bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Acute Sensitivity of Ph-like Acute Lymphoblastic Leukemia to the SMAC-Mimetic Birinapant
Authors: Richmond Jennifer , Robbins Alissa , Evans Kathryn , Beck Dominik , Kurmasheva Raushan T. , Billups Catherine A. , Carol Hernan , Heatley Sue , Sutton Rosemary , Marshall Glenn M. , White Deborah , Pimanda John , Houghton Peter J. , Smith Malcolm A. , Lock Richard B.
Published: March 2024

Abstract
Ph-like acute lymphoblastic leukemia (ALL) is a genetically defined high-risk ALL subtype with a generally poor prognosis. In this study, we evaluated the efficacy of birinapant, a small-molecule mimetic of the apoptotic regulator SMAC, against a diverse set of ALL subtypes. Birinapant exhibited potent and selective cytotoxicity against B-cell precursor ALL (BCP-ALL) cells that were cultured ex vivo or in vivo as patient-derived tumor xenografts (PDX). Cytotoxicity was consistently most acute in Ph-like BCP-ALL. Unbiased gene expression analysis of BCP-ALL PDX specimens identified a 68-gene signature associated with birinapant sensitivity, including an enrichment for genes involved in inflammatory response, hematopoiesis, and cell death pathways. All Ph-like PDXs analyzed clustered within this 68-gene classifier. Mechanistically, birinapant sensitivity was associated with expression of TNF receptor TNFR1 and was abrogated by interfering with the TNFα/TNFR1 interaction. In combination therapy, birinapant enhanced the in vivo efficacy of an induction-type regimen of vincristine, dexamethasone, and L-asparaginase against Ph-like ALL xenografts, offering a preclinical rationale to further evaluate this SMAC mimetic for BCP-ALL treatment. Cancer Res; 76(15); 4579–91. ©2016 AACR.
Data from Inhibiting Mitochondrial DNA Ligase IIIα Activates Caspase 1–Dependent Apoptosis in Cancer Cells
Authors: Sallmyr Annahita , Matsumoto Yoshihiro , Roginskaya Vera , Van Houten Bennett , Tomkinson Alan E.
Published: March 2024

Abstract
Elevated levels of DNA ligase IIIα (LigIIIα) have been identified as a biomarker of an alteration in DNA repair in cancer cells that confers hypersensitivity to a LigIIIα inhibitor, L67, in combination with a poly (ADP-ribose) polymerase inhibitor. Because LigIIIα functions in the nucleus and mitochondria, we examined the effect of L67 on these organelles. Here, we show that, although the DNA ligase inhibitor selectively targets mitochondria, cancer and nonmalignant cells respond differently to disruption of mitochondrial DNA metabolism. Inhibition of mitochondrial LigIIIα in cancer cells resulted in abnormal mitochondrial morphology, reduced levels of mitochondrial DNA, and increased levels of mitochondrially generated reactive oxygen species that caused nuclear DNA damage. In contrast, these effects did not occur in nonmalignant cells. Furthermore, inhibition of mitochondrial LigIIIα activated a caspase 1–dependent apoptotic pathway, which is known to be part of inflammatory responses induced by pathogenic microorganisms in cancer, but not nonmalignant cells. These results demonstrate that the disruption of mitochondrial DNA metabolism elicits different responses in nonmalignant and cancer cells and suggests that the abnormal response in cancer cells may be exploited in the development of novel therapeutic strategies that selectively target cancer cells. Cancer Res; 76(18); 5431–41. ©2016 AACR.
Data from High-Order Drug Combinations Are Required to Effectively Kill Colorectal Cancer Cells
Authors: Horn Thomas , Ferretti Stéphane , Ebel Nicolas , Tam Angela , Ho Samuel , Harbinski Fred , Farsidjani Ali , Zubrowski Matthew , Sellers William R. , Schlegel Robert , Porter Dale , Morris Erick , Wuerthner Jens , Jeay Sébastien , Greshock Joel , Halilovic Ensar , Garraway Levi A. , Caponigro Giordano , Lehár Joseph
Published: March 2024

Abstract
Like classical chemotherapy regimens used to treat cancer, targeted therapies will also rely upon polypharmacology, but tools are still lacking to predict which combinations of molecularly targeted drugs may be most efficacious. In this study, we used image-based proliferation and apoptosis assays in colorectal cancer cell lines to systematically investigate the efficacy of combinations of two to six drugs that target critical oncogenic pathways. Drug pairs targeting key signaling pathways resulted in synergies across a broad spectrum of genetic backgrounds but often yielded only cytostatic responses. Enhanced cytotoxicity was observed when additional processes including apoptosis and cell cycle were targeted as part of the combination. In some cases, where cell lines were resistant to paired and tripled drugs, increased expression of antiapoptotic proteins was observed, requiring a fourth-order combination to induce cytotoxicity. Our results illustrate how high-order drug combinations are needed to kill drug-resistant cancer cells, and they also show how systematic drug combination screening together with a molecular understanding of drug responses may help define optimal cocktails to overcome aggressive cancers. Cancer Res; 76(23); 6950–63. ©2016 AACR.
Data from The Biodistribution and Immune Suppressive Effects of Breast Cancer–Derived Exosomes
Authors: Wen Shu Wen , Sceneay Jaclyn , Lima Luize Goncalves , Wong Christina S.F. , Becker Melanie , Krumeich Sophie , Lobb Richard J. , Castillo Vanessa , Wong Ke Ni , Ellis Sarah , Parker Belinda S. , Möller Andreas
Published: March 2024

Abstract
Small membranous secretions from tumor cells, termed exosomes, contribute significantly to intercellular communication and subsequent reprogramming of the tumor microenvironment. Here, we use optical imaging to determine that exogenously administered fluorescently labeled exosomes derived from highly metastatic murine breast cancer cells distributed predominantly to the lung of syngeneic mice, a frequent site of breast cancer metastasis. At the sites of accumulation, exosomes were taken up by CD45+ bone marrow–derived cells. Subsequent long-term conditioning of naïve mice with exosomes from highly metastatic breast cancer cells revealed the accumulation of myeloid-derived suppressor cells in the lung and liver. This favorable immune suppressive microenvironment was capable of promoting metastatic colonization in the lung and liver, an effect not observed from exosomes derived from nonmetastatic cells and liposome control vesicles. Furthermore, we determined that breast cancer exosomes directly suppressed T-cell proliferation and inhibited NK cell cytotoxicity, and hence likely suppressed the anticancer immune response in premetastatic organs. Together, our findings provide novel insight into the tissue-specific outcomes of breast cancer–derived exosome accumulation and their contribution to immune suppression and promotion of metastases. Cancer Res; 76(23); 6816–27. ©2016 AACR.
Data from Differential Expression of VEGFA Isoforms Regulates Metastasis and Response to Anti-VEGFA Therapy in Sarcoma
Authors: English William R. , Lunt Sarah Jane , Fisher Matthew , Lefley Diane V. , Dhingra Mohit , Lee Yu-Chin , Bingham Karina , Hurrell Jack E. , Lyons Scott K. , Kanthou Chryso , Tozer Gillian M.
Published: March 2024

Abstract
Elevated plasma concentrations of soluble VEGFA isoforms are associated with poor prognosis in parallel with improved response to treatment with the anti-VEGFA antibody bevacizumab. To uncover the underlying mechanism to these observations, we administered anti-VEGFA therapy to mice bearing luminescent mouse fibrosarcomas expressing single VEGFA isoforms or their wild-type counterparts expressing all isoforms (fs120, fs164, fs188, or fsWT). Expression of the more soluble isoforms conferred an advantage for lung metastasis from subcutaneous tumors (fs120/164 vs. fs188/WT); fs120 cells also produced more lung colonies than fs188 cells when injected intravenously. Metastasis from subcutaneous fs120 tumors was more sensitive than fs188 to treatment with the anti-VEGFA antibody B20-4.1.1. Despite elevated plasma levels of VEGFA in fs120 tumor-bearing mice and a dependence on VEGF receptor 1 activity for metastasis to the lung, B20-4.1.1 did not affect survival in the lung on intravenous injection. B20-4.1.1 inhibited subcutaneous tumor growth and decreased vascular density in both fs120 and fs188 tumors. However, migration of fs120, but not fs188 cells, in vitro was inhibited by B20-4.1.1. The greater survival of fs120 cells in the lung was associated with VEGFR1-dependent accumulation of CD11b-positive myeloid cells and higher expression of the VEGFR1 ligand, PlGF2, by the fs120 cells in vitro and in the plasma and lungs of fs120 tumor-bearing mice. We conclude that soluble VEGFA isoform expression increases fibrosarcoma metastasis through multiple mechanisms that vary in their sensitivity to anti-VEGF/VEGFR inhibition, with VEGFA-targeted therapy suppressing metastasis through effects on the primary tumor rather than the metastatic site. Cancer Res; 77(10); 2633–46. ©2017 AACR.
Data from Imaging of Esophageal Lymph Node Metastases by Desorption Electrospray Ionization Mass Spectrometry
Authors: Abbassi-Ghadi Nima , Golf Ottmar , Kumar Sacheen , Antonowicz Stefan , McKenzie James S. , Huang Juzheng , Strittmatter Nicole , Kudo Hiromi , Jones Emrys A. , Veselkov Kirill , Goldin Robert , Takats Zoltan , Hanna George B.
Published: March 2024

Abstract
Histopathological assessment of lymph node metastases (LNM) depends on subjective analysis of cellular morphology with inter-/intraobserver variability. In this study, LNM from esophageal adenocarcinoma was objectively detected using desorption electrospray ionization-mass spectrometry imaging (DESI-MSI). Ninety lymph nodes (LN) and their primary tumor biopsies from 11 esophago-gastrectomy specimens were examined and analyzed by DESI-MSI. Images from mass spectrometry and corresponding histology were coregistered and analyzed using multivariate statistical tools. The MSIs revealed consistent lipidomic profiles of individual tissue types found within LNs. Spatial mapping of the profiles showed identical distribution patterns as per the tissue types in matched IHC images. Lipidomic profile comparisons of LNM versus the primary tumor revealed a close association in contrast to benign LN tissue types. This similarity was used for the objective prediction of LNM in mass spectrometry images utilizing the average lipidomic profile of esophageal adenocarcinoma. The multivariate statistical algorithm developed for LNM identification demonstrated a sensitivity, specificity, positive predictive value, and negative predictive value of 89.5%, 100%, 100%, and 97.2%, respectively, when compared with gold-standard IHC. DESI-MSI has the potential to be a diagnostic tool for perioperative identification of LNM and compares favorably with techniques currently used by histopathology experts. Cancer Res; 76(19); 5647–56. ©2016 AACR.
Data from IL4 Primes the Dynamics of Breast Cancer Progression via DUSP4 Inhibition
Authors: Gaggianesi Miriam , Turdo Alice , Chinnici Aurora , Lipari Elisa , Apuzzo Tiziana , Benfante Antonina , Sperduti Isabella , Di Franco Simone , Meraviglia Serena , Lo Presti Elena , Dieli Francesco , Caputo Valentina , Militello Gabriella , Vieni Salvatore , Stassi Giorgio , Todaro Matilde
Published: March 2024

Abstract
The tumor microenvironment supplies proinflammatory cytokines favoring a permissive milieu for cancer cell growth and invasive behavior. Here we show how breast cancer progression is facilitated by IL4 secreted by adipose tissue and estrogen receptor–positive and triple-negative breast cancer cell types. Blocking autocrine and paracrine IL4 signaling with the IL4Rα antagonist IL4DM compromised breast cancer cell proliferation, invasion, and tumor growth by downregulating MAPK pathway activity. IL4DM reduced numbers of CD44+/CD24− cancer stem-like cells and elevated expression of the dual specificity phosphatase DUSP4 by inhibiting NF-κB. Enforced expression of DUSP4 drove conversion of metastatic cells to nonmetastatic cells. Mechanistically, RNAi-mediated attenuation of DUSP4 activated the ERK and p38 MAPK pathways, increased stem-like properties, and spawned metastatic capacity. Targeting IL4 signaling sensitized breast cancer cells to anticancer therapy and strengthened immune responses by enhancing the number of IFNγ-positive CTLs. Our results showed the role of IL4 in promoting breast cancer aggressiveness and how its targeting may improve the efficacy of current therapies. Cancer Res; 77(12); 3268–79. ©2017 AACR.
Data from TPL2 Is an Oncogenic Driver in Keratocanthoma and Squamous Cell Carcinoma
Authors: Lee Jun-Han , Lee Joo-Hyung , Lee Sang Hyuk , Do Sung-Im , Cho Sung-Dae , Forslund Ola , Inn Kyung-Soo , Lee Jeong-Sang , Deng Fang-Ming , Melamed Jonathan , Jung Jae U. , Jeong Joseph H.
Published: March 2024

Abstract
Squamous cell carcinoma (SCC) and keratoacanthoma (KA; SCC/KA) research has been hampered mainly by our lack of understanding the underlying genetic and epigenetic alterations associated with SCC/KA development, as well as the lack of animal models that faithfully recapitulate histopathologic features of human SCC/KA. Here, we show that TPL2 overexpression induced both cell transformation in immortalized human keratinocytes and SCC and KA-like cutaneous SCC (cSCC) development in mice. Mechanistically, activation of TPL2 downstream signaling pathways such as MEK/ERK MAPK, mTOR, NF-κB, and p38 MAPK leads to TPL2-mediated cell transformation in immortalized human keratinocytes and tumorigenesis in mice. Most importantly, TPL2 overexpression is required for iTPL2 TG–driven SCC and KA-like cSCC tumor maintenance, validating TPL2 as a possible drug target for the treatment of SCC/KA. Finally, we verified that TPL2 is overexpressed in human cutaneous metastatic SCC and KA clinical specimens compared with normal skin. Taken together, our results establish TPL2 as an oncogenic driver in SCC/KA development. Cancer Res; 76(22); 6712–22. ©2016 AACR.
Data from Extracellular Matrix/Integrin Signaling Promotes Resistance to Combined Inhibition of HER2 and PI3K in HER2+ Breast Cancer
Authors: Hanker Ariella B. , Estrada Mónica Valeria , Bianchini Giampaolo , Moore Preston D. , Zhao Junfei , Cheng Feixiong , Koch James P. , Gianni Luca , Tyson Darren R. , Sánchez Violeta , Rexer Brent N. , Sanders Melinda E. , Zhao Zhongming , Stricker Thomas P. , Arteaga Carlos L.
Published: March 2024

Abstract
PIK3CA mutations are associated with resistance to HER2-targeted therapies. We previously showed that HER2+/PIK3CAH1047R transgenic mammary tumors are resistant to the HER2 antibodies trastuzumab and pertuzumab but respond to PI3K inhibitor buparlisib (TPB). In this study, we identified mechanisms of resistance to combined inhibition of HER2 and PI3K. TPB-resistant tumors were generated by treating HER2+/PIK3CAH1047R tumor-bearing mice long term with the drug combination. RNA sequencing of TPB-resistant tumors revealed that extracellular matrix and cell adhesion genes, including collagen II (Col2a1), were markedly upregulated, accompanied by activation of integrin β1/Src. Cells derived from drug-resistant tumors were sensitive to TBP when grown in vitro, but exhibited resistance when plated on collagen or when reintroduced into mice. Drug resistance was partially reversed by the collagen synthesis inhibitor ethyl-3,4-dihydroxybenzoate. Inhibition of integrin β1/Src blocked collagen-induced resistance to TPB and inhibited growth of drug-resistant tumors. High collagen II expression was associated with significantly lower clinical response to neoadjuvant anti-HER2 therapy in HER2+ breast cancer patients. Overall, these data suggest that upregulation of collagen/integrin/Src signaling contributes to resistance to combinatorial HER2 and PI3K inhibition. Cancer Res; 77(12); 3280–92. ©2017 AACR.
Data from A Squalene-Based Nanomedicine for Oral Treatment of Colon Cancer
Authors: Kotelevets Larissa , Chastre Eric , Caron Joachim , Mougin Julie , Bastian Gerard , Pineau Alain , Walker Francine , Lehy Therese , Desmaële Didier , Couvreur Patrick
Published: March 2024

Abstract
Nanotechnology offers many possibilities to improve drug treatments, including with regard to drug pharmacology. The current study reports a simple approach to improve cisplatin efficacy in the treatment of colon cancer through the creation of orally administered squalenoylated nanoparticles loaded with cisplatin (SQ-CDDP NP). Cytotoxic effects of SQ-CDDP NP were assessed in human colonic cells and in mouse models of intestinal cancer. In cell culture, SQ-CDDP NP exhibited at least 10-fold greater cytotoxic potency compared with uncomplexed cisplatin, reflecting an enhancement in intracellular accumulation and DNA platination. Mechanistic investigations showed that SQ-CDDP NP stimulated ROS production, expression of heavy metal–inducible and stress-inducible genes, stress kinase cascades, and apoptosis. In ApcMin/+ mice, a model of intestinal tumorigenesis, oral administration of SQ-CDDP NP curtailed spontaneous tumor formation and azoxymethane-induced colon carcinogenesis with no apparent evidence of tissue toxicity. Our results offer preclinical validation of a nanocarrier formulation that can safely improve chemotherapeutic efficacy, address risks of drug resistance, and improve patient compliance by enabling oral administration. Cancer Res; 77(11); 2964–75. ©2017 AACR.
Data from Adoptive Transfer of Tumor-Specific Th2 Cells Eradicates Tumors by Triggering an In Situ Inflammatory Immune Response
Authors: Lorvik Kristina Berg , Hammarström Clara , Fauskanger Marte , Haabeth Ole Audun Werner , Zangani Michael , Haraldsen Guttorm , Bogen Bjarne , Corthay Alexandre
Published: March 2024

Abstract
Adoptive cell therapy (ACT) trials to date have focused on transfer of autologous tumor-specific cytotoxic CD8+ T cells; however, the potential of CD4+ T helper (Th) cells for ACT is gaining interest. While encouraging results have been reported with IFNγ-producing Th1 cells, tumor-specific Th2 cells have been largely neglected for ACT due to their reported tumor-promoting properties. In this study, we tested the efficacy of idiotype-specific Th2 cells for the treatment of mice with MHC class II-negative myeloma. Th2 ACT efficiently eradicated subcutaneous myeloma in an antigen-specific fashion. Transferred Th2 cells persisted in vivo and conferred long-lasting immunity. Cancer eradication mediated by tumor-specific Th2 cells did not require B cells, natural killer T cells, CD8+ T cells, or IFNγ. Th2 ACT was also curative against B-cell lymphoma. Upon transfer, Th2 cells induced a type II inflammation at the tumor site with massive infiltration of M2-type macrophages producing arginase. In vivo blockade of arginase strongly inhibited Th2 ACT, consistent with a key role of arginase and M2 macrophages in myeloma elimination by Th2 cells. These results illustrate that cancer eradication may be achieved by induction of a tumor-specific Th2 inflammatory immune response at the tumor site. Thus, ACT with tumor-specific Th2 cells may represent a highly efficient immunotherapy protocol against cancer. Cancer Res; 76(23); 6864–76. ©2016 AACR.
Data from TRPA1 Mediates Aromatase Inhibitor–Evoked Pain by the Aromatase Substrate Androstenedione
Authors: De Logu Francesco , Tonello Raquel , Materazzi Serena , Nassini Romina , Fusi Camilla , Coppi Elisabetta , Li Puma Simone , Marone Ilaria M. , Sadofsky Laura R. , Morice Alyn H. , Susini Tommaso , Terreni Alessandro , Moneti Gloriano , Di Tommaso Mariarosaria , Geppetti Pierangelo , Benemei Silvia
Published: March 2024

Abstract
Aromatase inhibitors (AI) induce painful musculoskeletal symptoms (AIMSS), which are dependent upon the pain transducing receptor TRPA1. However, as the AI concentrations required to engage TRPA1 in mice are higher than those found in the plasma of patients, we hypothesized that additional factors may cooperate to induce AIMSS. Here we report that the aromatase substrate androstenedione, unique among several steroid hormones, targeted TRPA1 in peptidergic primary sensory neurons in rodent and human cells expressing the native or recombinant channel. Androstenedione dramatically lowered the concentration of letrozole required to engage TRPA1. Notably, addition of a minimal dose of androstenedione to physiologically ineffective doses of letrozole and oxidative stress byproducts produces AIMSS-like behaviors and neurogenic inflammatory responses in mice. Elevated androstenedione levels cooperated with low letrozole concentrations and inflammatory mediators were sufficient to provoke AIMSS-like behaviors. The generation of such painful conditions by small quantities of simultaneously administered TRPA1 agonists justifies previous failure to identify a precise link between AIs and AIMSS, underscoring the potential of channel antagonists to treat AIMSS. Cancer Res; 76(23); 7024–35. ©2016 AACR.
Data from Assessment of Breast Cancer Risk Factors Reveals Subtype Heterogeneity
Authors: Holm Johanna , Eriksson Louise , Ploner Alexander , Eriksson Mikael , Rantalainen Mattias , Li Jingmei , Hall Per , Czene Kamila
Published: March 2024

Abstract
Subtype heterogeneity for breast cancer risk factors has been suspected, potentially reflecting etiologic differences and implicating risk prediction. However, reports are conflicting regarding the presence of heterogeneity for many exposures. To examine subtype heterogeneity across known breast cancer risk factors, we conducted a case–control analysis of 2,632 breast cancers and 15,945 controls in Sweden. Molecular subtype was predicted from pathology record–derived IHC markers by a classifier trained on PAM50 subtyping. Multinomial logistic regression estimated separate ORs for each subtype by the exposures parity, age at first birth, breastfeeding, menarche, hormone replacement therapy use, somatotype at age 18, benign breast disease, mammographic density, polygenic risk score, family history of breast cancer, and BRCA mutations. We found clear subtype heterogeneity for genetic factors and breastfeeding. Polygenic risk score was associated with all subtypes except for the basal-like (Pheterogeneity < 0.0001). “Never breastfeeding” was associated with increased risk of basal-like subtype [OR 4.17; 95% confidence interval (CI) 1.89–9.21] compared with both nulliparity (reference) and breastfeeding. Breastfeeding was not associated with risk of HER2-overexpressing type, but protective for all other subtypes. The observed heterogeneity in risk of distinct breast cancer subtypes for germline variants supports heterogeneity in etiology and has implications for their use in risk prediction. The association between basal-like subtype and breastfeeding merits more research into potential causal mechanisms and confounders. Cancer Res; 77(13); 3708–17. ©2017 AACR.
Data from Preclinical Efficacy of the Auristatin-Based Antibody–Drug Conjugate BAY 1187982 for the Treatment of FGFR2-Positive Solid Tumors
Authors: Sommer Anette , Kopitz Charlotte , Schatz Christoph A. , Nising Carl F. , Mahlert Christoph , Lerchen Hans-Georg , Stelte-Ludwig Beatrix , Hammer Stefanie , Greven Simone , Schuhmacher Joachim , Braun Manuela , Zierz Ruprecht , Wittemer-Rump Sabine , Harrenga Axel , Dittmer Frank , Reetz Frank , Apeler Heiner , Jautelat Rolf , Huynh Hung , Ziegelbauer Karl , Kreft Bertolt
Published: March 2024

Abstract
The fibroblast growth factor receptor FGFR2 is overexpressed in a variety of solid tumors, including breast, gastric, and ovarian tumors, where it offers a potential therapeutic target. In this study, we present evidence of the preclinical efficacy of BAY 1187982, a novel antibody–drug conjugate (ADC). It consists of a fully human FGFR2 monoclonal antibody (mAb BAY 1179470), which binds to the FGFR2 isoforms FGFR2-IIIb and FGFR2-IIIc, conjugated through a noncleavable linker to a novel derivative of the microtubule-disrupting cytotoxic drug auristatin (FGFR2-ADC). In FGFR2-expressing cancer cell lines, this FGFR2-ADC exhibited potency in the low nanomolar to subnanomolar range and was more than 100-fold selective against FGFR2-negative cell lines. High expression levels of FGFR2 in cells correlated with efficient internalization, efficacy, and cytotoxic effects in vitro. Pharmacokinetic analyses in mice bearing FGFR2-positive NCI-H716 tumors indicated that the toxophore metabolite of FGFR2-ADC was enriched more than 30-fold in tumors compared with healthy tissues. Efficacy studies demonstrated that FGFR2-ADC treatment leads to a significant tumor growth inhibition or tumor regression of cell line–based or patient-derived xenograft models of human gastric or breast cancer. Furthermore, FGFR2 amplification or mRNA overexpression predicted high efficacy in both of these types of in vivo model systems. Taken together, our results strongly support the clinical evaluation of BAY 1187982 in cancer patients and a phase I study (NCT02368951) has been initiated. Cancer Res; 76(21); 6331–9. ©2016 AACR.
Data from An Integrated Nanotechnology-Enabled Transbronchial Image-Guided Intervention Strategy for Peripheral Lung Cancer
Authors: Jin Cheng S. , Wada Hironobu , Anayama Takashi , McVeigh Patrick Z. , Hu Hsin Pei , Hirohashi Kentaro , Nakajima Takahiro , Kato Tatsuya , Keshavjee Shaf , Hwang David , Wilson Brian C. , Zheng Gang , Yasufuku Kazuhiro
Published: March 2024

Abstract
Early detection and efficient treatment modality of early-stage peripheral lung cancer is essential. Current nonsurgical treatments for peripheral lung cancer show critical limitations associated with various complications, requiring alternative minimally invasive therapeutics. Porphysome nanoparticle-enabled fluorescence-guided transbronchial photothermal therapy (PTT) of peripheral lung cancer was developed and demonstrated in preclinical animal models. Systemically administered porphysomes accumulated in lung tumors with significantly enhanced disease-to-normal tissue contrast, as confirmed in three subtypes of orthotopic human lung cancer xenografts (A549, H460, and H520) in mice and in an orthotopic VX2 tumor in rabbits. An in-house prototype fluorescence bronchoscope demonstrated the capability of porphysomes for in vivo imaging of lung tumors in the mucosal/submucosal layers, providing real-time fluorescence guidance for transbronchial PTT. Porphysomes also enhanced the efficacy of transbronchial PTT significantly and resulted in selective and efficient tumor tissue ablation in the rabbit model. A clinically used cylindrical diffuser fiber successfully achieved tumor-specific thermal ablation, showing promising evidence for the clinical translation of this novel platform to impact upon nonsurgical treatment of early-stage peripheral lung cancer. Cancer Res; 76(19); 5870–80. ©2016 AACR.
Data from Personalized Management of Pancreatic Ductal Adenocarcinoma Patients through Computational Modeling
Authors: Yamamoto Kimiyo N. , Yachida Shinichi , Nakamura Akira , Niida Atsushi , Oshima Minoru , De Subhajyoti , Rosati Lauren M. , Herman Joseph M. , Iacobuzio-Donahue Christine A. , Haeno Hiroshi
Published: March 2024

Abstract
Phenotypic diversity in pancreatic ductal adenocarcinoma (PDAC) results in a variety of treatment responses. Rapid autopsy studies have revealed a subgroup of PDAC patients with a lower propensity to develop metastatic disease, challenging the common perception that all patients die of widely metastatic disease, but questions remain about root causes of this difference and the potential impact on treatment strategies. In this study, we addressed these questions through the development of a mathematical model of PDAC progression that incorporates the major alteration status of specific genes with predictive utility. The model successfully reproduced clinical outcomes regarding metastatic patterns and the genetic alteration status of patients from two independent cohorts from the United States and Japan. Using this model, we defined a candidate predictive signature in patients with low metastatic propensity. If a primary tumor contained a small fraction of cells with KRAS and additional alterations to CDKN2A, TP53, or SMAD4 genes, the patient was likely to exhibit low metastatic propensity. By using this predictive signature, we computationally simulated a set of clinical trials to model whether this subgroup would benefit from locally intensive therapies such as surgery or radiation therapy. The largest overall survival benefit resulted from complete resection, followed by adjuvant chemoradiation therapy and salvage therapies for isolated recurrence. While requiring prospective validation in a clinical trial, our results suggest a new tool to help personalize care in PDAC patients in seeking the most effective therapeutic modality for each individual. Cancer Res; 77(12); 3325–35. ©2017 AACR.
Data from Metastatic Progression of Prostate Cancer Is Mediated by Autonomous Binding of Galectin-4-O-Glycan to Cancer Cells
Authors: Tsai Chin-Hsien , Tzeng Sheue-Fen , Chao Tai-Kuang , Tsai Chia-Yun , Yang Yu-Chih , Lee Ming-Ting , Hwang Jiuan-Jiuan , Chou Yu-Ching , Tsai Mong-Hsun , Cha Tai-Lung , Hsiao Pei-Wen
Published: March 2024

Abstract
Metastatic prostate cancer continues to pose a difficult therapeutic challenge. Prostate cancer progression is associated with aberrant O-glycosylation of cancer cell surface receptors, but the functional impact of such events is uncertain. Here we report spontaneous metastasis of human prostate cancer xenografts that express high levels of galectin-4 along with genetic signatures of EGFR-HER2 signaling and O-glycosylation. Galectin-4 expression in clinical specimens of prostate cancer correlated with poor patient survival. Galectin-4 binding to multiple receptor tyrosine kinases stimulated their autophosphorylation, activated expression of pERK, pAkt, fibronectin, and Twist1, and lowered expression of E-cadherin, thereby facilitating epithelial–mesenchymal transition, invasion, and metastasis. In vivo investigations established that galectin-4 expression enabled prostate cancer cells to repopulate tumors in orthotopic and heterotopic tissues. Notably, these effects of galectin-4 relied upon O-glycosylation mediated by C1GALT1, a galactosyltransferase implicated in other cancers. Parallel changes in galectin-4 and O-glycosylation triggered aberrant receptor signaling and more aggressive invasive character in prostate cancer cells, which through better survival in the circulation also contributed to the bulk cell progeny of distal tumors. Our findings establish galectin-4 and C1GALT1-mediated glycosylation in a signaling axis that is activated during prostate cancer progression, with implications for therapeutic targeting of advanced metastatic disease. Cancer Res; 76(19); 5756–67. ©2016 AACR.
Data from A Model-Based Personalized Cancer Screening Strategy for Detecting Early-Stage Tumors Using Blood-Borne Biomarkers
Authors: Hori Sharon Seiko , Lutz Amelie M. , Paulmurugan Ramasamy , Gambhir Sanjiv Sam
Published: March 2024

Abstract
An effective cancer blood biomarker screening strategy must distinguish aggressive from nonaggressive tumors at an early, intervenable time. However, for blood-based strategies to be useful, the quantity of biomarker shed into the blood and its relationship to tumor growth or progression must be validated. To study how blood biomarker levels correlate with early-stage viable tumor growth in a mouse model of human cancer, we monitored early tumor growth of engineered human ovarian cancer cells (A2780) implanted orthotopically into nude mice. Biomarker shedding was monitored by serial blood sampling, whereas tumor viability and volume were monitored by bioluminescence imaging and ultrasound imaging. From these metrics, we developed a mathematical model of cancer biomarker kinetics that accounts for biomarker shedding from tumor and healthy cells, biomarker entry into vasculature, biomarker elimination from plasma, and subject-specific tumor growth. We validated the model in a separate set of mice in which subject-specific tumor growth rates were accurately predicted. To illustrate clinical translation of this strategy, we allometrically scaled model parameters from mouse to human and used parameters for PSA shedding and prostate cancer. In this manner, we found that blood biomarker sampling data alone were capable of enabling the detection and discrimination of simulated aggressive (2-month tumor doubling time) and nonaggressive (18-month tumor doubling time) tumors as early as 7.2 months and 8.9 years before clinical imaging, respectively. Our model and screening strategy offers broad impact in their applicability to any solid cancer and associated biomarkers shed, thereby allowing a distinction between aggressive and nonaggressive tumors using blood biomarker sampling data alone. Cancer Res; 77(10); 2570–84. ©2017 AACR.
Data from Antibody–Drug Conjugates Bearing Pyrrolobenzodiazepine or Tubulysin Payloads Are Immunomodulatory and Synergize with Multiple Immunotherapies
Authors: Rios-Doria Jonathan , Harper Jay , Rothstein Raymond , Wetzel Leslie , Chesebrough Jon , Marrero Allison , Chen Cui , Strout Patrick , Mulgrew Kathy , McGlinchey Kelly , Fleming Ryan , Bezabeh Binyam , Meekin John , Stewart David , Kennedy Maureen , Martin Philip , Buchanan Andrew , Dimasi Nazzareno , Michelotti Emil , Hollingsworth Robert
Published: March 2024

Abstract
Immunogenic cell death (ICD) is the process by which certain cytotoxic drugs induce apoptosis of tumor cells in a manner that stimulates the immune system. In this study, we investigated whether antibody–drug conjugates (ADCS) conjugated with pyrrolobenzodiazepine dimer (PBD) or tubulysin payloads induce ICD, modulate the immune microenvironment, and could combine with immuno-oncology drugs to enhance antitumor activity. We show that these payloads on their own induced an immune response that prevented the growth of tumors following subsequent tumor cell challenge. ADCs had greater antitumor activity in immunocompetent versus immunodeficient mice, demonstrating a contribution of the immune system to the antitumor activity of these ADCs. ADCs also induced immunologic memory. In the CT26 model, depletion of CD8+ T cells abrogated the activity of ADCs when used alone or in combination with a PD-L1 antibody, confirming a role for T cells in antitumor activity. Combinations of ADCs with immuno-oncology drugs, including PD-1 or PD-L1 antibodies, OX40 ligand, or GITR ligand fusion proteins, produced synergistic antitumor responses. Importantly, synergy was observed in some cases with suboptimal doses of ADCs, potentially providing an approach to achieve potent antitumor responses while minimizing ADC-induced toxicity. Immunophenotyping studies in different tumor models revealed broad immunomodulation of lymphoid and myeloid cells by ADC and ADC/immuno-oncology combinations. These results suggest that it may be possible to develop novel combinatorial therapies with PBD- and tubulysin-based ADC and immuno-oncology drugs that may increase clinical responses. Cancer Res; 77(10); 2686–98. ©2017 AACR.
Data from A Cell-Penetrating Peptide Targeting AAC-11 Specifically Induces Cancer Cells Death
Authors: Jagot-Lacoussiere Léonard , Kotula Ewa , Villoutreix Bruno O. , Bruzzoni-Giovanelli Heriberto , Poyet Jean-Luc
Published: March 2024

Abstract
AAC-11 is an antiapoptotic protein that is upregulated in most cancer cells. Increased expression of AAC-11 confers a survival advantage when cancer cells are challenged with various stresses and contributes to tumor invasion and metastases, whereas its deregulation reduces resistance to chemotherapeutic drugs. The antiapoptotic effect of AAC-11 may be clinically relevant as its expression correlates with poor prognosis in several human cancers. Thus, inactivation of AAC-11 might constitute an attractive approach for developing cancer therapeutics. We have developed an AAC-11–derived cell-penetrating peptide, herein named RT53, mimicking in part the heptad leucine repeat region of AAC-11, which functions as a protein–protein interaction module, and that can prevent AAC-11 antiapoptotic properties. In this study, we investigated the anticancer effects of RT53. Our results indicate that RT53 selectively kills cancer cells while sparing normal cells. RT53 selectively inserts into the membranes of cancer cells, where it adopts a punctate distribution and induces membranolysis and release of danger-associated molecular pattern molecules. Systemic administration of RT53 inhibited the growth of preexisting BRAF wild-type and V600E mutant melanoma xenograft tumors through induction of apoptosis and necrosis. Toxicological studies revealed that repetitive injections of RT53 did not produce significant toxicity. Finally, RT53-killed B16F10 cells induced tumor growth inhibition in immunocompetent mice following a rechallenge with live cancer cells of the same type. Collectively, our data demonstrate that RT53 possesses tumor-inhibitory activity with no toxicity in mice, suggesting its potential as a therapeutic agent for the treatment of melanoma and probably other cancers. Cancer Res; 76(18); 5479–90. ©2016 AACR.
Data from Stomach-Specific Activation of Oncogenic KRAS and STAT3-Dependent Inflammation Cooperatively Promote Gastric Tumorigenesis in a Preclinical Model
Authors: Thiem Stefan , Eissmann Moritz F. , Elzer Joachim , Jonas Anna , Putoczki Tracy L. , Poh Ashleigh , Nguyen Paul , Preaudet Adele , Flanagan Dustin , Vincan Elizabeth , Waring Paul , Buchert Michael , Jarnicki Andrew , Ernst Matthias
Published: March 2024

Abstract
About 5% to 10% of human gastric tumors harbor oncogenic mutations in the KRAS pathway, but their presence alone is often insufficient for inducing gastric tumorigenesis, suggesting a requirement for additional mutagenic events or microenvironmental stimuli, including inflammation. Assessing the contribution of such events in preclinical mouse models requires Cre recombinase–mediated conditional gene expression in stem or progenitor cells of normal and transformed gastric epithelium. We therefore constructed a bacterial artificial chromosome containing transgene (Tg), comprising the regulatory elements of the trefoil factor 1 (Tff1) gene and the tamoxifen-inducible Cre recombinase (CreERT2)–coding sequence. The resulting Tg(Tff1-CreERT2) mice were crossed with mice harboring conditional oncogenic mutations in Kras or Braf. The administration of tamoxifen to the resulting adult Tg(Tff1-CreERT2);KrasLSL-G12D/+ and Tg(Tff1-CreERT2);BrafLSL-V600E/+ mice resulted in gastric metaplasia, inflammation, and adenoma development, characterized by excessive STAT3 activity. To assess the contribution of STAT3 to the spontaneously developing gastric adenomas in gp130F/F mice, which carry a knockin mutation in the Il6 signal transducer (Il6st), we generated Tg(Tff1-CreERT2);Stat3fl/fl;gp130F/F mice that also harbor a conditional Stat3 knockout allele and found that tamoxifen administration conferred a significant reduction in their tumor burden. Conversely, excessive Kras activity in Tg(Tff1-CreERT2);KrasLSL-G12D/+;gp130F/F mice promoted more extensive gastric inflammation, metaplastic transformation, and tumorigenesis than observed in Tg(Tff1-CreERT2);KrasLSL-G12D/+ mice. Collectively, our findings demonstrate that advanced gastric tumorigenesis requires oncogenic KRAS or BRAF in concert with aberrant STAT3 activation in epithelial precursor cells of the glandular stomach, providing a new conditional model of gastric cancer in which to investigate candidate therapeutic targets and treatment strategies. Cancer Res; 76(8); 2277–87. ©2016 AACR.
Data from Stromal-Based Signatures for the Classification of Gastric Cancer
Authors: Uhlik Mark T. , Liu Jiangang , Falcon Beverly L. , Iyer Seema , Stewart Julie , Celikkaya Hilal , O'Mahony Marguerita , Sevinsky Christopher , Lowes Christina , Douglass Larry , Jeffries Cynthia , Bodenmiller Diane , Chintharlapalli Sudhakar , Fischl Anthony , Gerald Damien , Xue Qi , Lee Jee-yun , Santamaria-Pang Alberto , Al-Kofahi Yousef , Sui Yunxia , Desai Keyur , Doman Thompson , Aggarwal Amit , Carter Julia H. , Pytowski Bronislaw , Jaminet Shou-ching , Ginty Fiona , Nasir Aejaz , Nagy Janice A. , Dvorak Harold F. , Benjamin Laura E.
Published: March 2024

Abstract
Treatment of metastatic gastric cancer typically involves chemotherapy and monoclonal antibodies targeting HER2 (ERBB2) and VEGFR2 (KDR). However, reliable methods to identify patients who would benefit most from a combination of treatment modalities targeting the tumor stroma, including new immunotherapy approaches, are still lacking. Therefore, we integrated a mouse model of stromal activation and gastric cancer genomic information to identify gene expression signatures that may inform treatment strategies. We generated a mouse model in which VEGF-A is expressed via adenovirus, enabling a stromal response marked by immune infiltration and angiogenesis at the injection site, and identified distinct stromal gene expression signatures. With these data, we designed multiplexed IHC assays that were applied to human primary gastric tumors and classified each tumor to a dominant stromal phenotype representative of the vascular and immune diversity found in gastric cancer. We also refined the stromal gene signatures and explored their relation to the dominant patient phenotypes identified by recent large-scale studies of gastric cancer genomics (The Cancer Genome Atlas and Asian Cancer Research Group), revealing four distinct stromal phenotypes. Collectively, these findings suggest that a genomics-based systems approach focused on the tumor stroma can be used to discover putative predictive biomarkers of treatment response, especially to antiangiogenesis agents and immunotherapy, thus offering an opportunity to improve patient stratification. Cancer Res; 76(9); 2573–86. ©2016 AACR.
Data from Recurrent PPP2R1A Mutations in Uterine Cancer Act through a Dominant-Negative Mechanism to Promote Malignant Cell Growth
Authors: Haesen Dorien , Abbasi Asbagh Layka , Derua Rita , Hubert Antoine , Schrauwen Stefanie , Hoorne Yana , Amant Frédéric , Waelkens Etienne , Sablina Anna , Janssens Veerle
Published: March 2024

Abstract
Somatic missense mutations in the Ser/Thr protein phosphatase 2A (PP2A) Aα scaffold subunit gene PPP2R1A are among the few genomic alterations that occur frequently in serous endometrial carcinoma (EC) and carcinosarcoma, two clinically aggressive subtypes of uterine cancer with few therapeutic options. Previous studies reported that cancer-associated Aα mutants exhibit defects in binding to other PP2A subunits and contribute to cancer development by a mechanism of haploinsufficiency. Here we report on the functional significance of the most recurrent PPP2R1A mutations in human EC, which cluster in Aα HEAT repeats 5 and 7. Beyond predicted loss-of-function effects on the formation of a subset of PP2A holoenzymes, we discovered that Aα mutants behave in a dominant-negative manner due to gain-of-function interactions with the PP2A inhibitor TIPRL1. Dominant-negative Aα mutants retain binding to specific subunits of the B56/B′ family and form substrate trapping complexes with impaired phosphatase activity via increased recruitment of TIPRL1. Accordingly, overexpression of the Aα mutants in EC cells harboring wild-type PPP2R1A increased anchorage-independent growth and tumor formation, and triggered hyperphosphorylation of oncogenic PP2A-B56/B′ substrates in the GSK3β, Akt, and mTOR/p70S6K signaling pathways. TIPRL1 silencing restored GSK3β phosphorylation and rescued the EC cell growth advantage. Our results reveal how PPP2R1A mutations affect PP2A function and oncogenic signaling, illuminating the genetic basis for serous EC development and its potential control by rationally targeted therapies. Cancer Res; 76(19); 5719–31. ©2016 AACR.
Data from Morphoproteomic Characterization of Lung Squamous Cell Carcinoma Fragmentation, a Histological Marker of Increased Tumor Invasiveness
Authors: Casanova Ruben , Xia Daniel , Rulle Undine , Nanni Paolo , Grossmann Jonas , Vrugt Bart , Wettstein Reto , Ballester-Ripoll Rafael , Astolfo Alberto , Weder Walter , Moch Holger , Stampanoni Marco , Beck Andrew H. , Soltermann Alex
Published: March 2024

Abstract
Accurate stratification of tumors is imperative for adequate cancer management. In addition to staging, morphologic subtyping allows stratification of patients into additional prognostic groups. In this study, we used an image-based computational method on pan-cytokeratin IHC stainings to quantify tumor fragmentation (TF), a measure of tumor invasiveness of lung squamous cell carcinoma (LSCC). In two independent clinical cohorts from tissue microarrays (TMA: n = 208 patients) and whole sections (WS: n = 99 patients), TF was associated with poor prognosis and increased risk of blood vessel infiltration. A third cohort from The Cancer Genome Atlas (TCGA: n = 335 patients) confirmed the poor prognostic value of TF using a similar human-based score on hematoxylin-eosin staining. Integration of RNA-seq data from TCGA and LC-MS/MS proteomics from WS revealed an upregulation of extracellular matrix remodeling and focal adhesion processes in tumors with high TF, supporting their increased invasive potential. This proposed histologic parameter is an independent and unfavorable prognostic marker that could be established as a new grading parameter for LSCC. Cancer Res; 77(10); 2585–93. ©2017 AACR.
Data from Mechanisms through Which Hypoxia-Induced Caveolin-1 Drives Tumorigenesis and Metastasis in Hepatocellular Carcinoma
Authors: Mao Xiaowen , Wong Sivia Yuen Sze , Tse Edith Yuk Ting , Ko Frankie Chi Fat , Tey Sze Keong , Yeung Yin Shan , Man Kwan , Lo Regina Cheuk-Lam , Ng Irene Oi-Lin , Yam Judy Wai Ping
Published: March 2024

Abstract
In solid tumors, hypoxia triggers an aberrant vasculogenesis, enhances malignant character, and elevates metastatic risk. The plasma membrane organizing protein caveolin-1 (Cav1) is increased in a variety of cancers, including hepatocellular carcinoma (HCC), where it contributes to metastatic capability. However, the reason for elevation of Cav1 in tumor cells and the mechanistic basis for its contributions to metastatic risk are not fully understood. Here, we show that in HCC cells, hypoxia elevates expression of Cav1, which then acts through the calcium-binding protein S100P to promote metastasis. Hypoxic regions of HCC xenografts displayed elevated expression of Cav1. Hypoxia promoted HCC cell migration and invasion and distant pulmonary metastases, whereas Cav1 silencing abolished these effects. Gene expression profiling revealed that hypoxia-induced Cav1 functioned as a positive regulator of S100P via activation of the NF-κB pathway. S100P elevation under hypoxic conditions was abrogated by silencing of Cav1 or NF-κB function. Conversely, restoring S100P in Cav1-silenced cells rescued the migratory potential of HCC cells along with tumor formation and lung metastasis. In clinical specimens of HCC, we observed S100P overexpression to correlate with venous invasion, microsatellites, direct liver invasion, and absence of tumor encapsulation. Collectively, our findings demonstrated how hypoxia-induced expression of Cav1 in HCC cells enhances their invasive and metastatic potential. Cancer Res; 76(24); 7242–53. ©2016 AACR.