or -independent receptor, FGFR3Δ7-9 exerted multiple potent oncogenic functions in HCC cells, including proliferation, migration, and lung metastatic capacity. Overall, FGFR3 mRNA missplicing in HCC contributes significantly to its malignant character, with implications for therapeutic targeting. Cancer Res; 76(14); 4205–15. ©2016 AACR.
Data from MNX1 Is Oncogenically Upregulated in African-American Prostate Cancer
Authors: Zhang Li , Wang Jianghua , Wang Yongquan , Zhang Yiqun , Castro Patricia , Shao Longjiang , Sreekumar Arun , Putluri Nagireddy , Guha Nilanjan , Deepak Saligrama , Padmanaban Arunkumar , Creighton Chad J. , Ittmann Michael
Published: March 2024

Abstract
Incidence and mortality rates for prostate cancer are higher in African-American (AA) men than in European-American (EA) men, but the biologic basis for this disparity is unclear. We carried out a detailed analysis of gene expression changes in prostate cancer compared with their matched benign tissues in a cohort of AA men and compared them with existing data from EA men. In this manner, we identified MNX1 as a novel oncogene upregulated to a relatively greater degree in prostate cancer from AA men. Androgen and AKT signaling play a central role in the pathogenesis of prostate cancer and we found that both of these signaling pathways increased MNX1 expression. MNX1 in turn upregulated lipid synthesis by stimulating expression of SREBP1 and fatty acid synthetase. Our results define MNX1 as a novel targetable oncogene increased in AA prostate cancer that is associated with aggressive disease. Cancer Res; 76(21); 6290–8. ©2016 AACR.
Data from IDH2 Mutations Define a Unique Subtype of Breast Cancer with Altered Nuclear Polarity
Authors: Chiang Sarah , Weigelt Britta , Wen Huei-Chi , Pareja Fresia , Raghavendra Ashwini , Martelotto Luciano G. , Burke Kathleen A. , Basili Thais , Li Anqi , Geyer Felipe C. , Piscuoglio Salvatore , Ng Charlotte K.Y. , Jungbluth Achim A. , Balss Jörg , Pusch Stefan , Baker Gabrielle M. , Cole Kimberly S. , von Deimling Andreas , Batten Julie M. , Marotti Jonathan D. , Soh Hwei-Choo , McCalip Benjamin L. , Serrano Jonathan , Lim Raymond S. , Siziopikou Kalliopi P. , Lu Song , Liu Xiaolong , Hammour Tarek , Brogi Edi , Snuderl Matija , Iafrate A. John , Reis-Filho Jorge S. , Schnitt Stuart J.
Published: March 2024

Abstract
Solid papillary carcinoma with reverse polarity (SPCRP) is a rare breast cancer subtype with an obscure etiology. In this study, we sought to describe its unique histopathologic features and to identify the genetic alterations that underpin SPCRP using massively parallel whole-exome and targeted sequencing. The morphologic and immunohistochemical features of SPCRP support the invasive nature of this subtype. Ten of 13 (77%) SPCRPs harbored hotspot mutations at R172 of the isocitrate dehydrogenase IDH2, of which 8 of 10 displayed concurrent pathogenic mutations affecting PIK3CA or PIK3R1. One of the IDH2 wild-type SPCRPs harbored a TET2 Q548* truncating mutation coupled with a PIK3CA H1047R hotspot mutation. Functional studies demonstrated that IDH2 and PIK3CA hotspot mutations are likely drivers of SPCRP, resulting in its reversed nuclear polarization phenotype. Our results offer a molecular definition of SPCRP as a distinct breast cancer subtype. Concurrent IDH2 and PIK3CA mutations may help diagnose SPCRP and possibly direct effective treatment. Cancer Res; 76(24); 7118–29. ©2016 AACR.
Data from Protective Role for TWEAK/Fn14 in Regulating Acute Intestinal Inflammation and Colitis-Associated Tumorigenesis
Authors: Di Martino Luca , Dave Maneesh , Menghini Paola , Xin Wei , Arseneau Kristen O. , Pizarro Theresa T. , Cominelli Fabio
Published: March 2024

Abstract
Inflammatory bowel disease causes chronic, relapsing intestinal inflammation that can lead to the development of colorectal cancer. Members of the TNF superfamily are key regulators of intestinal inflammation. In particular, TNF-like weak inducer of apoptosis (TWEAK) and its receptor, Fn14, are involved in normal and pathologic intestinal tissue remodeling. In this study, we show that the TWEAK/Fn14 signaling complex plays a protective role during the acute stage of intestinal inflammation and contributes to the prevention of colitis-associated cancer during chronic inflammation through its proapoptotic effects. Colitis was induced in Fn14−/− and Fn14+/+ wild-type littermates by administering 3% dextran sodium sulfate (DSS) for 7 days followed by 2-week recovery; azoxymethane (AOM) administration followed by two cycles of DSS/recovery was used to induce tumors. Reciprocal bone marrow chimeric mice were generated to compare hematopoietic and nonhematopoietic-specific effector tissues. Fn14−/− mice had enhanced susceptibility to colitis compared with Fn14+/+ controls as assessed by endoscopic and histologic inflammatory scores, daily weight loss, and mortality rates during recovery after DSS administration. Bone marrow transfer experiments showed that both hematopoietic and nonhematopoietic components are involved in protection against colitis. Tumor lesions were found in the colons of most Fn14−/− mice, but not Fn14+/+ controls. AOM/DSS administration enhanced susceptibility to tumorigenesis in Fn14−/− mice. Overall, these findings show that Fn14 plays a protective role during the acute stages of intestinal inflammation, and its absence promotes the development of colitis-associated cancer. Cancer Res; 76(22); 6533–42. ©2016 AACR.
Data from Adaptive NK Cells with Low TIGIT Expression Are Inherently Resistant to Myeloid-Derived Suppressor Cells
Authors: Sarhan Dhifaf , Cichocki Frank , Zhang Bin , Yingst Ashley , Spellman Stephen R. , Cooley Sarah , Verneris Michael R. , Blazar Bruce R. , Miller Jeffrey S.
Published: March 2024

Abstract
Human cytomegalovirus (CMV)-induced adaptive natural killer (NK) cells display distinct phenotypic and functional characteristics, including properties of immune memory. We hypothesized that these cells may be more resistant to suppression mediated by immunoregulatory cell subsets, making them attractive for use in cancer therapy. Here we report that relative to conventional NK cells, adaptive NK cells express lower levels of the inhibitory receptor T-cell Ig and ITIM domain (TIGIT), which results in resistance to immune suppression mediated by myeloid-derived suppressor cells (MDSC), as derived from cytokine induction in normal blood or patients with myelodysplastic syndrome. In contrast, conventional NK cells were potently suppressed by MDSCs, an effect abrogated completely by TIGIT blockade. Mechanistically, TIGIT signaling in NK cells after MDSC coculture led to a decrease in the phosphorylation of ZAP70/Syk and ERK1/2. These effects were reversed by blocking TIGIT on NK cells or by inhibiting production of reactive oxygen species (ROS) by MDSCs, the latter of which upregulated the TIGIT ligand CD155 on MDSCs. Accordingly, the blunted cytotoxicity of NK cells cocultured with MDSCs against tumor cells could be reversed by blocking TIGIT or ROS production. Overall, our results show how adaptive NK cells arising in response to CMV infection can escape MDSC-mediated suppression, and defined TIGIT antagonists as a novel type of checkpoint inhibitor to enhance NK-cell–mediated responses against cancer and infection. Cancer Res; 76(19); 5696–706. ©2016 AACR.
Data from Predicting Responses to Neoadjuvant Chemotherapy in Breast Cancer: ACRIN 6691 Trial of Diffuse Optical Spectroscopic Imaging
Authors: Tromberg Bruce J. , Zhang Zheng , Leproux Anaïs , O'Sullivan Thomas D. , Cerussi Albert E. , Carpenter Philip M. , Mehta Rita S. , Roblyer Darren , Yang Wei , Paulsen Keith D. , Pogue Brian W. , Jiang Shudong , Kaufman Peter A. , Yodh Arjun G. , Chung So Hyun , Schnall Mitchell , Snyder Bradley S. , Hylton Nola , Boas David A. , Carp Stefan A. , Isakoff Steven J. , Mankoff David
Published: March 2024

Abstract
The prospective multicenter ACRIN 6691 trial was designed to evaluate whether changes from baseline to mid-therapy in a diffuse optical spectroscopic imaging (DOSI)–derived imaging endpoint, the tissue optical index (TOI), predict pathologic complete response (pCR) in women undergoing breast cancer neoadjuvant chemotherapy (NAC). DOSI instruments were constructed at the University of California, Irvine (Irvine, CA), and delivered to six institutions where 60 subjects with newly diagnosed breast tumors (at least 2 cm in the longest dimension) were enrolled over a 2-year period. Bedside DOSI images of the tissue concentrations of deoxy-hemoglobin (ctHHb), oxy-hemoglobin (ctHbO2), water (ctH2O), lipid, and TOI (ctHHb × ctH2O/lipid) were acquired on both breasts up to four times during NAC treatment: baseline, 1-week, mid-point, and completion. Of the 34 subjects (mean age 48.4 ± 10.7 years) with complete, evaluable data from both normal and tumor-containing breast, 10 (29%) achieved pCR as determined by central pathology review. The percent change in tumor-to-normal TOI ratio (%TOITN) from baseline to mid-therapy ranged from −82% to 321%, with a median of −36%. Using pCR as the reference standard and ROC curve methodology, %TOITN AUC was 0.60 (95% CI, 0.39–0.81). In the cohort of 17 patients with baseline tumor oxygen saturation (%StO2) greater than the 77% population median, %TOITN AUC improved to 0.83 (95% CI, 0.63–1.00). We conclude that the combination of baseline functional properties and dynamic optical response shows promise for clinical outcome prediction. Cancer Res; 76(20); 5933–44. ©2016 AACR.
Data from CXCL1 Is Critical for Premetastatic Niche Formation and Metastasis in Colorectal Cancer
Authors: Wang Dingzhi , Sun Haiyan , Wei Jie , Cen Bo , DuBois Raymond N.
Published: March 2024

Abstract
Emerging evidence suggests that the primary tumor influences the development of supportive metastatic microenvironments, referred to as premetastatic niches, in certain distant organs before arrival of metastatic cells. However, the mechanisms underlying the contributions of the primary tumor to premetastatic niche formation are not fully understood. Here, we demonstrate that colorectal carcinoma cells secrete VEGFA, which stimulates tumor-associated macrophages to produce CXCL1 in the primary tumor. Elevation of CXCL1 in premetastatic liver tissue recruited CXCR2-positive myeloid-derived suppressor cells (MDSC) to form a premetastatic niche that ultimately promoted liver metastases. Importantly, premetastatic liver-infiltrating MDSCs induced tumor cell survival without involvement of innate or adaptive immune responses. Our study provides the first evidence that primary malignant cell-secreted VEGFA stimulates tumor-associated macrophages to produce CXCL1, which recruits CXCR2-positive MDSCs to form a premetastatic niche to promote liver metastases. Our findings not only shed light on how the tumor microenvironment contributes to premetastatic niche formation at distant sites, but they also provide comprehensive insights into how MDSCs are recruited to other organs where they contribute to metastatic spread of disease. Moreover, our work also provides a rationale for development of CXCR2 antagonists to inhibit or prevent metastatic spread of disease. Cancer Res; 77(13); 3655–65. ©2017 AACR.
Data from SIRT2 Deacetylates and Inhibits the Peroxidase Activity of Peroxiredoxin-1 to Sensitize Breast Cancer Cells to Oxidant Stress-Inducing Agents
Authors: Fiskus Warren , Coothankandaswamy Veena , Chen Jianguang , Ma Hongwei , Ha Kyungsoo , Saenz Dyana T. , Krieger Stephanie S. , Mill Christopher P. , Sun Baohua , Huang Peng , Mumm Jeffrey S. , Melnick Ari M. , Bhalla Kapil N.
Published: March 2024

Abstract
SIRT2 is a protein deacetylase with tumor suppressor activity in breast and liver tumors where it is mutated; however, the critical substrates mediating its antitumor activity are not fully defined. Here we demonstrate that SIRT2 binds, deacetylates, and inhibits the peroxidase activity of the antioxidant protein peroxiredoxin (Prdx-1) in breast cancer cells. Ectopic overexpression of SIRT2, but not its catalytically dead mutant, increased intracellular levels of reactive oxygen species (ROS) induced by hydrogen peroxide, which led to increased levels of an overoxidized and multimeric form of Prdx-1 with activity as a molecular chaperone. Elevated levels of SIRT2 sensitized breast cancer cells to intracellular DNA damage and cell death induced by oxidative stress, as associated with increased levels of nuclear FOXO3A and the proapoptotic BIM protein. In addition, elevated levels of SIRT2 sensitized breast cancer cells to arsenic trioxide, an approved therapeutic agent, along with other intracellular ROS-inducing agents. Conversely, antisense RNA-mediated attenuation of SIRT2 reversed ROS-induced toxicity as demonstrated in a zebrafish embryo model system. Collectively, our findings suggest that the tumor suppressor activity of SIRT2 requires its ability to restrict the antioxidant activity of Prdx-1, thereby sensitizing breast cancer cells to ROS-induced DNA damage and cell cytotoxicity. Cancer Res; 76(18); 5467–78. ©2016 AACR.
Data from ARHGAP18 Downregulation by miR-200b Suppresses Metastasis of Triple-Negative Breast Cancer by Enhancing Activation of RhoA
Authors: Humphries Brock , Wang Zhishan , Li Yunfei , Jhan Jing-Ru , Jiang Yiguo , Yang Chengfeng
Published: March 2024

Abstract
Rho GTPases activated in cancer cells drive proliferation, migration, and metastasis. Thus, RhoGAP proteins, which negatively regulate Rho GTPases, are generally thought to function as tumor suppressors. Here this expectation was challenged by characterization of ARHGAP18, a RhoGAP family member that is selectively overexpressed in highly migratory triple-negative breast cancer (TNBC) cells. In human breast tumors, higher ARHGAP18 levels associated with worse overall survival, recurrence-free survival, and metastasis-free survival. In TNBC cells, ARHGAP18 deletion increased RhoA activation but reduced growth, migration, and metastatic capacity. Mechanistic investigations revealed that ARHGAP18 levels were controlled by miR-200b, the enforced expression of which was sufficient to activate RhoA, enhanced formation of focal adhesions and actin stress fibers, and reduced migration and metastasis. Enforced elevation of ARHGAP18 where miR-200b was stably expressed reduced RhoA activity but increased cell migration. Pharmacologic inhibition of the Rho effector kinase ROCK blocked RhoA signaling and reversed the inhibitory effect of miR-200b on cell migration. Finally, ARHGAP18 overexpression or ROCK inhibition was sufficient to overcome metastatic blockade by miR-200b. Taken together, these results define opposing roles for oncogenic ARHGAP18 and tumor suppressive miR-200b in determining TNBC cell migration and metastatic prowess. Cancer Res; 77(15); 4051–64. ©2017 AACR.
Data from Human Pancreatic Cancer Cells Induce a MyD88-Dependent Stromal Response to Promote a Tumor-Tolerant Immune Microenvironment
Authors: Delitto Daniel , Delitto Andrea E. , DiVita Bayli B. , Pham Kien , Han Song , Hartlage Emily R. , Newby Brittney N. , Gerber Michael H. , Behrns Kevin E. , Moldawer Lyle L. , Thomas Ryan M. , George Thomas J. , Brusko Todd M. , Mathews Clayton E. , Liu Chen , Trevino Jose G. , Hughes Steven J. , Wallet Shannon M.
Published: March 2024

Abstract
Cancer cells exert mastery over the local tumor-associated stroma (TAS) to configure protective immunity within the tumor microenvironment. The immunomodulatory character of pancreatic lysates of patients with cancer differs from those with pancreatitis. In this study, we evaluated the cross-talk between pancreatic cancer and its TAS in primary human cell culture models. Upon exposure of TAS to pancreatic cancer cell-conditioned media, we documented robust secretion of IL6 and IL8. This TAS response was MyD88-dependent and sufficient to directly suppress both CD4+ and CD8+ T-cell proliferation, inducing Th17 polarization at the expense of Th1. We found that patients possessed a similar shift in circulating effector memory Th17:Th1 ratios compared with healthy controls. The TAS response also directly suppressed CD8+ T-cell–mediated cytotoxicity. Overall, our results demonstrate how TAS contributes to the production of an immunosuppressive tumor microenvironment in pancreatic cancer. Cancer Res; 77(3); 672–83. ©2016 AACR.
Data from Adaptation to TKI Treatment Reactivates ERK Signaling in Tyrosine Kinase–Driven Leukemias and Other Malignancies
Authors: Bruner J. Kyle , Ma Hayley S. , Li Li , Qin Alice Can Ran , Rudek Michelle A. , Jones Richard J. , Levis Mark J. , Pratz Keith W. , Pratilas Christine A. , Small Donald
Published: March 2024

Abstract
FMS-like tyrosine kinase-3 (FLT3) tyrosine kinase inhibitors (TKI) have been tested extensively to limited benefit in acute myeloid leukemia (AML). We hypothesized that FLT3/internal tandem duplication (ITD) leukemia cells exhibit mechanisms of intrinsic signaling adaptation to TKI treatment that are associated with an incomplete response. Here, we identified reactivation of ERK signaling within hours following treatment of FLT3/ITD AML cells with selective inhibitors of FLT3. When these cells were treated with inhibitors of both FLT3 and MEK in combination, ERK reactivation was abrogated and anti-leukemia effects were more pronounced compared with either drug alone. ERK reactivation was also observed following inhibition of other tyrosine kinase–driven cancer cells, including EGFR-mutant lung cancer, HER2-amplified breast cancer, and BCR–ABL leukemia. These studies reveal an adaptive feedback mechanism in tyrosine kinase–driven cancers associated with reactivation of ERK signaling in response to targeted inhibition. Cancer Res; 77(20); 5554–63. ©2017 AACR.
Data from CHK1 Inhibition in Small-Cell Lung Cancer Produces Single-Agent Activity in Biomarker-Defined Disease Subsets and Combination Activity with Cisplatin or Olaparib
Authors: Sen Triparna , Tong Pan , Stewart C. Allison , Cristea Sandra , Valliani Aly , Shames David S. , Redwood Abena B. , Fan You Hong , Li Lerong , Glisson Bonnie S. , Minna John D. , Sage Julien , Gibbons Don L. , Piwnica-Worms Helen , Heymach John V. , Wang Jing , Byers Lauren Averett
Published: March 2024

Abstract
Effective targeted therapies for small-cell lung cancer (SCLC), the most aggressive form of lung cancer, remain urgently needed. Here we report evidence of preclinical efficacy evoked by targeting the overexpressed cell-cycle checkpoint kinase CHK1 in SCLC. Our studies employed RNAi-mediated attenuation or pharmacologic blockade with the novel second-generation CHK1 inhibitor prexasertib (LY2606368), currently in clinical trials. In SCLC models in vitro and in vivo, LY2606368 exhibited strong single-agent efficacy, augmented the effects of cisplatin or the PARP inhibitor olaparib, and improved the response of platinum-resistant models. Proteomic analysis identified CHK1 and MYC as top predictive biomarkers of LY2606368 sensitivity, suggesting that CHK1 inhibition may be especially effective in SCLC with MYC amplification or MYC protein overexpression. Our findings provide a preclinical proof of concept supporting the initiation of a clinical efficacy trial in patients with platinum-sensitive or platinum-resistant relapsed SCLC. Cancer Res; 77(14); 3870–84. ©2017 AACR.
Data from De Novo Lipid Synthesis Facilitates Gemcitabine Resistance through Endoplasmic Reticulum Stress in Pancreatic Cancer
Authors: Tadros Saber , Shukla Surendra K. , King Ryan J. , Gunda Venugopal , Vernucci Enza , Abrego Jaime , Chaika Nina V. , Yu Fang , Lazenby Audrey J. , Berim Lyudmyla , Grem Jean , Sasson Aaron R. , Singh Pankaj K.
Published: March 2024

Abstract
Pancreatic adenocarcinoma is moderately responsive to gemcitabine-based chemotherapy, the most widely used single-agent therapy for pancreatic cancer. Although the prognosis in pancreatic cancer remains grim in part due to poor response to therapy, previous attempts at identifying and targeting the resistance mechanisms have not been very successful. By leveraging The Cancer Genome Atlas dataset, we identified lipid metabolism as the metabolic pathway that most significantly correlated with poor gemcitabine response in pancreatic cancer patients. Furthermore, we investigated the relationship between alterations in lipogenesis pathway and gemcitabine resistance by utilizing tissues from the genetically engineered mouse model and human pancreatic cancer patients. We observed a significant increase in fatty acid synthase (FASN) expression with increasing disease progression in spontaneous pancreatic cancer mouse model, and a correlation of high FASN expression with poor survival in patients and poor gemcitabine responsiveness in cell lines. We observed a synergistic effect of FASN inhibitors with gemcitabine in pancreatic cancer cells in culture and orthotopic implantation models. Combination of gemcitabine and the FASN inhibitor orlistat significantly diminished stemness, in part due to induction of endoplasmic reticulum (ER) stress that resulted in apoptosis. Moreover, direct induction of ER stress with thapsigargin caused a similar decrease in stemness and showed synergistic activity with gemcitabine. Our in vivo studies with orthotopic implantation models demonstrated a robust increase in gemcitabine responsiveness upon inhibition of fatty acid biosynthesis with orlistat. Altogether, we demonstrate that fatty acid biosynthesis pathway manipulation can help overcome the gemcitabine resistance in pancreatic cancer by regulating ER stress and stemness. Cancer Res; 77(20); 5503–17. ©2017 AACR.
Data from Trastuzumab Increases HER2 Uptake and Cross-Presentation by Dendritic Cells
Authors: Gall Victor A. , Philips Anne V. , Qiao Na , Clise-Dwyer Karen , Perakis Alexander A. , Zhang Mao , Clifton Guy T. , Sukhumalchandra Pariya , Ma Qing , Reddy Sangeetha M. , Yu Dihua , Molldrem Jeffrey J. , Peoples George E. , Alatrash Gheath , Mittendorf Elizabeth A.
Published: March 2024

Abstract
Early-phase clinical trials evaluating CD8+ T cell–eliciting, HER2-derived peptide vaccines administered to HER2+ breast cancer patients in the adjuvant setting suggest synergy between the vaccines and trastuzumab, the mAb targeting the HER2 protein. Among 60 patients enrolled in clinical trials evaluating the E75 + GM-CSF and GP2 + GM-CSF vaccines, there have been no recurrences in patients vaccinated after receiving trastuzumab as part of standard therapy in the per treatment analyses conducted after a median follow-up of greater than 34 months. Here, we describe a mechanism by which this synergy may occur. Flow cytometry showed that trastuzumab facilitated uptake of HER2 by dendritic cells (DC), which was mediated by the Fc receptor and was specific to trastuzumab. In vitro, increased HER2 uptake by DC increased cross-presentation of E75, the immunodominant epitope derived from the HER2 protein, an observation confirmed in two in vivo mouse models. This increased E75 cross-presentation, mediated by trastuzumab treatment, enabled more efficient expansion of E75-specific cytotoxic T cells (E75-CTL). These results demonstrate a mechanism by which trastuzumab links innate and adaptive immunity by facilitating activation of antigen-specific T cells. On the basis of these data, we conclude that HER2-positive breast cancer patients that have been treated with trastuzumab may experience a more robust antitumor immune response by restimulation of T cells with the E75 peptide vaccine, thereby accounting for the improved disease-free survival observed with combination therapy. Cancer Res; 77(19); 5374–83. ©2017 AACR.
Data from Chemopreventive Effects of ROS Targeting in a Murine Model of BRCA1-Deficient Breast Cancer
Authors: Li Mo , Chen Qian , Yu Xiaochun
Published: March 2024

Abstract
There remains great interest in practical strategies to limit the elevated risks of familial breast and ovarian cancers driven by BRCA1 mutation. Here, we report that limiting the production of reactive oxygen species (ROS) is sufficient to reduce DNA lesions and delay tumorigenesis in a murine model of BRCA1-deficient breast cancer. We documented a large amount of endogenous estrogen oxidative metabolites in the mammary gland of the model, which induced DNA adducts and apurinic/apyrimidinic sites associated with DNA double-strand breaks and genomic instability. Repressing estrogen oxidation via antioxidant treatments reduced oxidative DNA lesions and delayed the onset of mammary tumors. Overall our work suggests an answer to the long-standing question of why germline BRCA1 mutations cause tissue-specific tumors, in showing how tissue-specific, ROS-induced DNA lesions create a nongenetic force to promote mammary tumors in BRCA1-deficient mice. Our findings create a rationale for evaluating suitable antioxidant modalities as a chemopreventive strategy for familial breast cancer. Cancer Res; 77(2); 448–58. ©2016 AACR.
Data from IGFBP7 Deletion Promotes Hepatocellular Carcinoma
Authors: Akiel Maaged , Guo Chunqing , Li Xia , Rajasekaran Devaraja , Mendoza Rachel G. , Robertson Chadia L. , Jariwala Nidhi , Yuan Fang , Subler Mark A. , Windle Jolene , Garcia Dawn K. , Lai Zhao , Chen Hung-I Harry , Chen Yidong , Giashuddin Shah , Fisher Paul B. , Wang Xiang-Yang , Sarkar Devanand
Published: March 2024

Abstract
Activation of IGF signaling is a major oncogenic event in diverse cancers, including hepatocellular carcinoma (HCC). In this setting, the insulin-like growth factor binding protein IGFBP7 inhibits IGF signaling by binding the IGF1 receptor (IGF1R), functioning as a candidate tumor suppressor. IGFBP7 abrogates tumors by inhibiting angiogenesis and inducing cancer-specific senescence and apoptosis. Here, we report that Igfbp7-deficient mice exhibit constitutively active IGF signaling, presenting with proinflammatory and immunosuppressive microenvironments and spontaneous liver and lung tumors occurring with increased incidence in carcinogen-treated subjects. Igfbp7 deletion increased proliferation and decreased senescence of hepatocytes and mouse embryonic fibroblasts, effects that were blocked by treatment with IGF1 receptor inhibitor. Significant inhibition of genes regulating immune surveillance was observed in Igfbp7−/− murine livers, which was associated with a marked inhibition in antigen cross-presentation by Igfbp7−/− dendritic cells. Conversely, IGFBP7 overexpression inhibited growth of HCC cells in syngeneic immunocompetent mice. Depletion of CD4+ or CD8+ T lymphocytes abolished this growth inhibition, identifying it as an immune-mediated response. Our findings define an immune component of the pleiotropic mechanisms through which IGFBP7 suppresses HCC. Furthermore, they offer a genetically based preclinical proof of concept for IGFBP7 as a therapeutic target for immune management of HCC. Cancer Res; 77(15); 4014–25. ©2017 AACR.
Data from Evolution of Cancer Stem-like Cells in Endocrine-Resistant Metastatic Breast Cancers Is Mediated by Stromal Microvesicles
Authors: Sansone Pasquale , Berishaj Marjan , Rajasekhar Vinagolu K. , Ceccarelli Claudio , Chang Qing , Strillacci Antonio , Savini Claudia , Shapiro Lauren , Bowman Robert L. , Mastroleo Chiara , De Carolis Sabrina , Daly Laura , Benito-Martin Alberto , Perna Fabiana , Fabbri Nicola , Healey John H. , Spisni Enzo , Cricca Monica , Lyden David , Bonafé Massimiliano , Bromberg Jacqueline
Published: March 2024

Abstract
The hypothesis that microvesicle-mediated miRNA transfer converts noncancer stem cells into cancer stem cells (CSC) leading to therapy resistance remains poorly investigated. Here we provide direct evidence supporting this hypothesis, by demonstrating how microvesicles derived from cancer-associated fibroblasts (CAF) transfer miR-221 to promote hormonal therapy resistance (HTR) in models of luminal breast cancer. We determined that CAF-derived microvesicles horizontally transferred miR-221 to tumor cells and, in combination with hormone therapy, activated an ERlo/Notchhi feed-forward loop responsible for the generation of CD133hi CSCs. Importantly, microvesicles from patients with HTR metastatic disease expressed high levels of miR-221. We further determined that the IL6–pStat3 pathway promoted the biogenesis of onco-miR-221hi CAF microvesicles and established stromal CSC niches in experimental and patient-derived breast cancer models. Coinjection of patient-derived CAFs from bone metastases led to de novo HTR tumors, which was reversed with IL6R blockade. Finally, we generated patient-derived xenograft (PDX) models from patient-derived HTR bone metastases and analyzed tumor cells, stroma, and microvesicles. Murine and human CAFs were enriched in HTR tumors expressing high levels of CD133hi cells. Depletion of murine CAFs from PDX restored sensitivity to HT, with a concurrent reduction of CD133hi CSCs. Conversely, in models of CD133neg, HT-sensitive cancer cells, both murine and human CAFs promoted de novo HT resistance via the generation of CD133hi CSCs that expressed low levels of estrogen receptor alpha. Overall, our results illuminate how microvesicle-mediated horizontal transfer of genetic material from host stromal cells to cancer cells triggers the evolution of therapy-resistant metastases, with potentially broad implications for their control. Cancer Res; 77(8); 1927–41. ©2017 AACR.
Data from Mechanisms of Acquired Resistance to BRAF V600E Inhibition in Colon Cancers Converge on RAF Dimerization and Are Sensitive to Its Inhibition
Authors: Yaeger Rona , Yao Zhan , Hyman David M. , Hechtman Jaclyn F. , Vakiani Efsevia , Zhao HuiYong , Su Wenjing , Wang Lu , Joelson Andrew , Cercek Andrea , Baselga Jose , de Stanchina Elisa , Saltz Leonard , Berger Michael F. , Solit David B. , Rosen Neal
Published: March 2024

Abstract
BRAF V600E colorectal cancers are insensitive to RAF inhibitor monotherapy due to feedback reactivation of receptor tyrosine kinase signaling. Combined RAF and EGFR inhibition exerts a therapeutic effect, but resistance invariably develops through undefined mechanisms. In this study, we determined that colorectal cancer progression specimens invariably harbored lesions in elements of the RAS–RAF–MEK–ERK pathway. Genetic amplification of wild-type RAS was a recurrent mechanism of resistance in colorectal cancer patients that was not seen in similarly resistant melanomas. We show that wild-type RAS amplification increases receptor tyrosine kinase-dependent activation of RAS more potently in colorectal cancer than in melanoma and causes resistance only in the former. Currently approved RAF inhibitors inhibit RAF monomers but not dimers. All the drug-resistant lesions we identified activate BRAF V600E dimerization directly or by elevating RAS-GTP. Overall, our results show that mechanisms of resistance converge on formation of RAF dimers and that inhibiting EGFR and RAF dimers can effectively suppress ERK-driven growth of resistant colorectal cancer. Cancer Res; 77(23); 6513–23. ©2017 AACR.
Data from BET Inhibition Overcomes Receptor Tyrosine Kinase–Mediated Cetuximab Resistance in HNSCC
Authors: Leonard Brandon , Brand Toni M. , O'Keefe Rachel A. , Lee Eliot D. , Zeng Yan , Kemmer Jacquelyn D. , Li Hua , Grandis Jennifer R. , Bhola Neil E.
Published: March 2024

Abstract
Cetuximab, the FDA-approved anti-EGFR antibody for head and neck squamous cell carcinoma (HNSCC), has displayed limited efficacy due to the emergence of intrinsic and acquired resistance. We and others have demonstrated that cetuximab resistance in HNSCC is driven by alternative receptor tyrosine kinases (RTK), including HER3, MET, and AXL. In an effort to overcome cetuximab resistance and circumvent toxicities associated with the administration of multiple RTK inhibitors, we sought to identify a common molecular target that regulates expression of multiple RTK. Bromodomain-containing protein-4 (BRD4) has been shown to regulate the transcription of various RTK in the context of resistance to PI3K and HER2 inhibition in breast cancer models. We hypothesized that, in HNSCC, targeting BRD4 could overcome cetuximab resistance by depleting alternative RTK expression. We generated independent models of cetuximab resistance in HNSCC cell lines and interrogated their RTK and BRD4 expression profiles. Cetuximab-resistant clones displayed increased expression and activation of several RTK, such as MET and AXL, as well as an increased percentage of BRD4-expressing cells. Both genetic and pharmacologic inhibition of BRD4 abrogated cell viability in models of acquired and intrinsic cetuximab resistance and was associated with a robust decrease in alternative RTK expression by cetuximab. Combined treatment with cetuximab and bromodomain inhibitor JQ1 significantly delayed acquired resistance and RTK upregulation in patient-derived xenograft models of HNSCC. These findings indicate that the combination of cetuximab and bromodomain inhibition may be a promising therapeutic strategy for patients with HNSCC.

Significance: Inhibition of bromodomain protein BRD4 represents a potential therapeutic strategy to circumvent the toxicities and financial burden of targeting the multiple receptor tyrosine kinases that drive cetuximab resistance in HNSCC and NSCLC.

Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/15/4331/F1.large.jpg. Cancer Res; 78(15); 4331–43. ©2018 AACR.
Data from Familial and Somatic BAP1 Mutations Inactivate ASXL1/2-Mediated Allosteric Regulation of BAP1 Deubiquitinase by Targeting Multiple Independent Domains
Authors: Peng Hongzhuang , Prokop Jeremy , Karar Jayashree , Park Kyewon , Cao Li , Harbour J. William , Bowcock Anne M. , Malkowicz S. Bruce , Cheung Mitchell , Testa Joseph R. , Rauscher Frank J.
Published: March 2024

Abstract
Deleterious mutations of the ubiquitin carboxy-terminal hydrolase BAP1 found in cancers are predicted to encode inactive truncated proteins, suggesting that loss of enzyme function is a primary tumorigenic mechanism. However, many tumors exhibit missense mutations or in-frame deletions or insertions, often outside the functionally critical UCH domain in this tumor suppressor protein. Thus, precisely how these mutations inactivate BAP1 is unknown. Here, we show how these mutations affect BAP1 interactions with the Polycomb group-like protein, ASXL2, using combinations of computational modeling technology, molecular biology, and in vitro reconstitution biochemistry. We found that the BAP1–ASXL2 interaction is direct and high affinity, occurring through the ASXH domain of ASXL2, an obligate partner for BAP1 enzymatic activity. The ASXH domain was the minimal domain for binding the BAP1 ULD domain, and mutations on the surfaces of predicted helices of ASXH abolished BAP1 association and stimulation of BAP1 enzymatic activity. The BAP1-UCH, BAP1-ULD, and ASXH domains formed a cooperative stable ternary complex required for deubiquitination. We defined four classes of alterations in BAP1 outside the UCH domain, each failing to productively recruit ASXH to the wild-type BAP1 catalytic site via the ULD, resulting in loss of BAP1 ubiquitin hydrolase activity. Our results indicate that many BAP1 mutations act allosterically to inhibit ASXH binding, thereby leading to loss of enzyme activity. Small-molecule approaches to reactivate latent wild-type UCH activity of these mutants might be therapeutically viable.

Significance: Combined computational and biochemical approaches demonstrate that the BAP1–ASXL2 interaction is direct and high affinity and that many BAP1 mutations act allosterically to inhibit BAP1–ASXL2 binding. Cancer Res; 78(5); 1200–13. ©2017 AACR.
Data from PDX-MI: Minimal Information for Patient-Derived Tumor Xenograft Models
Authors: Meehan Terrence F. , Conte Nathalie , Goldstein Theodore , Inghirami Giorgio , Murakami Mark A. , Brabetz Sebastian , Gu Zhiping , Wiser Jeffrey A. , Dunn Patrick , Begley Dale A. , Krupke Debra M. , Bertotti Andrea , Bruna Alejandra , Brush Matthew H. , Byrne Annette T. , Caldas Carlos , Christie Amanda L. , Clark Dominic A. , Dowst Heidi , Dry Jonathan R. , Doroshow James H. , Duchamp Olivier , Evrard Yvonne A. , Ferretti Stephane , Frese Kristopher K. , Goodwin Neal C. , Greenawalt Danielle , Haendel Melissa A. , Hermans Els , Houghton Peter J. , Jonkers Jos , Kemper Kristel , Khor Tin O. , Lewis Michael T. , Lloyd K.C. Kent , Mason Jeremy , Medico Enzo , Neuhauser Steven B. , Olson James M. , Peeper Daniel S. , Rueda Oscar M. , Seong Je Kyung , Trusolino Livio , Vinolo Emilie , Wechsler-Reya Robert J. , Weinstock David M. , Welm Alana , Weroha S. John , Amant Frédéric , Pfister Stefan M. , Kool Marcel , Parkinson Helen , Butte Atul J. , Bult Carol J.
Published: March 2024

Abstract
Patient-derived tumor xenograft (PDX) mouse models have emerged as an important oncology research platform to study tumor evolution, mechanisms of drug response and resistance, and tailoring chemotherapeutic approaches for individual patients. The lack of robust standards for reporting on PDX models has hampered the ability of researchers to find relevant PDX models and associated data. Here we present the PDX models minimal information standard (PDX-MI) for reporting on the generation, quality assurance, and use of PDX models. PDX-MI defines the minimal information for describing the clinical attributes of a patient's tumor, the processes of implantation and passaging of tumors in a host mouse strain, quality assurance methods, and the use of PDX models in cancer research. Adherence to PDX-MI standards will facilitate accurate search results for oncology models and their associated data across distributed repository databases and promote reproducibility in research studies using these models. Cancer Res; 77(21); e62–66. ©2017 AACR.
Data from The E2F1–miR-520/372/373–SPOP Axis Modulates Progression of Renal Carcinoma
Authors: Ding Meng , Lu Xiaolan , Wang Cheng , Zhao Quan , Ge Jingping , Xia Qiuyuan , Wang Junjun , Zen Ke , Zhang Chen-Yu , Zhang Chunni
Published: March 2024

Abstract
Although renal cell carcinoma (RCC) is the most malignant urologic cancer, its pathogenesis remains unclear, and effective treatments for advanced RCC are still lacking. Here, we report that a novel E2F1–miR-520/372/373–SPOP axis controls RCC carcinogenesis. Speckle-type POZ protein (SPOP) was upregulated in over 90% of RCC tissues, whereas the miR-520/372/373 family was downregulated and correlated inversely with SPOP protein levels in RCC tissues. The miR-520/372/373 family targeted the SPOP 3′-UTR and suppressed SPOP protein expression, leading to elevation of PTEN and DUSP7 levels and, consequently, decreased proliferation, invasion/migration, and metastasis of RCC cells in vitro and in vivo. Tail-vein delivery of therapeutic miR-520/372/373 family significantly decreased both tumor size and lung metastasis ratio in mice bearing orthotopic xenograft tumors. Decreased expression of miR-520/372/373 family was mediated by transcription factor E2F1. In conclusion, our results demonstrate that the E2F1-miR-520/372/373–SPOP axis functions as a key signaling pathway in RCC progression and metastasis and represents a promising opportunity for targeted therapies.
Significance:
These findings show that the E2F1-miR-520/372/373 family–SPOP axis promotes RCC progression, thereby contributing to our understanding of RCC pathogenesis and unveiling new avenues for more effective targeted therapies.