bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Eva1 Maintains the Stem-like Character of Glioblastoma-Initiating Cells by Activating the Noncanonical NF-κB Signaling Pathway
Authors: Ohtsu Naoki , Nakatani Yuka , Yamashita Daisuke , Ohue Shiro , Ohnishi Takanori , Kondo Toru
Published: April 2023

Abstract
Glioblastoma (GBM)–initiating cells (GIC) are a tumorigenic subpopulation that are resistant to radio- and chemotherapies and are the source of disease recurrence. Therefore, the identification and characterization of GIC-specific factors is critical toward the generation of effective GBM therapeutics. In this study, we investigated the role of epithelial V-like antigen 1 (Eva1, also known as myelin protein zero-like 2) in stemness and GBM tumorigenesis. Eva1 was prominently expressed in GICs in vitro and in stem cell marker (Sox2, CD15, CD49f)-expressing cells derived from human GBM tissues. Eva1 knockdown in GICs reduced their self-renewal and tumor-forming capabilities, whereas Eva1 overexpression enhanced these properties. Eva1 deficiency was also associated with decreased expression of stemness-related genes, indicating a requirement for Eva1 in maintaining GIC pluripotency. We further demonstrate that Eva1 induced GIC proliferation through the activation of the RelB-dependent noncanonical NF-κB pathway by recruiting TRAF2 to the cytoplasmic tail. Taken together, our findings highlight Eva1 as a novel regulator of GIC function and also provide new mechanistic insight into the role of noncanonical NF-κB activation in GIC, thus offering multiple potential therapeutic targets for preclinical investigation in GBM. Cancer Res; 76(1); 171–81. ©2015 AACR.
Data from Effective Targeting of the Survivin Dimerization Interface with Small-Molecule Inhibitors
Authors: Qi Jing , Dong Zizheng , Liu Jianguo , Peery Robert C. , Zhang Shaobo , Liu Jing-Yuan , Zhang Jian-Ting
Published: April 2023

Abstract
Many oncoproteins are considered undruggable because they lack enzymatic activities. In this study, we present a small-molecule–based anticancer agent that acts by inhibiting dimerization of the oncoprotein survivin, thereby promoting its degradation along with spontaneous apoptosis in cancer cells. Through a combination of computational analysis of the dimerization interface and in silico screening, we identified one compound that induced proteasome-dependent survivin degradation. Analysis of a set of structural analogues led us to identify a lead compound (LQZ-7F), which was effective in blocking the survival of multiple cancer cell lines in a low micromolar concentration range. LQZ-7F induced proteasome-dependent survivin degradation, mitotic arrest, and apoptosis, and it blocked the growth of human tumors in mouse xenograft assays. In addition to providing preclinical proof of concept for a survivin-targeting anticancer agent, our work offers novel in silico screening strategies to therapeutically target homodimeric oncogenic proteins considered undruggable. Cancer Res; 76(2); 453–62. ©2016 AACR.
Data from Upregulation of Cytosolic Phosphoenolpyruvate Carboxykinase Is a Critical Metabolic Event in Melanoma Cells That Repopulate Tumors
Authors: Li Yong , Luo Shunqun , Ma Ruihua , Liu Jing , Xu Pingwei , Zhang Huafeng , Tang Ke , Ma Jingwei , Zhang Yi , Liang Xiaoyu , Sun Yanling , Ji Tiantian , Wang Ning , Huang Bo
Published: March 2023

Abstract
Although metabolic defects have been investigated extensively in differentiated tumor cells, much less attention has been directed to the metabolic properties of stem-like cells that repopulate tumors [tumor-repopulating cells (TRC)]. Here, we show that melanoma TRCs cultured in three-dimensional soft fibrin gels reprogram glucose metabolism by hijacking the cytosolic enzyme phosphoenolpyruvate carboxykinase (PCK1), a key player in gluconeogenesis. Surprisingly, upregulated PCK1 in TRCs did not mediate gluconeogenesis but promoted glucose side-branch metabolism, including in the serine and glycerol-3-phosphate pathways. Moreover, this retrograde glucose carbon flow strengthened rather than antagonized glycolysis and glucose consumption. Silencing PCK1 or inhibiting its enzymatic activity slowed the growth of TRCs in vitro and impeded tumorigenesis in vivo. Overall, our work unveiled metabolic features of TRCs in melanoma that have implications for targeting a unique aspect of this disease. Cancer Res; 75(7); 1191–6. ©2015 AACR.
Data from Multinucleation and Mesenchymal-to-Epithelial Transition Alleviate Resistance to Combined Cabazitaxel and Antiandrogen Therapy in Advanced Prostate Cancer
Authors: Martin Sarah K. , Pu Hong , Penticuff Justin C. , Cao Zheng , Horbinski Craig , Kyprianou Natasha
Published: April 2023

Abstract
Patients with metastatic castration-resistant prostate cancer (CRPC) frequently develop therapeutic resistance to taxane chemotherapy and antiandrogens. Cabazitaxel is a second-line taxane chemotherapeutic agent that provides additional survival benefits to patients with advanced disease. In this study, we sought to identify the mechanism of action of combined cabazitaxel and androgen receptor (AR) targeting in preclinical models of advanced prostate cancer. We found that cabazitaxel induced mitotic spindle collapse and multinucleation by targeting the microtubule depolymerizing kinesins and inhibiting AR. In androgen-responsive tumors, treatment with the AR inhibitor, enzalutamide, overcame resistance to cabazitaxel. Combination treatment of human CRPC xenografts with cabazitaxel and enzalutamide reversed epithelial–mesenchymal transition (EMT) to mesenchymal–epithelial transition (MET) and led to multinucleation, while retaining nuclear AR. In a transgenic mouse model of androgen-responsive prostate cancer, cabazitaxel treatment induced MET, glandular redifferentiation, and AR nuclear localization that was inhibited by androgen deprivation. Collectively, our preclinical studies demonstrate that prostate tumor resistance to cabazitaxel can be overcome by antiandrogen-mediated EMT-MET cycling in androgen-sensitive tumors but not in CRPC. Moreover, AR splice variants may preclude patients with advanced disease from responding to cabazitaxel chemotherapy and antiandrogen combination therapy. This evidence enables a significant insight into therapeutic cross-resistance to taxane chemotherapy and androgen deprivation therapy in advanced prostate cancer. Cancer Res; 76(4); 912–26. ©2015 AACR.
Data from The Proliferative Activity of Mammary Epithelial Cells in Normal Tissue Predicts Breast Cancer Risk in Premenopausal Women
Authors: Huh Sung Jin , Oh Hannah , Peterson Michael A. , Almendro Vanessa , Hu Rong , Bowden Michaela , Lis Rosina L. , Cotter Maura B. , Loda Massimo , Barry William T. , Polyak Kornelia , Tamimi Rulla M.
Published: April 2023

Abstract
The frequency and proliferative activity of tissue-specific stem and progenitor cells are suggested to correlate with cancer risk. In this study, we investigated the association between breast cancer risk and the frequency of mammary epithelial cells expressing p27, estrogen receptor (ER), and Ki67 in normal breast tissue. We performed a nested case–control study of 302 women (69 breast cancer cases, 233 controls) who had been initially diagnosed with benign breast disease according to the Nurses' Health Studies. Immunofluorescence for p27, ER, and Ki67 was performed on tissue microarrays constructed from benign biopsies containing normal mammary epithelium and scored by computational image analysis. We found that the frequency of Ki67+ cells was positively associated with breast cancer risk among premenopausal women [OR = 10.1, 95% confidence interval (CI) = 2.12–48.0]. Conversely, the frequency of ER+ or p27+ cells was inversely, but not significantly, associated with subsequent breast cancer risk (ER+: OR = 0.70, 95% CI, 0.33–1.50; p27+: OR = 0.89, 95% CI, 0.45–1.75). Notably, high Ki67+/low p27+ and high Ki67+/low ER+ cell frequencies were significantly associated with a 5-fold higher risk of breast cancer compared with low Ki67+/low p27+ and low Ki67+/low ER+ cell frequencies, respectively, among premenopausal women (Ki67hi/p27lo: OR = 5.08, 95% CI, 1.43–18.1; Ki67hi/ERlo: OR = 4.68, 95% CI, 1.63–13.5). Taken together, our data suggest that the fraction of actively cycling cells in normal breast tissue may represent a marker for breast cancer risk assessment, which may therefore impact the frequency of screening procedures in at-risk women. Cancer Res; 76(7); 1926–34. ©2016 AACR.
Data from Deguelin Analogue SH-1242 Inhibits Hsp90 Activity and Exerts Potent Anticancer Efficacy with Limited Neurotoxicity
Authors: Lee Su-Chan , Min Hye-Young , Choi Hoon , Bae Song Yi , Park Kwan Hee , Hyun Seung Yeob , Lee Ho Jin , Moon Jayoung , Park Shin-Hyung , Kim Jun Yong , An Hongchan , Park So-Jung , Seo Ji Hae , Lee Seungbeom , Kim Young-Myeong , Park Hyun-Ju , Lee Sang Kook , Lee Jeewoo , Lee Jeeyeon , Kim Kyu-Won , Suh Young-Ger , Lee Ho-Young
Published: April 2023

Abstract
The Hsp90 facilitates proper folding of signaling proteins associated with cancer progression, gaining attention as a target for therapeutic intervention. The natural rotenoid deguelin was identified as an Hsp90 inhibitor, but concerns about neurotoxicity have limited prospects for clinical development. In this study, we report progress on deguelin analogues that address this limitation, focusing on the novel analogue SH-1242 as a candidate to broadly target human lung cancer cells, including those that are chemoresistant or harboring KRAS mutations. In a KRAS-driven mouse model of lung cancer, SH-1242 administration reduced tumor multiplicity, volume, and load. Similarly, in human cell line–based or patient-derived tumor xenograft models, SH-1242 induced apoptosis and reduced tumor vasculature in the absence of detectable toxicity. In contrast to deguelin, SH-1242 toxicity was greatly reduced in normal cells and when administered to rats did not produce obvious histopathologic features in the brain. Mechanistic studies revealed that SH-1242 bound to the C-terminal ATP-binding pocket of Hsp90, disrupting the ability to interact with its co-chaperones and clients and triggering a degradation of client proteins without affecting Hsp70 expression. Taken together, our findings illustrate the superior properties of SH-1242 as an Hsp90 inhibitor and as an effective antitumor and minimally toxic agent, providing a foundation for advancing further preclinical and clinical studies. Cancer Res; 76(3); 686–99. ©2015 AACR.
Data from Peptide–Drug Conjugate GnRH–Sunitinib Targets Angiogenesis Selectively at the Site of Action to Inhibit Tumor Growth
Authors: Argyros Orestis , Karampelas Theodoros , Asvos Xenophon , Varela Aimilia , Sayyad Nisar , Papakyriakou Athanasios , Davos Constantinos H. , Tzakos Andreas G. , Fokas Demosthenes , Tamvakopoulos Constantin
Published: April 2023

Abstract
The potential to heighten the efficacy of antiangiogenic agents was explored in this study based on active targeting of tumor cells overexpressing the gonadotropin-releasing hormone receptor (GnRH-R). The rational design pursued focused on five analogues of a clinically established antiangiogenic compound (sunitinib), from which a lead candidate (SAN1) was conjugated to the targeting peptide [d-Lys6]-GnRH, generating SAN1GSC. Conjugation of SAN1 did not disrupt any of its antiangiogenic or cytotoxic properties in GnRH-R–expressing prostate and breast tumor cells. Daily SAN1GSC treatments in mouse xenograft models of castration-resistant prostate cancer resulted in significant tumor growth delay compared with equimolar SAN1 or sunitinib alone. This efficacy correlated with inhibited phosphorylation of AKT and S6, together with reduced Ki-67 and CD31 expression. The superior efficacy of the peptide–drug conjugate was also attributed to the finding that higher amounts of SAN1 were delivered to the tumor site (∼4-fold) following dosing of SAN1GSC compared with equimolar amounts of nonconjugated SAN1. Importantly, treatment with SAN1GSC was associated with minimal hematotoxicity and cardiotoxicity based on measurements of the left ventricular systolic function in treated mice. Our results offer preclinical proof-of-concept for SAN1GSC as a novel molecule that selectively reaches the tumor site and downregulates angiogenesis with negligible cardiotoxicity, thus encouraging its further clinical development and evaluation. Cancer Res; 76(5); 1181–92. ©2015 AACR.
Data from Decoding Intratumoral Heterogeneity of Breast Cancer by Multiparametric In Vivo Imaging: A Translational Study
Authors: Schmitz Jennifer , Schwab Julian , Schwenck Johannes , Chen Qian , Quintanilla-Martinez Leticia , Hahn Markus , Wietek Beate , Schwenzer Nina , Staebler Annette , Kohlhofer Ursula , Aina Olulanu H. , Hubbard Neil E. , Reischl Gerald , Borowsky Alexander D. , Brucker Sara , Nikolaou Konstantin , la Fougère Christian , Cardiff Robert D. , Pichler Bernd J. , Schmid Andreas M.
Published: April 2023

Abstract
Differential diagnosis and therapy of heterogeneous breast tumors poses a major clinical challenge. To address the need for a comprehensive, noninvasive strategy to define the molecular and functional profiles of tumors in vivo, we investigated a novel combination of metabolic PET and diffusion-weighted (DW)-MRI in the polyoma virus middle T antigen transgenic mouse model of breast cancer. The implementation of a voxelwise analysis for the clustering of intra- and intertumoral heterogeneity in this model resulted in a multiparametric profile based on [18F]Fluorodeoxyglucose ([18F]FDG)-PET and DW-MRI, which identified three distinct tumor phenotypes in vivo, including solid acinar, and solid nodular malignancies as well as cystic hyperplasia. To evaluate the feasibility of this approach for clinical use, we examined estrogen receptor-positive and progesterone receptor-positive breast tumors from five patient cases using DW-MRI and [18F]FDG-PET in a simultaneous PET/MRI system. The postsurgical in vivo PET/MRI data were correlated to whole-slide histology using the latter traditional diagnostic standard to define phenotype. By this approach, we showed how molecular, structural (microscopic, anatomic), and functional information could be simultaneously obtained noninvasively to identify precancerous and malignant subtypes within heterogeneous tumors. Combined with an automatized analysis, our results suggest that multiparametric molecular and functional imaging may be capable of providing comprehensive tumor profiling for noninvasive cancer diagnostics. Cancer Res; 76(18); 5512–22. ©2016 AACR.
Data from M-COPA, a Golgi Disruptor, Inhibits Cell Surface Expression of MET Protein and Exhibits Antitumor Activity against MET-Addicted Gastric Cancers
Authors: Ohashi Yoshimi , Okamura Mutsumi , Hirosawa Asaka , Tamaki Naomi , Akatsuka Akinobu , Wu Kuo-Ming , Choi Hyeong-Wook , Yoshimatsu Kentaro , Shiina Isamu , Yamori Takao , Dan Shingo
Published: April 2023

Abstract
The Golgi apparatus is responsible for transporting, processing, and sorting numerous proteins in the cell, including cell surface-expressed receptor tyrosine kinases (RTK). The small-molecule compound M-COPA [2-methylcoprophilinamide (AMF-26)] disrupts the Golgi apparatus by inhibiting the activation of Arf1, resulting in suppression of tumor growth. Here, we report an evaluation of M-COPA activity against RTK-addicted cancers, focusing specifically on human gastric cancer (GC) cells with or without MET amplification. As expected, the MET-addicted cell line MKN45 exhibited a better response to M-COPA than cell lines without MET amplification. Upon M-COPA treatment, cell surface expression of MET was downregulated with a concurrent accumulation of its precursor form. M-COPA also reduced levels of the phosphorylated form of MET along with the downstream signaling molecules Akt and S6. Similar results were obtained in additional GC cell lines with amplification of MET or the FGF receptor FGFR2. MKN45 murine xenograft experiments demonstrated the antitumor activity of M-COPA in vivo. Taken together, our results offer an initial preclinical proof of concept for the use of M-COPA as a candidate treatment option for MET-addicted GC, with broader implications for targeting the Golgi apparatus as a novel cancer therapeutic approach. Cancer Res; 76(13); 3895–903. ©2016 AACR.
Data from Autophagy Differentially Regulates Distinct Breast Cancer Stem-like Cells in Murine Models via EGFR/Stat3 and Tgfβ/Smad Signaling
Authors: Yeo Syn Kok , Wen Jian , Chen Song , Guan Jun-Lin
Published: April 2023

Abstract
Cancer stem-like cells contribute to tumor heterogeneity and have been implicated in disease relapse and drug resistance. Here we show the coexistence of distinct breast cancer stem-like cells (BCSC) as identified by ALDH+ and CD29hiCD61+ markers, respectively, in murine models of breast cancer. While both BCSC exhibit enhanced tumor-initiating potential, CD29hiCD61+ BCSC displayed increased invasive abilities and higher expression of epithelial-to-mesenchymal transition and mammary stem cell–associated genes, whereas ALDH+ BCSC were more closely associated with luminal progenitors. Attenuating the autophagy regulator FIP200 diminished the tumor-initiating properties of both ALDH+ and CD29hiCD61+ BCSC, as achieved by impairing either the Stat3 or TGFβ/Smad pathways, respectively. Furthermore, combining the Stat3 inhibitor Stattic and the Tgfβ-R1 inhibitor LY-2157299 inhibited the formation of both epithelial and mesenchymal BCSC colonies. In vivo, this combination treatment was sufficient to limit tumor growth and reduce BCSC number. Overall, our findings reveal a differential dependence of heterogeneous BCSC populations on divergent signaling pathways, with implications on how to tailor drug combinations to improve therapeutic efficacy. Cancer Res; 76(11); 3397–410. ©2016 AACR.
Data from Aberrant Activation of Notch Signaling Inhibits PROX1 Activity to Enhance the Malignant Behavior of Thyroid Cancer Cells
Authors: Choi Dongwon , Ramu Swapnika , Park Eunkyung , Jung Eunson , Yang Sara , Jung Wonhyeuk , Choi Inho , Lee Sunju , Kim Kyu Eui , Seong Young Jin , Hong Mingu , Daghlian George , Kim Daniel , Shin Eugene , Seo Jung In , Khatchadourian Vicken , Zou Mengchen , Li Wei , De Filippo Roger , Kokorowski Paul , Chang Andy , Kim Steve , Bertoni Ana , Furlanetto Tania Weber , Shin Sung , Li Meng , Chen Yibu , Wong Alex , Koh Chester , Geliebter Jan , Hong Young-Kwon
Published: March 2023

Abstract
Papillary thyroid cancer (PTC) is one of the most common endocrine malignancies associated with significant morbidity and mortality. Although multiple studies have contributed to a better understanding of the genetic alterations underlying this frequently arising disease, the downstream molecular effectors that impact PTC pathogenesis remain to be further defined. Here, we report that the regulator of cell fate specification, PROX1, becomes inactivated in PTC through mRNA downregulation and cytoplasmic mislocalization. Expression studies in clinical specimens revealed that aberrantly activated NOTCH signaling promoted PROX1 downregulation and that cytoplasmic mislocalization significantly altered PROX1 protein stability. Importantly, restoration of PROX1 activity in thyroid carcinoma cells revealed that PROX1 not only enhanced Wnt/β-catenin signaling but also regulated several genes known to be associated with PTC, including thyroid cancer protein (TC)-1, SERPINA1, and FABP4. Furthermore, PROX1 reexpression suppressed the malignant phenotypes of thyroid carcinoma cells, such as proliferation, motility, adhesion, invasion, anchorage-independent growth, and polyploidy. Moreover, animal xenograft studies demonstrated that restoration of PROX1 severely impeded tumor formation and suppressed the invasiveness and the nuclear/cytoplasmic ratio of PTC cells. Taken together, our findings demonstrate that NOTCH-induced PROX1 inactivation significantly promotes the malignant behavior of thyroid carcinoma and suggest that PROX1 reactivation may represent a potential therapeutic strategy to attenuate disease progression Cancer Res; 76(3); 582–93. ©2015 AACR.
Data from Mesenchymal Stem Cell–Derived Exosomes Stimulate Cycling Quiescence and Early Breast Cancer Dormancy in Bone Marrow
Authors: Bliss Sarah A. , Sinha Garima , Sandiford Oleta A. , Williams Lisa M. , Engelberth Daniel J. , Guiro Khadidiatou , Isenalumhe Leidy L. , Greco Steven J. , Ayer Seda , Bryan Margarette , Kumar Rakesh , Ponzio Nicholas M. , Rameshwar Pranela
Published: March 2023

Abstract
Dormant breast cancers resurge as metastatic disease after a long dormancy period in the bone marrow, where cancer cells interact with mesenchymal stem cells (MSC). However, the nature of early interactions between breast cancer cells and MSCs in the bone marrow microenvironment that facilitate adaptation to a quiescent state remains poorly understood. Here, we report that breast cancer cells prime MSC to release exosomes containing distinct miRNA contents, such as miR-222/223, which in turn promotes quiescence in a subset of cancer cells and confers drug resistance. Building on these results, we developed a novel, nontoxic therapeutic strategy to target dormant breast cancer cells based on systemic administration of MSC loaded with antagomiR-222/223. In an immunodeficient mouse model of dormant breast cancer, this therapy sensitized breast cancer cells to carboplatin-based therapy and increased host survival. Overall, our findings illuminate the nature of the regulatory interactions between breast cancer cells and MSCs in the evolution of tumor dormancy and resurgence in the micrometastatic microenvironment of the bone marrow. Cancer Res; 76(19); 5832–44. ©2016 AACR.
Data from HSP70 Inhibition Limits FAK-Dependent Invasion and Enhances the Response to Melanoma Treatment with BRAF Inhibitors
Authors: Budina-Kolomets Anna , Webster Marie R. , Leu Julia I-Ju , Jennis Matthew , Krepler Clemens , Guerrini Anastasia , Kossenkov Andrew V. , Xu Wei , Karakousis Giorgos , Schuchter Lynn , Amaravadi Ravi K. , Wu Hong , Yin Xiangfan , Liu Qin , Lu Yiling , Mills Gordon B. , Xu Xiaowei , George Donna L. , Weeraratna Ashani T. , Murphy Maureen E.
Published: March 2023

Abstract
The stress-inducible chaperone protein HSP70 (HSPA1) is implicated in melanoma development, and HSP70 inhibitors exert tumor-specific cytotoxic activity in cancer. In this study, we documented that a significant proportion of melanoma tumors express high levels of HSP70, particularly at advanced stages, and that phospho-FAK (PTK2) and BRAF are HSP70 client proteins. Treatment of melanoma cells with HSP70 inhibitors decreased levels of phospho-FAK along with impaired migration, invasion, and metastasis in vitro and in vivo. Moreover, the HSP70 inhibitor PET-16 reduced levels of mutant BRAF, synergized with the BRAF inhibitor PLX4032 in vitro, and enhanced the durability of response to BRAF inhibition in vivo. Collectively, these findings provide strong support for HSP70 inhibition as a therapeutic strategy in melanoma, especially as an adjuvant approach for overcoming the resistance to BRAF inhibitors frequently observed in melanoma patients. Cancer Res; 76(9); 2720–30. ©2016 AACR.
Data from DNMT1 Inhibition Reprograms Pancreatic Cancer Stem Cells via Upregulation of the miR-17-92 Cluster
Authors: Zagorac Sladjana , Alcala Sonia , Fernandez Bayon Gustavo , Bou Kheir Tony , Schoenhals Matthieu , González-Neira Anna , Fernandez Fraga Mario , Aicher Alexandra , Heeschen Christopher , Sainz Bruno
Published: March 2023

Abstract
Pancreatic ductal adenocarcinoma (PDAC) and other carcinomas are hierarchically organized, with cancer stem cells (CSC) residing at the top of the hierarchy, where they drive tumor progression, metastasis, and chemoresistance. As CSC and non-CSC share an identical genetic background, we hypothesize that differences in epigenetics account for the striking functional differences between these two cell populations. Epigenetic mechanisms, such as DNA methylation, play an important role in maintaining pluripotency and regulating the differentiation of stem cells, but the role of DNA methylation in pancreatic CSC is obscure. In this study, we investigated the genome-wide DNA methylation profile of PDAC CSC, and we determined the importance of DNA methyltransferases for CSC maintenance and tumorigenicity. Using high-throughput methylation analysis, we discovered that sorted CSCs have a higher level of DNA methylation, regardless of the heterogeneity or polyclonality of the CSC populations present in the tumors analyzed. Mechanistically, CSC expressed higher DNMT1 levels than non-CSC. Pharmacologic or genetic targeting of DNMT1 in CSCs reduced their self-renewal and in vivo tumorigenic potential, defining DNMT1 as a candidate CSC therapeutic target. The inhibitory effect we observed was mediated in part through epigenetic reactivation of previously silenced miRNAs, in particular the miR-17-92 cluster. Together, our findings indicate that DNA methylation plays an important role in CSC biology and also provide a rationale to develop epigenetic modulators to target CSC plasticity and improve the poor outcome of PDAC patients. Cancer Res; 76(15); 4546–58. ©2016 AACR.
Data from Spatial Modeling of Drug Delivery Routes for Treatment of Disseminated Ovarian Cancer
Authors: Winner Kimberly R. Kanigel , Steinkamp Mara P. , Lee Rebecca J. , Swat Maciej , Muller Carolyn Y. , Moses Melanie E. , Jiang Yi , Wilson Bridget S.
Published: April 2023

Abstract
In ovarian cancer, metastasis is typically confined to the peritoneum. Surgical removal of the primary tumor and macroscopic secondary tumors is a common practice, but more effective strategies are needed to target microscopic spheroids persisting in the peritoneal fluid after debulking surgery. To treat this residual disease, therapeutic agents can be administered by either intravenous or intraperitoneal infusion. Here, we describe the use of a cellular Potts model to compare tumor penetration of two classes of drugs (cisplatin and pertuzumab) when delivered by these two alternative routes. The model considers the primary route when the drug is administered either intravenously or intraperitoneally, as well as the subsequent exchange into the other delivery volume as a secondary route. By accounting for these dynamics, the model revealed that intraperitoneal infusion is the markedly superior route for delivery of both small-molecule and antibody therapies into microscopic, avascular tumors typical of patients with ascites. Small tumors attached to peritoneal organs, with vascularity ranging from 2% to 10%, also show enhanced drug delivery via the intraperitoneal route, even though tumor vessels can act as sinks during the dissemination of small molecules. Furthermore, we assessed the ability of the antibody to enter the tumor by in silico and in vivo methods and suggest that optimization of antibody delivery is an important criterion underlying the efficacy of these and other biologics. The use of both delivery routes may provide the best total coverage of tumors, depending on their size and vascularity. Cancer Res; 76(6); 1320–34. ©2015 AACR.
Data from Molecular Pathology of Patient Tumors, Patient-Derived Xenografts, and Cancer Cell Lines
Authors: Guo Sheng , Qian Wubin , Cai Jie , Zhang Likun , Wery Jean-Pierre , Li Qi-Xiang
Published: March 2023

Abstract
The Cancer Genome Atlas (TCGA) project has generated abundant genomic data for human cancers of various histopathology types and enabled exploring cancer molecular pathology per big data approach. We developed a new algorithm based on most differentially expressed genes (DEG) per pairwise comparisons to calculate correlation coefficients to be used to quantify similarity within and between cancer types. We systematically compared TCGA cancers, demonstrating high correlation within types and low correlation between types, thus establishing molecular specificity of cancer types and an alternative diagnostic method largely equivalent to histopathology. Different coefficients for different cancers in study may reveal that the degree of the within-type homogeneity varies by cancer types. We also performed the same calculation using the TCGA-derived DEGs on patient-derived xenografts (PDX) of different histopathology types corresponding to the TCGA types, as well as on cancer cell lines. We, for the first time, demonstrated highly similar patterns for within- and between-type correlation between PDXs and patient samples in a systematic study, confirming the high relevance of PDXs as surrogate experimental models for human diseases. In contrast, cancer cell lines have drastically reduced expression similarity to both PDXs and patient samples. The studies also revealed high similarity between some types, for example, LUSC and HNSCC, but low similarity between certain subtypes, for example, LUAD and LUSC. Our newly developed algorithm seems to be a practical diagnostic method to classify and reclassify a disease, either human or xenograft, with better accuracy than traditional histopathology. Cancer Res; 76(16); 4619–26. ©2016 AACR.
Data from Syndecan-1 (CD138) Suppresses Apoptosis in Multiple Myeloma by Activating IGF1 Receptor: Prevention by SynstatinIGF1R Inhibits Tumor Growth
Authors: Beauvais DeannaLee M. , Jung Oisun , Yang Yang , Sanderson Ralph D. , Rapraeger Alan C.
Published: March 2023

Abstract
Syndecan-1 (Sdc1/CD138) expression is linked to disease severity in multiple myeloma, although the causal basis for this link remains unclear. Here we report that capture of the IGF1 receptor (IGF1R) by Sdc1 suppresses ASK1-dependent apoptosis in multiple myeloma cells. Sdc1 binds two different fractions of IGF1R, one that is constitutively active and a second that is activated by IGF1 ligand. Notably, IGF1R kinase activity in both fractions is blocked by synstatinIGF1R (SSTNIGF1R), a peptide that inhibits IGF1R capture by Sdc1, as well as by a truncated peptide (SSTNIGF1R-T) that appears to be specific for multiple myeloma cells. Mechanistically, we show that ASK1 is bound to active IGF1R and inhibited by Tyr and Ser83/Ser966 phosphorylation. When IGF1R engagement with Sdc1 is blocked by SSTNIGF1R, ASK1 becomes activated, and initiates JNK- and caspase-3–mediated apoptosis. In pharmacologic tests, we find SSTNIGF1R is highly stable in human plasma and displays a half-life of 27 hours in mice, wherein it significantly reduces both the size and neovascularization of CAG myeloma tumor xenografts. Taken together, our results offer a preclinical proof of concept and mechanistic rationale for the exploration of SSTNIGF1R as an experimental therapeutic to dually attack multiple myeloma tumor cell survival and tumor angiogenesis. Cancer Res; 76(17); 4981–93. ©2016 AACR.
Data from Early Prediction of Cancer Progression by Depth-Resolved Nanoscale Mapping of Nuclear Architecture from Unstained Tissue Specimens
Authors: Uttam Shikhar , Pham Hoa V. , LaFace Justin , Leibowitz Brian , Yu Jian , Brand Randall E. , Hartman Douglas J. , Liu Yang
Published: March 2023

Abstract
Early cancer detection currently relies on screening the entire at-risk population, as with colonoscopy and mammography. Therefore, frequent, invasive surveillance of patients at risk for developing cancer carries financial, physical, and emotional burdens because clinicians lack tools to accurately predict which patients will actually progress into malignancy. Here, we present a new method to predict cancer progression risk via nanoscale nuclear architecture mapping (nanoNAM) of unstained tissue sections based on the intrinsic density alteration of nuclear structure rather than the amount of stain uptake. We demonstrate that nanoNAM detects a gradual increase in the density alteration of nuclear architecture during malignant transformation in animal models of colon carcinogenesis and in human patients with ulcerative colitis, even in tissue that appears histologically normal according to pathologists. We evaluated the ability of nanoNAM to predict “future” cancer progression in patients with ulcerative colitis who did and did not develop colon cancer up to 13 years after their initial colonoscopy. NanoNAM of the initial biopsies correctly classified 12 of 15 patients who eventually developed colon cancer and 15 of 18 who did not, with an overall accuracy of 85%. Taken together, our findings demonstrate great potential for nanoNAM in predicting cancer progression risk and suggest that further validation in a multicenter study with larger cohorts may eventually advance this method to become a routine clinical test. Cancer Res; 75(22); 4718–27. ©2015 AACR.
Data from Preclinical Efficacy of Bevacizumab with CRLX101, an Investigational Nanoparticle–Drug Conjugate, in Treatment of Metastatic Triple-Negative Breast Cancer
Authors: Pham Elizabeth , Yin Melissa , Peters Christian G. , Lee Christina R. , Brown Donna , Xu Ping , Man Shan , Jayaraman Lata , Rohde Ellen , Chow Annabelle , Lazarus Douglas , Eliasof Scott , Foster F. Stuart , Kerbel Robert S.
Published: March 2023

Abstract
VEGF pathway–targeting antiangiogenic drugs, such as bevacizumab, when combined with chemotherapy have changed clinical practice for the treatment of a broad spectrum of human cancers. However, adaptive resistance often develops, and one major mechanism is elevated tumor hypoxia and upregulated hypoxia-inducible factor-1α (HIF1α) caused by antiangiogenic treatment. Reduced tumor vessel numbers and function following antiangiogenic therapy may also affect intratumoral delivery of concurrently administered chemotherapy. Nonetheless, combining chemotherapy and bevacizumab can lead to improved response rates, progression-free survival, and sometimes, overall survival, the extent of which can partly depend on the chemotherapy backbone. A rational, complementing chemotherapy partner for combination with bevacizumab would not only reduce HIF1α to overcome hypoxia-induced resistance, but also improve tumor perfusion to maintain intratumoral drug delivery. Here, we evaluated bevacizumab and CRLX101, an investigational nanoparticle–drug conjugate containing camptothecin, in preclinical mouse models of orthotopic primary triple-negative breast tumor xenografts, including a patient-derived xenograft. We also evaluated long-term efficacy of CRLX101 and bevacizumab to treat postsurgical, advanced metastatic breast cancer in mice. CRLX101 alone and combined with bevacizumab was highly efficacious, leading to complete tumor regressions, reduced metastasis, and greatly extended survival of mice with metastatic disease. Moreover, CRLX101 led to improved tumor perfusion and reduced hypoxia, as measured by contrast-enhanced ultrasound and photoacoustic imaging. CRLX101 durably suppressed HIF1α, thus potentially counteracting undesirable effects of elevated tumor hypoxia caused by bevacizumab. Our preclinical results show pairing a potent cytotoxic nanoparticle chemotherapeutic that complements and improves concurrent antiangiogenic therapy may be a promising treatment strategy for metastatic breast cancer. Cancer Res; 76(15); 4493–503. ©2016 AACR.
Data from Transcriptional Induction of Periostin by a Sulfatase 2–TGFβ1–SMAD Signaling Axis Mediates Tumor Angiogenesis in Hepatocellular Carcinoma
Authors: Chen Gang , Nakamura Ikuo , Dhanasekaran Renumathy , Iguchi Eriko , Tolosa Ezequiel J. , Romecin Paola A. , Vera Renzo E. , Almada Luciana L. , Miamen Alexander G. , Chaiteerakij Roongruedee , Zhou Mengtao , Asiedu Michael K. , Moser Catherine D. , Han Shaoshan , Hu Chunling , Banini Bubu A. , Oseini Abdul M. , Chen Yichun , Fang Yong , Yang Dongye , Shaleh Hassan M. , Wang Shaoqing , Wu Dehai , Song Tao , Lee Ju-Seog , Thorgeirsson Snorri S. , Chevet Eric , Shah Vijay H. , Fernandez-Zapico Martin E. , Roberts Lewis R.
Published: March 2023

Abstract
Existing antiangiogenic approaches to treat metastatic hepatocellular carcinoma (HCC) are weakly effectual, prompting further study of tumor angiogenesis in this disease setting. Here, we report a novel role for sulfatase 2 (SULF2) in driving HCC angiogenesis. Sulf2-deficient mice (Sulf2 KO) exhibited resistance to diethylnitrosamine-induced HCC and did not develop metastases like wild-type mice (Sulf2 WT). The smaller and less numerous tumors formed in Sulf2 KO mice exhibited a markedly lower microvascular density. In human HCC cells, SULF2 overexpression increased endothelial proliferation, adhesion, chemotaxis, and tube formation in a paracrine fashion. Mechanistic analyses identified the extracellular matrix protein periostin (POSTN), a ligand of αvβ3/5 integrins, as an effector protein in SULF2-induced angiogenesis. POSTN silencing in HCC cells attenuated SULF2-induced angiogenesis and tumor growth in vivo. The TGFβ1/SMAD pathway was identified as a critical signaling axis between SULF2 and upregulation of POSTN transcription. In clinical HCC specimens, elevated levels of SULF2 correlated with increased microvascular density, POSTN levels, and relatively poorer patient survival. Together, our findings define an important axis controlling angiogenesis in HCC and a mechanistic foundation for rational drug development. Cancer Res; 77(3); 632–45. ©2016 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 2023

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 Pyruvate Kinase Inhibits Proliferation during Postnatal Cerebellar Neurogenesis and Suppresses Medulloblastoma Formation
Authors: Tech Katherine , Tikunov Andrey P. , Farooq Hamza , Morrissy A. Sorana , Meidinger Jessica , Fish Taylor , Green Sarah C. , Liu Hedi , Li Yisu , Mungall Andrew J. , Moore Richard A. , Ma Yussanne , Jones Steven J.M. , Marra Marco A. , Vander Heiden Matthew G. , Taylor Michael D. , Macdonald Jeffrey M. , Gershon Timothy R.
Published: March 2023

Abstract
Aerobic glycolysis supports proliferation through unresolved mechanisms. We have previously shown that aerobic glycolysis is required for the regulated proliferation of cerebellar granule neuron progenitors (CGNP) and for the growth of CGNP-derived medulloblastoma. Blocking the initiation of glycolysis via deletion of hexokinase-2 (Hk2) disrupts CGNP proliferation and restricts medulloblastoma growth. Here, we assessed whether disrupting pyruvate kinase-M (Pkm), an enzyme that acts in the terminal steps of glycolysis, would alter CGNP metabolism, proliferation, and tumorigenesis. We observed a dichotomous pattern of PKM expression, in which postmitotic neurons throughout the brain expressed the constitutively active PKM1 isoform, while neural progenitors and medulloblastomas exclusively expressed the less active PKM2. Isoform-specific Pkm2 deletion in CGNPs blocked all Pkm expression. Pkm2-deleted CGNPs showed reduced lactate production and increased SHH-driven proliferation. 13C-flux analysis showed that Pkm2 deletion reduced the flow of glucose carbons into lactate and glutamate without markedly increasing glucose-to-ribose flux. Pkm2 deletion accelerated tumor formation in medulloblastoma-prone ND2:SmoA1 mice, indicating the disrupting PKM releases CGNPs from a tumor-suppressive effect. These findings show that distal and proximal disruptions of glycolysis have opposite effects on proliferation, and that efforts to block the oncogenic effect of aerobic glycolysis must target reactions upstream of PKM. Cancer Res; 77(12); 3217–30. ©2017 AACR.
Data from Landscape of Combination Immunotherapy and Targeted Therapy to Improve Cancer Management
Authors: Colli Leandro M. , Machiela Mitchell J. , Zhang Han , Myers Timothy A. , Jessop Lea , Delattre Olivier , Yu Kai , Chanock Stephen J.
Published: March 2023

Abstract
Cancer treatments composed of immune checkpoint inhibitors and oncogene-targeted drugs might improve cancer management, but there has been little investigation of their combined potential as yet. To estimate the fraction of cancer cases that might benefit from such combination therapy, we conducted an exploratory study of cancer genomic datasets to determine the proportion with somatic mutation profiles amenable to either immunotherapy or targeted therapy. We surveyed 13,349 genomic profiles from public databases for cases with specific mutations targeted by current agents or a burden of exome-wide nonsynonymous mutations (NsM) that exceed a proposed threshold for response to checkpoint inhibitors. Overall, 8.9% of cases displayed profiles that could benefit from combination therapy, which corresponded to approximately 11.2% of U.S. annual incident cancer cases. Frequently targetable mutations were in PIK3CA, BRAF, NF1, NRAS, and PTEN. We also noted a high burden of NsM in cases with targetable mutations in SMO, DDR2, FGFR1, PTCH1, FGFR2, and MET. Our results indicate that a significant proportion of solid tumor patients are eligible for immuno-targeted combination therapy, and they suggest prioritizing specific cancers for trials of certain targeted and checkpoint inhibitor drugs. Cancer Res; 77(13); 3666–71. ©2017 AACR.
Data from Pancreatic Cancer Risk Associated with Prediagnostic Plasma Levels of Leptin and Leptin Receptor Genetic Polymorphisms
Authors: Babic Ana , Bao Ying , Qian Zhi Rong , Yuan Chen , Giovannucci Edward L. , Aschard Hugues , Kraft Peter , Amundadottir Laufey T. , Stolzenberg-Solomon Rachael , Morales-Oyarvide Vicente , Ng Kimmie , Stampfer Meir J. , Ogino Shuji , Buring Julie E. , Sesso Howard D. , Gaziano John Michael , Rifai Nader , Pollak Michael N. , Anderson Matthew L. , Cochrane Barbara B. , Luo Juhua , Manson JoAnn E. , Fuchs Charles S. , Wolpin Brian M.
Published: March 2023

Abstract
Leptin is an adipokine involved in regulating energy balance, which has been identified as a potential biologic link in the development of obesity-associated cancers, such as pancreatic cancer. In this prospective, nested case–control study of 470 cases and 1,094 controls from five U.S. cohorts, we used conditional logistic regression to evaluate pancreatic cancer risk by prediagnostic plasma leptin, adjusting for race/ethnicity, diabetes, body mass index, physical activity, plasma C-peptide, adiponectin, and 25-hydroxyvitamin D. Because of known differences in leptin levels by gender, analyses were conducted separately for men and women. We also evaluated associations between 32 tagging SNPs in the leptin receptor (LEPR) gene and pancreatic cancer risk. Leptin levels were higher in female versus male control participants (median, 20.8 vs. 6.7 ng/mL; P < 0.0001). Among men, plasma leptin was positively associated with pancreatic cancer risk and those in the top quintile had a multivariable-adjusted OR of 3.02 [95% confidence interval (CI), 1.27–7.16; Ptrend = 0.02] compared with men in the bottom quintile. Among women, circulating leptin was not associated with pancreatic cancer risk (Ptrend = 0.21). Results were similar across cohorts (Pheterogeneity = 0.88 for two male cohorts and 0.35 for three female cohorts). In genetic analyses, rs10493380 in LEPR was associated with increased pancreatic cancer risk among women, with an OR per minor allele of 1.54 (95% CI, 1.18–2.02; multiple hypothesis-corrected P = 0.03). No SNPs were significantly associated with risk in men. In conclusion, higher prediagnostic levels of plasma leptin were associated with an elevated risk of pancreatic cancer among men, but not among women. Cancer Res; 76(24); 7160–7. ©2016 AACR.
Data from The BRCA1-Δ11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapeutic Resistance to PARP Inhibition and Cisplatin
Authors: Wang Yifan , Bernhardy Andrea J. , Cruz Cristina , Krais John J. , Nacson Joseph , Nicolas Emmanuelle , Peri Suraj , van der Gulden Hanneke , van der Heijden Ingrid , O'Brien Shane W. , Zhang Yong , Harrell Maribel I. , Johnson Shawn F. , Candido Dos Reis Francisco J. , Pharoah Paul D. P. , Karlan Beth , Gourley Charlie , Lambrechts Diether , Chenevix-Trench Georgia , Olsson Håkan , Benitez Javier J. , Greene Mark H. , Gore Martin , Nussbaum Robert , Sadetzki Siegal , Gayther Simon A. , Kjaer Susanne K. , D'Andrea Alan D. , Shapiro Geoffrey I. , Wiest David L. , Connolly Denise C. , Daly Mary B. , Swisher Elizabeth M. , Bouwman Peter , Jonkers Jos , Balmaña Judith , Serra Violeta , Johnson Neil
Published: March 2023

Abstract
Breast and ovarian cancer patients harboring BRCA1/2 germline mutations have clinically benefitted from therapy with PARP inhibitor (PARPi) or platinum compounds, but acquired resistance limits clinical impact. In this study, we investigated the impact of mutations on BRCA1 isoform expression and therapeutic response. Cancer cell lines and tumors harboring mutations in exon 11 of BRCA1 express a BRCA1-Δ11q splice variant lacking the majority of exon 11. The introduction of frameshift mutations to exon 11 resulted in nonsense-mediated mRNA decay of full-length, but not the BRCA1-Δ11q isoform. CRISPR/Cas9 gene editing as well as overexpression experiments revealed that the BRCA1-Δ11q protein was capable of promoting partial PARPi and cisplatin resistance relative to full-length BRCA1, both in vitro and in vivo. Furthermore, spliceosome inhibitors reduced BRCA1-Δ11q levels and sensitized cells carrying exon 11 mutations to PARPi treatment. Taken together, our results provided evidence that cancer cells employ a strategy to remove deleterious germline BRCA1 mutations through alternative mRNA splicing, giving rise to isoforms that retain residual activity and contribute to therapeutic resistance. Cancer Res; 76(9); 2778–90. ©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 2023

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.