bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Progesterone Receptor Signaling in the Microenvironment of Endometrial Cancer Influences Its Response to Hormonal Therapy
Authors: Janzen Deanna M. , Rosales Miguel A. , Paik Daniel Y. , Lee Daniel S. , Smith Daniel A. , Witte Owen N. , Iruela-Arispe M. Luisa , Memarzadeh Sanaz
Published: March 2024

Abstract
Progesterone, an agonist for the progesterone receptor (PR), can be an efficacious and well-tolerated treatment in endometrial cancer. The clinical use of progesterone is limited because of the lack of biomarkers that predict hormone sensitivity. Despite its efficacy in cancer therapy, mechanisms and site of action for progesterone remain unknown. Using an in vivo endometrial cancer mouse model driven by clinically relevant genetic changes but dichotomous responses to hormonal therapy, we show that signaling through stromal PR is necessary and sufficient for progesterone antitumor effects. Endometrial cancers resulting from epithelial loss of PTEN (PTENKO) were hormone sensitive and had abundant expression of stromal PR. Stromal deletion of PR as a single genetic change in these tumors induced progesterone resistance indicating that paracrine signaling through the stroma is essential for the progesterone therapeutic effects. A hormone-refractory endometrial tumor with low levels of stromal PR developed when activation of KRAS was coupled with PTEN-loss (PTENKO/Kras). The innate progesterone resistance in PTENKO/Kras tumors stemmed from methylation of PR in the tumor microenvironment. Add-back of stromal PR expressed from a constitutively active promoter sensitized these tumors to progesterone therapy. Results show that signaling through stromal PR is sufficient for inducing hormone responsiveness. Our findings suggest that epigenetic derepression of stromal PR could be a potential therapeutic target for sensitizing hormone-refractory endometrial tumors to progesterone therapy. On the basis of these results, stromal expression of PR may emerge as a reliable biomarker in predicting response to hormonal therapy. Cancer Res; 73(15); 4697–710. ©2013 AACR.
Data from RhoJ Regulates Melanoma Chemoresistance by Suppressing Pathways That Sense DNA Damage
Authors: Ho Hsiang , Aruri Jayavani , Kapadia Rubina , Mehr Hootan , White Michael A. , Ganesan Anand K.
Published: March 2024

Abstract
Melanomas resist conventional chemotherapeutics, in part, through intrinsic disrespect of apoptotic checkpoint activation. In this study, using an unbiased genome-wide RNA interference screen, we identified RhoJ and its effector PAK1, as key modulators of melanoma cell sensitivity to DNA damage. We find that RhoJ activates PAK1 in response to drug-induced DNA damage, which then uncouples ATR from its downstream effectors, ultimately resulting in a blunted DNA damage response (DDR). In addition, ATR suppression leads to the decreased phosphorylation of ATF2 and consequent increased expression of the melanocyte survival gene Sox10 resulting in a higher DDR threshold required to engage melanoma cell death. In the setting of normal melanocyte behavior, this regulatory relationship may facilitate appropriate epidermal melanization in response to UV-induced DNA damage. However, pathologic pathway activation during oncogenic transformation produces a tumor that is intrinsically resistant to chemotherapy and has the propensity to accumulate additional mutations. These findings identify DNA damage agents and pharmacologic inhibitors of RhoJ/PAK1 as novel synergistic agents that can be used to treat melanomas that are resistant to conventional chemotherapies. Cancer Res; 72(21); 5516–28. ©2012 AACR.
Data from RANKL Expression, Function, and Therapeutic Targeting in Multiple Myeloma and Chronic Lymphocytic Leukemia
Authors: Schmiedel Benjamin Joachim , Scheible Carolin Andrea , Nuebling Tina , Kopp Hans-Georg , Wirths Stefan , Azuma Miyuki , Schneider Pascal , Jung Gundram , Grosse-Hovest Ludger , Salih Helmut Rainer
Published: March 2024

Abstract
Bone destruction is a prominent feature of multiple myeloma, but conflicting data exist on the expression and pathophysiologic involvement of the bone remodeling ligand RANKL in this disease and the potential therapeutic benefits of its targeted inhibition. Here, we show that RANKL is expressed by primary multiple myeloma and chronic lymphocytic leukemia (CLL) cells, whereas release of soluble RANKL was observed exclusively with multiple myeloma cells and was strongly influenced by posttranscriptional/posttranslational regulation. Signaling via RANKL into multiple myeloma and CLL cells induced release of cytokines involved in disease pathophysiology. Both the effects of RANKL on osteoclastogenesis and cytokine production by malignant cells could be blocked by disruption of RANK–RANKL interaction with denosumab. As we aimed to combine neutralization of RANKL with induction of antibody-dependent cellular cytotoxicity of natural killer (NK) cells against RANKL-expressing malignant cells and as denosumab does not stimulate NK reactivity, we generated RANK-Fc fusion proteins with modified Fc moieties. The latter displayed similar capacity compared with denosumab to neutralize the effects of RANKL on osteoclastogenesis in vitro, but also potently stimulated NK cell reactivity against primary RANKL-expressing malignant B cells, which was dependent on their engineered affinity to CD16. Our findings introduce Fc-optimized RANK-Ig fusion proteins as attractive tools to neutralize the detrimental function of RANKL while at the same time potently stimulating NK cell antitumor immunity. Cancer Res; 73(2); 683–94. ©2012 AACR.
Data from Supramolecular Nanoparticles That Target Phosphoinositide-3-Kinase Overcome Insulin Resistance and Exert Pronounced Antitumor Efficacy
Authors: Kulkarni Ashish A. , Roy Bhaskar , Rao Poornima S. , Wyant Gregory A. , Mahmoud Ayaat , Ramachandran Madhumitha , Sengupta Poulomi , Goldman Aaron , Kotamraju Venkata Ramana , Basu Sudipta , Mashelkar Raghunath A. , Ruoslahti Erkki , Dinulescu Daniela M. , Sengupta Shiladitya
Published: March 2024

Abstract
The centrality of phosphoinositide-3-kinase (PI3K) in cancer etiology is well established, but clinical translation of PI3K inhibitors has been limited by feedback signaling, suboptimal intratumoral concentration, and an insulin resistance “class effect.” This study was designed to explore the use of supramolecular nanochemistry for targeting PI3K to enhance antitumor efficacy and potentially overcome these limitations. PI3K inhibitor structures were rationally modified using a cholesterol-based derivative, facilitating supramolecular nanoassembly with L-α-phosphatidylcholine and DSPE-PEG [1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polythylene glycol)]. The supramolecular nanoparticles (SNP) that were assembled were physicochemically characterized and functionally evaluated in vitro. Antitumor efficacy was quantified in vivo using 4T1 breast cancer and K-RasLSL/+/Ptenfl/fl ovarian cancer models, with effects on glucose homeostasis evaluated using an insulin sensitivity test. The use of PI103 and PI828 as surrogate molecules to engineer the SNPs highlighted the need to keep design principles in perspective; specifically, potency of the active molecule and the linker chemistry were critical principles for efficacy, similar to antibody–drug conjugates. We found that the SNPs exerted a temporally sustained inhibition of phosphorylation of Akt, mTOR, S6K, and 4EBP in vivo. These effects were associated with increased antitumor efficacy and survival as compared with PI103 and PI828. Efficacy was further increased by decorating the nanoparticle surface with tumor-homing peptides. Notably, the use of SNPs abrogated the insulin resistance that has been associated widely with other PI3K inhibitors. This study provides a preclinical foundation for the use of supramolecular nanochemistry to overcome current challenges associated with PI3K inhibitors, offering a paradigm for extension to other molecularly targeted therapeutics being explored for cancer treatment. Cancer Res; 73(23); 6987–97. ©2013 AACR.
Data from Inhibition of AMPK and Krebs Cycle Gene Expression Drives Metabolic Remodeling of Pten-Deficient Preneoplastic Thyroid Cells
Authors: Antico Arciuch Valeria G. , Russo Marika A. , Kang Kristy S. , Di Cristofano Antonio
Published: March 2024

Abstract
Rapidly proliferating and neoplastically transformed cells generate the energy required to support rapid cell division by increasing glycolysis and decreasing flux through the oxidative phosphorylation (OXPHOS) pathway, usually without alterations in mitochondrial function. In contrast, little is known of the metabolic alterations, if any, which occur in cells harboring mutations that prime their neoplastic transformation. To address this question, we used a Pten-deficient mouse model to examine thyroid cells where a mild hyperplasia progresses slowly to follicular thyroid carcinoma. Using this model, we report that constitutive phosphoinositide 3-kinase (PI3K) activation caused by PTEN deficiency in nontransformed thyrocytes results in a global downregulation of Krebs cycle and OXPHOS gene expression, defective mitochondria, reduced respiration, and an enhancement in compensatory glycolysis. We found that this process does not involve any of the pathways classically associated with the Warburg effect. Moreover, this process was independent of proliferation but contributed directly to thyroid hyperplasia. Our findings define a novel metabolic switch to glycolysis driven by PI3K-dependent AMPK inactivation with a consequent repression in the expression of key metabolic transcription regulators. Cancer Res; 73(17); 5459–72. ©2013 AACR.
Data from MIG-7 Controls COX-2/PGE2-Mediated Lung Cancer Metastasis
Authors: Ho Ming-Yi , Liang Shu-Mei , Hung Shao-Wen , Liang Chi-Ming
Published: March 2024

Abstract
More effective treatments for metastatic lung cancer remain a pressing clinical need. In this study, we identified migration inducting gene-7 (MIG-7) protein as critical for COX-2/prostaglandin E2 (PGE2)- and Akt/GSK-3β-dependent tumor invasion/metastasis. COX-2/PGE2 activated EP4 to enhance Akt and GSK-3β phosphorylation and β-catenin/T-cell factor/lymphoid enhancer factor signaling leading to MIG-7 upregulation. RNAi-mediated attenuation of MIG-7 blocked COX-2/PGE2- and Akt/GSK-3β-mediated migration/invasion effects. Furthermore, MIG-7 protein inhibited protein phosphatase 2A to sustain Akt/GSK-3β phosphorylation and cancer-cell migration/invasion. Cancer cells overexpressing MIG-7 exhibited increased expression of ZEB-1 and Twist in parallel with epithelial–mesenchymal transition, metastasis and cancer lethality. MIG-7 protein level positively correlated with advanced stages of human lung cancers. MIG-7 thus offers a theranostic target for cancer metastases arising from aberrant activation of the cellular COX-2/PGE2 and Akt/GSK-3β signaling pathways. Cancer Res; 73(1); 439–49. ©2012 AACR.
Data from Lysyl Oxidase Plays a Critical Role in Endothelial Cell Stimulation to Drive Tumor Angiogenesis
Authors: Baker Ann-Marie , Bird Demelza , Welti Jonathan C. , Gourlaouen Morgane , Lang Georgina , Murray Graeme I. , Reynolds Andrew R. , Cox Thomas R. , Erler Janine T.
Published: March 2024

Abstract
Identification of key molecules that drive angiogenesis is critical for the development of new modalities for the prevention of solid tumor progression. Using multiple models of colorectal cancer, we show that activity of the extracellular matrix–modifying enzyme lysyl oxidase (LOX) is essential for stimulating endothelial cells in vitro and angiogenesis in vivo. We show that LOX activates Akt through platelet-derived growth factor receptor β (PDGFRβ) stimulation, resulting in increased VEGF expression. LOX-driven angiogenesis can be abrogated through targeting LOX directly or using inhibitors of PDGFRβ, Akt, and VEGF signaling. Furthermore, we show that LOX is clinically correlated with VEGF expression and blood vessel formation in 515 colorectal cancer patient samples. Finally, we validate our findings in a breast cancer model, showing the universality of these observations. Taken together, our findings have broad clinical and therapeutic implications for a wide variety of solid tumor types. Cancer Res; 73(2); 583–94. ©2012 AACR.
Data from Dose-Dense Chemotherapy Improves Mechanisms of Antitumor Immune Response
Authors: Chang Chih-Long , Hsu Yun-Ting , Wu Chao-Chih , Lai Yan-Zen , Wang Connie , Yang Yuh-Cheng , Wu T.-C. , Hung Chien-Fu
Published: March 2024

Abstract
Dose-dense (DD) regimens of combination chemotherapy may produce superior clinical outcomes, but the basis for these effects are not completely clear. In this study, we assessed whether a DD combinatorial regimen of low-dose cisplatin and paclitaxel produces superior immune-mediated efficacy when compared with a maximum tolerated dose (MTD) regimen in treating platinum-resistant ovarian cancer as modeled in mice. Immune responses generated by the DD regimen were identified with regard to the immune cell subset responsible for the antitumor effects observed. The DD regimen was less toxic to the immune system, reduced immunosuppression by the tumor microenvironment, and triggered recruitment of macrophages and tumor-specific CD8+ T-cell responses to tumors [as determined by interleukin (IL)-2 and IFN-γ secretion]. In this model, we found that the DD regimen exerted greater therapeutic effects than the MTD regimen, justifying its further clinical investigation. Fourteen patients with platinum-resistant relapse of ovarian cancer received DD chemotherapy consisting of weekly carboplatin (AUC2) and paclitaxel (60–80 mg/m2) as the third- or fourth-line treatment. Serum was collected over the course of treatment, and serial IFN-γ and IL-2 levels were used to determine CD8+ T-cell activation. Of the four patients with disease control, three had serum levels of IL-2 and IFN-γ associated with cytotoxic CD8+ T-cell activity. The therapeutic effect of the DD chemotherapy relied on the preservation of the immune system and the treatment-mediated promotion of tumor-specific immunity, especially the antitumor CD8+ T-cell response. Because the DD regimen controlled drug-resistant disease through a novel immune mechanism, it may offer a fine strategy for salvage treatment. Cancer Res; 73(1); 119–27. ©2012 AACR.
Data from PD-1–Expressing Tumor-Infiltrating T Cells Are a Favorable Prognostic Biomarker in HPV-Associated Head and Neck Cancer
Authors: Badoual Cécile , Hans Stéphane , Merillon Nathalie , Van Ryswick Cordélia , Ravel Patrice , Benhamouda Nadine , Levionnois Emeline , Nizard Mevyn , Si-Mohamed Ali , Besnier Nicolas , Gey Alain , Rotem-Yehudar Rinat , Pere Hélène , Tran Thi , Guerin Coralie L. , Chauvat Anne , Dransart Estelle , Alanio Cécile , Albert Sebastien , Barry Beatrix , Sandoval Federico , Quintin-Colonna Françoise , Bruneval Patrick , Fridman Wolf H. , Lemoine Francois M. , Oudard Stephane , Johannes Ludger , Olive Daniel , Brasnu Daniel , Tartour Eric
Published: March 2024

Abstract
Head and neck cancers positive for human papillomavirus (HPV) have a more favorable clinical outcome than HPV-negative cancers, but it is unknown why this is the case. We hypothesized that prognosis was affected by intrinsic features of HPV-infected tumor cells or differences in host immune response. In this study, we focused on a comparison of regulatory Foxp3+ T cells and programmed death-1 (PD-1)+ T cells in the microenvironment of tumors that were positive or negative for HPV, in two groups that were matched for various clinical and biologic parameters. HPV-positive head and neck cancers were more heavily infiltrated by regulatory T cells and PD-1+ T cells and the levels of PD-1+ cells were positively correlated with a favorable clinical outcome. In explaining this paradoxical result, we showed that these PD-1+ T cells expressed activation markers and were functional after blockade of the PD-1–PD-L1 axis in vitro. Approximately 50% of PD-1+ tumor-infiltrating T cells lacked Tim-3 expression and may indeed represent activated T cells. In mice, administration of a cancer vaccine increased PD-1 on T cells with concomitant tumor regression. In this setting, PD-1 blockade synergized with vaccine in eliciting antitumor efficacy. Our findings prompt a need to revisit the significance of PD-1–infiltrating T cells in cancer, where we suggest that PD-1 detection may reflect a previous immune response against tumors that might be reactivated by PD-1/PD-L1 blockade. Cancer Res; 73(1); 128–38. ©2012 AACR.
Data from Molecular Profiling of Tumor Cells in Cerebrospinal Fluid and Matched Primary Tumors from Metastatic Breast Cancer Patients with Leptomeningeal Carcinomatosis
Authors: Magbanua Mark Jesus M. , Melisko Michelle , Roy Ritu , Sosa Eduardo V. , Hauranieh Louai , Kablanian Andrea , Eisenbud Lauren E. , Ryazantsev Artem , Au Alfred , Scott Janet H. , Park John W.
Published: March 2024

Abstract
Although leptomeningeal carcinomatosis is a well-established clinical syndrome, virtually nothing is known about the tumor cells responsible for this particularly aggressive metastatic process. To isolate cerebrospinal fluid–derived tumor cells (CSFTC) from 15 patients with metastatic breast cancer diagnosed with leptomeningeal carcinomatosis, CSF samples were subjected to a two-step method involving immunomagnetic enrichment and fluorescence-activated cell sorting (IE/FACS), a technique previously used for isolating circulating tumor cells (CTC) from blood. CSFTCs were subjected to genome-wide copy number analysis by array comparative genomic hybridization. Genomic profiling was successfully performed for 13 of 15 patients (87%). Copy number analysis in CSFTCs revealed genomic alterations commonly observed in primary breast cancer and CTCs, indicating their malignant origin. Interestingly, 12 (92%) harbored high-level gains on the 8q24 locus, which includes the MYC oncogene. Comparison of CSFTCs against corresponding archival primary tumors in six patients revealed clonal relationships with some divergence. Good concordance among serial samples attested to the reproducibility of the assay. Our approach for isolation and molecular analysis of CSFTCs yielded new insights into the molecular nature of these cells. Further genomic and functional analyses may help elucidate mechanisms by which tumor cells metastasize to the central nervous system. Cancer Res; 73(23); 7134–43. ©2013 AACR.
Data from Bone Marrow–Derived CD11b+Jagged2+ Cells Promote Epithelial-to-Mesenchymal Transition and Metastasization in Colorectal Cancer
Authors: Caiado Francisco , Carvalho Tânia , Rosa Isadora , Remédio Leonor , Costa Ana , Matos João , Heissig Beate , Yagita Hideo , Hattori Koichi , da Silva João Pereira , Fidalgo Paulo , Pereira António Dias , Dias Sérgio
Published: March 2024

Abstract
Timely detection of colorectal cancer metastases may permit improvements in their clinical management. Here, we investigated a putative role for bone marrow–derived cells in the induction of epithelial-to-mesenchymal transition (EMT) as a marker for onset of metastasis. In ectopic and orthotopic mouse models of colorectal cancer, bone marrow–derived CD11b(Itgam)+Jagged2 (Jag2)+ cells infiltrated primary tumors and surrounded tumor cells that exhibited diminished expression of E-cadherin and increased expression of vimentin, 2 hallmarks of EMT. In vitro coculture experiments showed that the bone marrow–derived CD11b+Jag2+ cells induced EMT through a Notch-dependent pathway. Using neutralizing antibodies, we imposed a blockade on CD11b+ cells' recruitment to tumors, which decreased the tumor-infiltrating CD11b+Jag2+ cell population of interest, decreasing tumor growth, restoring E-cadherin expression, and delaying EMT. In support of these results, we found that peripheral blood levels of CD11b+Jag2+ cells in mouse models of colorectal cancer and in a cohort of untreated patients with colorectal cancer were indicative of metastatic disease. In patients with colorectal cancer, the presence of circulating CD11b+Jag2+ cells was accompanied by loss of E-cadherin in the corresponding patient tumors. Taken together, our results show that bone marrow–derived CD11b+Jag2+ cells, which infiltrate primary colorectal tumors, are sufficient to induce EMT in tumor cells, thereby triggering onset of metastasis. Furthermore, they argue that quantifying circulating CD11b+Jag2+ cells in patients may offer an indicator of colorectal cancer progression to metastatic levels of the disease. Cancer Res; 73(14); 4233–46. ©2013 AACR.
Data from FOXC2 Expression Links Epithelial–Mesenchymal Transition and Stem Cell Properties in Breast Cancer
Authors: Hollier Brett G. , Tinnirello Agata A. , Werden Steven J. , Evans Kurt W. , Taube Joseph H. , Sarkar Tapasree Roy , Sphyris Nathalie , Shariati Maryam , Kumar Sreedevi V. , Battula Venkata L. , Herschkowitz Jason I. , Guerra Rudy , Chang Jeffrey T. , Miura Naoyuki , Rosen Jeffrey M. , Mani Sendurai A.
Published: March 2024

Abstract
Resistance to chemotherapy and metastases are the major causes of breast cancer-related mortality. Moreover, cancer stem cells (CSC) play critical roles in cancer progression and treatment resistance. Previously, it was found that CSC-like cells can be generated by aberrant activation of epithelial–mesenchymal transition (EMT), thereby making anti-EMT strategies a novel therapeutic option for treatment of aggressive breast cancers. Here, we report that the transcription factor FOXC2 induced in response to multiple EMT signaling pathways as well as elevated in stem cell-enriched factions is a critical determinant of mesenchymal and stem cell properties, in cells induced to undergo EMT- and CSC-enriched breast cancer cell lines. More specifically, attenuation of FOXC2 expression using lentiviral short hairpin RNA led to inhibition of the mesenchymal phenotype and associated invasive and stem cell properties, which included reduced mammosphere-forming ability and tumor initiation. Whereas, overexpression of FOXC2 was sufficient to induce CSC properties and spontaneous metastasis in transformed human mammary epithelial cells. Furthermore, a FOXC2-induced gene expression signature was enriched in the claudin-low/basal B breast tumor subtype that contains EMT and CSC features. Having identified PDGFR-β to be regulated by FOXC2, we show that the U.S. Food and Drug Administration-approved PDGFR inhibitor, sunitinib, targets FOXC2-expressing tumor cells leading to reduced CSC and metastatic properties. Thus, FOXC2 or its associated gene expression program may provide an effective target for anti-EMT-based therapies for the treatment of claudin-low/basal B breast tumors or other EMT-/CSC-enriched tumors. Cancer Res; 73(6); 1981–92. ©2012 AACR.
Data from PTEN Loss Mitigates the Response of Medulloblastoma to Hedgehog Pathway Inhibition
Authors: Metcalfe Ciara , Alicke Bruno , Crow Ailey , Lamoureux Marlea , Dijkgraaf Gerrit J.P. , Peale Franklin , Gould Stephen E. , de Sauvage Frederic J.
Published: March 2024

Abstract
Medulloblastoma is a cancer of the cerebellum, for which there is currently no approved targeted therapy. Recent transcriptomics approaches have demonstrated that medulloblastoma is composed of molecularly distinct subgroups, one of which is characterized by activation of the Hedgehog pathway, which in mouse models is sufficient to drive medulloblastoma development. There is thus considerable interest in targeting the Hedgehog pathway for therapeutic benefit in medulloblastoma, particularly given the recent approval of the Hedgehog pathway inhibitor vismodegib for metastatic and locally advanced basal cell carcinoma. Like other molecularly targeted therapies, however, there have been reports of acquired resistance to vismodegib, driven by secondary Hedgehog pathway mutations and potentially by activation of the phosphatidylinositol 3-kinase (PI3K) pathway. Given that acquired resistance to vismodegib may occur as a result of inappropriate PI3K pathway activation, we asked if loss of the PI3K pathway regulator, phosphatase and tensin homologue (Pten), which has been reported to occur in patients within the Hedgehog subgroup, would constitute a mechanism of innate resistance to vismodegib in Hedgehog-driven medulloblastoma. We find that Hedgehog pathway inhibition successfully restrains growth of Pten-deficient medulloblastoma in this mouse model, but does not drive tumor regression, as it does in Pten-wild-type medulloblastoma. Combined inhibition of the Hedgehog and PI3K pathways may lead to superior antitumor activity in PTEN-deficient medulloblastoma in the clinic. Cancer Res; 73(23); 7034–42. ©2013 AACR.
Data from Epigenetic Repression of miR-31 Disrupts Androgen Receptor Homeostasis and Contributes to Prostate Cancer Progression
Authors: Lin Pei-Chun , Chiu Ya-Lin , Banerjee Samprit , Park Kyung , Mosquera Juan Miguel , Giannopoulou Eugenia , Alves Pedro , Tewari Ashutosh K. , Gerstein Mark B. , Beltran Himisha , Melnick Ari M. , Elemento Olivier , Demichelis Francesca , Rubin Mark A.
Published: March 2024

Abstract
Androgen receptor signaling plays a critical role in prostate cancer pathogenesis. Yet, the regulation of androgen receptor signaling remains elusive. Even with stringent androgen deprivation therapy, androgen receptor signaling persists. Here, our data suggest that there is a complex interaction between the expression of the tumor suppressor miRNA, miR-31, and androgen receptor signaling. We examined primary and metastatic prostate cancer and found that miR-31 expression was reduced as a result of promoter hypermethylation, and importantly, the levels of miR-31 expression were inversely correlated with the aggressiveness of the disease. As the expression of androgen receptor and miR-31 was inversely correlated in the cell lines, our study further suggested that miR-31 and androgen receptor could mutually repress each other. Upregulation of miR-31 effectively suppressed androgen receptor expression through multiple mechanisms and inhibited prostate cancer growth in vivo. Notably, we found that miR-31 targeted androgen receptor directly at a site located in the coding region, which was commonly mutated in prostate cancer. In addition, miR-31 suppressed cell-cycle regulators including E2F1, E2F2, EXO1, FOXM1, and MCM2. Together, our findings suggest a novel androgen receptor regulatory mechanism mediated through miR-31 expression. The downregulation of miR-31 may disrupt cellular homeostasis and contribute to the evolution and progression of prostate cancer. We provide implications for epigenetic treatment and support clinical development of detecting miR-31 promoter methylation as a novel biomarker. Cancer Res; 73(3); 1232–44. ©2012 AACR.
Data from Systems Analysis of BCL2 Protein Family Interactions Establishes a Model to Predict Responses to Chemotherapy
Authors: Lindner Andreas U. , Concannon Caoimhín G. , Boukes Gerhardt J. , Cannon Mary D. , Llambi Fabien , Ryan Deborah , Boland Karen , Kehoe Joan , McNamara Deborah A. , Murray Frank , Kay Elaine W. , Hector Suzanne , Green Douglas R. , Huber Heinrich J. , Prehn Jochen H.M.
Published: March 2024

Abstract
Apoptotic desensitization is a hallmark of cancer cells, but present knowledge of molecular systems controlling apoptosis has yet to provide significant prognostic insights. Here, we report findings from a systems study of the intrinsic pathway of apoptosis by BCL2 family proteins and clinical translation of its findings into a model with applications in colorectal cancer (CRC). By determining absolute protein quantifications in CRC cells and patient tumor samples, we found that BAK and BAX were expressed more highly than their antiapoptotic inhibitors. This counterintuitive finding suggested that sole inhibition of effector BAX and BAK could not be sufficient for systems stability in nonstressed cells. Assuming a model of direct effector activation by BH3-only proteins, we calculated that the amount of stress-induced BH3-only proteins required to activate mitochondrial apoptosis could predict individual death responses of CRC cells to 5-fluorouracil/oxaliplatin. Applying this model predictor to protein profiles in tumor and matched normal tissue samples from 26 patients with CRCs, we found that differences in protein quantities were sufficient to model the increased tumor sensitivity to chemotherapy compared with normal tissue. In addition, these differences were sufficient to differentiate clinical responders from nonresponders with high confidence. Applications of our model, termed DR_MOMP, were used to assess the impact of apoptosis-sensitizing dugs in lowering the necessary dose of state-of-the-art chemotherapy in individual patients. Together, our findings offer a ready clinical tool with the potential to tailor chemotherapy to individual patients. Cancer Res; 73(2); 519–28. ©2012 AACR.
Data from Homing of Human B Cells to Lymphoid Organs and B-Cell Lymphoma Engraftment Are Controlled by Cell Adhesion Molecule JAM-C
Authors: Doñate Carmen , Ody Christiane , McKee Thomas , Ruault-Jungblut Sylvie , Fischer Nicolas , Ropraz Patricia , Imhof Beat A. , Matthes Thomas
Published: March 2024

Abstract
Junctional adhesion molecule C (JAM-C) is expressed by vascular endothelium and human but not mouse B lymphocytes. The level of JAM-C expression defines B-cell differentiation stages and allows the classification of marginal zone–derived (JAM-C–positive) and germinal center–derived (JAM-C–negative) B-cell lymphomas. In the present study, we investigated the role of JAM-C in homing of human B cells, using a xenogeneic nonobese diabetic/severe combined immunodeficient mouse model. Treatment with anti-JAM-C antibodies in short-term experiments reduced migration of normal and malignant JAM-C–expressing B cells to bone marrow, lymph nodes, and spleen. Blocking homing to the spleen is remarkable, as most other antiadhesion antibodies reduce homing of B cells only to bone marrow and lymph nodes. Long-term administration of anti-JAM-C antibodies prevented engraftment of JAM-Cpos lymphoma cells in bone marrow, spleen, and lymph nodes of mice. Plasmon resonance studies identified JAM-B as the major ligand for JAM-C, whereas homotypic JAM-C interactions remained at background levels. Accordingly, anti-JAM-C antibodies blocked adhesion of JAM-C–expressing B cells to their ligand JAM-B, and immunofluorescence analysis showed the expression of JAM-B on murine and human lymphatic endothelial cells. Targeting JAM-C could thus constitute a new therapeutic strategy to prevent lymphoma cells from reaching supportive microenvironments not only in the bone marrow and lymph nodes but also in the spleen. Cancer Res; 73(2); 640–51. ©2012 AACR.
Data from Combination Therapy Targeting the Chk1 and Wee1 Kinases Shows Therapeutic Efficacy in Neuroblastoma
Authors: Russell Mike R. , Levin Kirill , Rader JulieAnn , Belcastro Lili , Li Yimei , Martinez Daniel , Pawel Bruce , Shumway Stuart D. , Maris John M. , Cole Kristina A.
Published: March 2024

Abstract
Neuroblastoma is uniquely sensitive to single-agent inhibition of the DNA damage checkpoint kinase Chk1, leading us to examine downstream effectors of this pathway and identify mitotic regulator Wee1 as an additional therapeutic target in this disease. Wee1 was overexpressed in both neuroblastoma cell lines and high-risk patient tumors. Genetic or pharmacologic abrogation of Wee1 signaling results in marked cytotoxicity in 10 of 11 neuroblastoma cell lines with a median IC50 of 300 nmol/L for the Wee1-selective small-molecule inhibitor MK-1775. Murine tumor lines derived from mice that were either heterozygous or homozygous for MycN were particularly sensitive to single-agent inhibition of Wee1 (IC50s of 160 and 62 nmol/L, respectively). Simultaneous pharmacologic inhibition of Chk1 and Wee1 acted in a synergistic fashion to further impede neuroblastoma cell growth in vitro, in a manner greater than the individual inhibitors either alone or combined with chemotherapy. Combination Chk1 and Wee1 inhibition also revealed in vivo efficacy in neuroblastoma xenografts. Taken together, our results show that neuroblastoma cells depend on Wee1 activity for growth and that inhibition of this kinase may serve as a therapeutic for patients with neuroblastoma. Cancer Res; 73(2); 776–84. ©2012 AACR.
Data from Hypomethylating Therapy in an Aggressive Stroma-Rich Model of Pancreatic Carcinoma
Authors: Shakya Reena , Gonda Tamas , Quante Michael , Salas Martha , Kim Samuel , Brooks Jenna , Hirsch Steffen , Davies Justine , Cullo Angelica , Olive Kenneth , Wang Timothy C. , Szabolcs Matthias , Tycko Benjamin , Ludwig Thomas
Published: March 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that resists current treatments. To test epigenetic therapy against this cancer, we used the DNA demethylating drug 5-aza-2′-deoxycytidine (DAC) in an aggressive mouse model of stromal rich PDAC (KPC-Brca1 mice). In untreated tumors, we found globally decreased 5-methyl-cytosine (5-mC) in malignant epithelial cells and in cancer-associated myofibroblasts (CAF), along with increased amounts of 5-hydroxymethyl-cytosine (5-HmC) in CAFs, in progression from pancreatic intraepithelial neoplasia to PDAC. DAC further reduced DNA methylation and slowed PDAC progression, markedly extending survival in an early-treatment protocol and significantly though transiently inhibiting tumor growth when initiated later, without adverse side effects. Escaping tumors contained areas of sarcomatoid transformation with disappearance of CAFs. Mixing-allografting experiments and proliferation indices showed that DAC efficacy was due to inhibition of both the malignant epithelial cells and the CAFs. Expression profiling and immunohistochemistry highlighted DAC induction of STAT1 in the tumors, and DAC plus IFN-γ produced an additive antiproliferative effect on PDAC cells. DAC induced strong expression of the testis antigen deleted in azoospermia-like (DAZL) in CAFs. These data show that DAC is effective against PDAC in vivo and provide a rationale for future studies combining hypomethylating agents with cytokines and immunotherapy. Cancer Res; 73(2); 885–96. ©2012 AACR.
Data from Midkine Promotes Neuroblastoma through Notch2 Signaling
Authors: Kishida Satoshi , Mu Ping , Miyakawa Shin , Fujiwara Masatoshi , Abe Tomoyuki , Sakamoto Kazuma , Onishi Akira , Nakamura Yoshikazu , Kadomatsu Kenji
Published: March 2024

Abstract
Midkine is a heparin-binding growth factor highly expressed in various cancers, including neuroblastoma, the most common extracranial pediatric solid tumor. Prognosis of patients with neuroblastoma in which MYCN is amplified remains particularly poor. In this study, we used a MYCN transgenic model for neuroblastoma in which midkine is highly expressed in precancerous lesions of sympathetic ganglia. Genetic ablation of midkine in this model delayed tumor formation and reduced tumor incidence. Furthermore, an RNA aptamer that specifically bound midkine suppressed the growth of neuroblastoma cells in vitro and in vivo in tumor xenografts. In precancerous lesions, midkine-deficient MYCN transgenic mice exhibited defects in activation of Notch2, a candidate midkine receptor, and expression of the Notch target gene HES1. Similarly, RNA aptamer-treated tumor xenografts also showed attenuation of Notch2-HES1 signaling. Our findings establish a critical role for the midkine-Notch2 signaling axis in neuroblastoma tumorigenesis, which implicates new strategies to treat neuroblastoma. Cancer Res; 73(4); 1318–27. ©2012 AACR.
Data from Ex Vivo Expansion of Highly Cytotoxic Human NK Cells by Cocultivation with Irradiated Tumor Cells for Adoptive Immunotherapy
Authors: Lim Seon Ah , Kim Tae-Jin , Lee Jung Eun , Sonn Chung Hee , Kim Kwanghee , Kim Jiyoung , Choi Jong Gwon , Choi Il-Kyu , Yun Chae-Ok , Kim Jae-Hong , Yee Cassian , Kumar Vinay , Lee Kyung-Mi
Published: March 2024

Abstract
Adoptive natural killer (NK) cell therapy may offer an effective treatment regimen for cancer patients whose disease is refractory to conventional therapy. NK cells can kill a wide range of tumor cells by patterned recognition of target ligands. We hypothesized that tumor targets sensitive to NK lysis would drive vigorous expansion of NK cells from human peripheral blood mononuclear cells (PBMC). Here, we provide the basis for developing a novel ex vivo expansion process. By screening class I–negative or –mismatched tumor cell lines we identified a Jurkat T-lymphoblast subline termed KL-1, which was highly effective in specifically expanding NK cells. KL-1 addition to PBMC cultures achieved approximately 100-fold expansion of NK cells with nearly 90% purity, accompanied by reciprocal inhibition of T-cell growth. Marked elevations in expression of activation receptors, natural cytotoxicity receptors (NKp30, NKp44), and adhesion molecules (CD11a, ICAM-1) were associated with high tumor-lytic capacity, in both in vitro and in vivo models. KL-1–mediated expansion of NK cells was contact dependent and required interactions with CD16, the Fcγ receptor on NK cells, with ligands that are expressed on B cells. Indeed, B-cell depletion during culture abrogated selective NK cell expansion, while addition of EBV-transformed B cells further augmented NK expansion to approximately 740-fold. Together, our studies define a novel method for efficient activation of human NK cells that employs KL-1–lysed tumor cells and cocultured B cells, which drive a robust expansion of potent antitumor effector cells that will be useful for clinical evaluation. Cancer Res; 73(8); 2598–607. ©2012 AACR.
Data from ATIP3, a Novel Prognostic Marker of Breast Cancer Patient Survival, Limits Cancer Cell Migration and Slows Metastatic Progression by Regulating Microtubule Dynamics
Authors: Molina Angie , Velot Lauriane , Ghouinem Lydia , Abdelkarim Mohamed , Bouchet Benjamin Pierre , Luissint Anny-Claude , Bouhlel Imène , Morel Marina , Sapharikas Elène , Di Tommaso Anne , Honoré Stéphane , Braguer Diane , Gruel Nadège , Vincent-Salomon Anne , Delattre Olivier , Sigal-Zafrani Brigitte , André Fabrice , Terris Benoit , Akhmanova Anna , Di Benedetto Mélanie , Nahmias Clara , Rodrigues-Ferreira Sylvie
Published: March 2024

Abstract
Metastasis, a fatal complication of breast cancer, does not fully benefit from available therapies. In this study, we investigated whether ATIP3, the major product of 8p22 MTUS1 gene, may be a novel biomarker and therapeutic target for metastatic breast tumors. We show that ATIP3 is a prognostic marker for overall survival among patients with breast cancer. Notably, among metastatic tumors, low ATIP3 levels associate with decreased survival of the patients. By using a well-defined experimental mouse model of cancer metastasis, we show that ATIP3 expression delays the time-course of metastatic progression and limits the number and size of metastases in vivo. In functional studies, ATIP3 silencing increases breast cancer cell migration, whereas ATIP3 expression significantly reduces cell motility and directionality. We report here that ATIP3 is a potent microtubule-stabilizing protein whose depletion increases microtubule dynamics. Our data support the notion that by decreasing microtubule dynamics, ATIP3 controls the ability of microtubule tips to reach the cell cortex during migration, a mechanism that may account for reduced cancer cell motility and metastasis. Of interest, we identify a functional ATIP3 domain that associates with microtubules and recapitulates the effects of ATIP3 on microtubule dynamics, cell proliferation, and migration. Our study is a major step toward the development of new personalized treatments against metastatic breast tumors that have lost ATIP3 expression. Cancer Res; 73(9); 2905–15. ©2013 AACR.
Data from Parathyroid Hormone–Related Protein Drives a CD11b+Gr1+ Cell–Mediated Positive Feedback Loop to Support Prostate Cancer Growth
Authors: Park Serk In , Lee Changki , Sadler W. David , Koh Amy J. , Jones Jacqueline , Seo Jung Won , Soki Fabiana N. , Cho Sun Wook , Daignault Stephanie D. , McCauley Laurie K.
Published: March 2024

Abstract
In the tumor microenvironment, CD11b+Gr1+ bone marrow–derived cells are a predominant source of protumorigenic factors such as matrix metalloproteinases (MMP), but how distal tumors regulate these cells in the bone marrow is unclear. Here we addressed the hypothesis that the parathyroid hormone–related protein (PTHrP) potentiates CD11b+Gr1+ cells in the bone marrow of prostate tumor hosts. In two xenograft models of prostate cancer, levels of tumor-derived PTHrP correlated with CD11b+Gr1+ cell recruitment and microvessel density in the tumor tissue, with evidence for mediation of CD11b+Gr1+ cell–derived MMP-9 but not tumor-derived VEGF-A. CD11b+Gr1+ cells isolated from mice with PTHrP-overexpressing tumors exhibited relatively increased proangiogenic potential, suggesting that prostate tumor–derived PTHrP potentiates this activity of CD11b+Gr1+ cells. Administration of neutralizing PTHrP monoclonal antibody reduced CD11b+Gr1+ cells and MMP-9 in the tumors. Mechanistic investigations in vivo revealed that PTHrP elevated Y418 phosphorylation levels in Src family kinases in CD11b+Gr1+ cells via osteoblast-derived interleukin-6 and VEGF-A, thereby upregulating MMP-9. Taken together, our results showed that prostate cancer–derived PTHrP acts in the bone marrow to potentiate CD11b+Gr1+ cells, which are recruited to tumor tissue where they contribute to tumor angiogenesis and growth. Cancer Res; 73(22); 6574–83. ©2013 AACR.
Data from Nitric Oxide–Dependent Downregulation of BRCA1 Expression Promotes Genetic Instability
Authors: Yakovlev Vasily A.
Published: March 2024

Abstract
Elevated levels of nitric oxide (NO) and reactive nitrogen species (RNS) may link inflammation to the initiation, promotion, and progression of cancer. Traditionally, this link has been thought to be mediated by the effects of NO/RNS in generating DNA damage. However, this damage also stimulates DNA repair responses with subsequent blocks to cell proliferation and apoptosis, thereby preventing accumulation of NO/RNS-generated mutations. In addressing this conundrum, I describe here an alternative mechanism for understanding mutagenesis by NO/RNS. Moderate NO/RNS concentrations stimulated mutagenesis not directly by generating DNA damage but indirectly by modifying the activities of DNA repair and genome stability factors without affecting cell proliferation. NO/RNS at concentrations physiologically relevant to inflammation stimulated PP2A activity, leading to dephosphorylation of RBL2, its accumulation in the nucleus, and formation of RBL2/E2F4 complexes. RBL2/E2F4 formation in turn led to a shift in BRCA1 promoter occupancy from complexes containing activator E2F1 to complexes containing repressor E2F4, downregulating BRCA1 expression. By inhibiting BRCA1 expression, NO/RNS thereby reduces the ability of cells to repair DNA double-strand breaks through homologous recombination repair, increasing the involvement of error-prone nonhomologous end joining (NHEJ). In summary, NO/RNS stimulates genetic instability by inhibiting BRCA1 expression and shifting DNA repair from high fidelity to error-prone mechanisms. Cancer Res; 73(2); 706–15. ©2012 AACR.
Data from Glioblastoma Stem Cells Are Regulated by Interleukin-8 Signaling in a Tumoral Perivascular Niche
Authors: Infanger David W. , Cho YouJin , Lopez Brina S. , Mohanan Sunish , Liu S. Chris , Gursel Demirkan , Boockvar John A. , Fischbach Claudia
Published: March 2024

Abstract
Glioblastoma multiforme contains a subpopulation of cancer stem–like cells (CSC) believed to underlie tumorigenesis and therapeutic resistance. Recent studies have localized CSCs in this disease adjacent to endothelial cells (EC) in what has been termed a perivascular niche, spurring investigation into the role of EC–CSC interactions in glioblastoma multiforme pathobiology. However, these studies have been limited by a lack of in vitro models of three-dimensional disease that can recapitulate the relevant conditions of the niche. In this study, we engineered a scaffold-based culture system enabling brain endothelial cells to form vascular networks. Using this system, we showed that vascular assembly induces CSC maintenance and growth in vitro and accelerates tumor growth in vivo through paracrine interleukin (IL)-8 signaling. Relative to conventional monolayers, endothelial cells cultured in this three-dimensional system not only secreted enhanced levels of IL-8 but also induced CSCs to upregulate the IL-8 cognate receptors CXCR1 and CXCR2, which collectively enhanced CSC migration, growth, and stemness properties. CXCR2 silencing in CSCs abolished the tumor-promoting effects of endothelial cells in vivo, confirming a critical role for this signaling pathway in GMB pathogenesis. Together, our results reveal synergistic interactions between endothelial cells and CSCs that promote the malignant properties of CSCs in an IL-8–dependent manner. Furthermore, our findings underscore the relevance of tissue-engineered cell culture platforms to fully analyze signaling mechanisms in the tumor microenvironment. Cancer Res; 73(23); 7079–89. ©2013 AACR.
Data from Redox Modulation of Adjacent Thiols in VLA-4 by AS101 Converts Myeloid Leukemia Cells from a Drug-Resistant to Drug-Sensitive State
Authors: Layani-Bazar Adi , Skornick Itai , Berrebi Alain , Pauker Maor H. , Noy Elad , Silberman Alon , Albeck Michael , Longo Dan L. , Kalechman Yona , Sredni Benjamin
Published: March 2024

Abstract
Interaction between the integrin VLA-4 on acute myelogenous leukemia (AML) cells with stromal fibronectin is a decisive factor in chemotherapeutic resistance. In this study, we provide a rationale for a drug repositioning strategy to blunt integrin activation in AML cells and restore their sensitivity to chemotherapy. Specifically, we demonstrate that the nontoxic tellurium compound AS101, currently being evaluated in clinical trials, can abrogate the acquired resistance of AML. Mechanistic investigations revealed that AS101 caused redox inactivation of adjacent thiols in the exofacial domain of VLA-4 after its ligation to stromal fibronectin. This effect triggered cytoskeletal conformational changes that decreased PI3K/Akt/Bcl2 signaling, an obligatory step in chemosensitization by AS101. In a mouse xenograft of AML derived from patient leukemic cells with high VLA-4 expression and activity, we demonstrated that AS101 abrogated drug resistance and prolonged survival in mice receiving chemotherapy. Decreased integrin activity was confirmed on AML cells in vivo. The chemosensitizing activity of AS101 persisted in hosts with defective adaptive and innate immunity, consistent with evidence that integrin deactivation was not mediated by heightening immune attack. Our findings provide a mechanistic rationale to reposition the experimental clinical agent, AS101, to degrade VLA-4–mediated chemoresistance and improve clinical responses in patients with AML. Cancer Res; 74(11); 3092–103. ©2014 AACR.