bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from PolyI:C and CpG Synergize with Anti-ErbB2 mAb for Treatment of Breast Tumors Resistant to Immune Checkpoint Inhibitors
Authors: Charlebois Roxanne , Allard Bertrand , Allard David , Buisseret Laurence , Turcotte Martin , Pommey Sandra , Chrobak Pavel , Stagg John
Published: March 2023

Abstract
Innate and adaptive immune cells play an important role in the therapeutic activity of anti-ErbB2 mAbs, such as trastuzumab. In the clinic, breast tumors poorly infiltrated with immune cells are more resistant to trastuzumab, and patients have a worse prognosis. Because type I and II IFNs are critical to the immune-mediated activity of anti-ErbB2 mAb, we investigated the effect of combining polyI:C and CpG with trastuzumab-like therapy in immunocompetent mouse models of ErbB2+ breast cancer. We demonstrated that in situ delivery of polyI:C and CpG combined to systemic anti-ErbB2 mAb triggered a potent inflammatory response in breast tumors able to induce long-lasting CD8+ T cell–dependent antitumor immunity. Remarkably, polyI:C and CpG was superior to combined PD-1/CTLA-4 blockade in sensitizing tumors to anti-ErbB2 mAb therapy. Local injection of CpG and polyI:C in a primary tumor significantly enhanced the activity of systemic anti-ErbB2 mAb against a distant untreated tumor. Type I and II IFNs, as well as natural killer cells and CD8+ T cells, were indispensible to the synergistic activity of the combination treatment. Because synthetic RNA analogues and CpG oligodeoxynucleotides have been safely used in clinical trials, our study supports combination treatments with anti-ErbB2 mAbs. Cancer Res; 77(2); 312–9. ©2016 AACR.
Data from STK33 Promotes Growth and Progression of Pancreatic Cancer as a Critical Downstream Mediator of HIF1α
Authors: Kong Fanyang , Kong Xiangyu , Du Yiqi , Chen Ying , Deng Xuan , Zhu Jianwei , Du Jiawei , Li Lei , Jia Zhiliang , Xie Dacheng , Li Zhaoshen , Xie Keping
Published: March 2023

Abstract
The serine/threonine kinase STK33 has been implicated in cancer cell proliferation. Here, we provide evidence of a critical role for STK33 in the pathogenesis and metastatic progression of pancreatic ductal adenocarcinoma (PDAC). STK33 expression in PDAC was regulated by the hypoxia-inducible transcription factor HIF1α. In human PDAC specimens, STK33 was overexpressed and associated with poor prognosis. Enforced STK33 expression promoted PDAC proliferation, migration, invasion, and tumor growth, whereas STK33 depletion exerted opposing effects. Mechanistic investigations showed that HIF1α regulated STK33 via direct binding to a hypoxia response element in its promoter. In showing that dysregulated HIF1α/STK33 signaling promotes PDAC growth and progression, our results suggest STK33 as a candidate therapeutic target to improve PDAC treatment. Cancer Res; 77(24); 6851–62. ©2017 AACR.
Data from S100A4 Elevation Empowers Expression of Metastasis Effector Molecules in Human Breast Cancer
Authors: Ismail Thamir M. , Bennett Daimark , Platt-Higgins Angela M. , Al-Medhity Morteta , Barraclough Roger , Rudland Philip S.
Published: March 2023

Abstract
Many human glandular cancers metastasize along nerve tracts, but the mechanisms involved are generally poorly understood. The calcium-binding protein S100A4 is expressed at elevated levels in human cancers, where it has been linked to increased invasion and metastasis. Here we report genetic studies in a Drosophila model to define S100A4 effector functions that mediate metastatic dissemination of mutant Ras-induced tumors in the developing nervous system. In flies overexpressing mutant RasVal12 and S100A4, there was a significant increase in activation of the stress kinase JNK and production of the matrix metalloproteinase MMP1. Genetic or chemical blockades of JNK and MMP1 suppressed metastatic dissemination associated with S100A4 elevation, defining required signaling pathway(s) for S100A4 in this setting. In clinical specimens of human breast cancer, elevated levels of the mammalian paralogs MMP2, MMP9, and MMP13 are associated with a 4- to 9-fold relative decrease in patient survival. In individual tumors, levels of MMP2 and MMP13 correlated more closely with levels of S100A4, whereas MMP9 levels correlated more closely with the S100 family member S100P. Overall, our results suggest the existence of evolutionarily conserved pathways used by S100A4 to promote metastatic dissemination, with potential prognostic and therapeutic implications for metastasis by cancers that preferentially exploit nerve tract migration routes. Cancer Res; 77(3); 780–9. ©2016 AACR.
Data from Mitosis-Mediated Intravasation in a Tissue-Engineered Tumor–Microvessel Platform
Authors: Wong Andrew D. , Searson Peter C.
Published: March 2023

Abstract
Intravasation involves the migration of tumor cells across the local endothelium and escape into vessel flow. Although tumor cell invasiveness has been correlated to increased intravasation, the details of transendothelial migration and detachment into circulation are still unclear. Here, we analyzed the intravasation of invasive human breast cancer cells within a tissue-engineered microvessel model of the tumor microenvironment. Using live-cell fluorescence microscopy, we captured 2,330 hours of tumor cell interactions with functional microvessels and provide evidence for a mitosis-mediated mechanism where tumor cells located along the vessel periphery are able to disrupt the vessel endothelium through cell division and detach into circulation. This model provides a framework for understanding the physical and biological parameters of the tumor microenvironment that mediate intravasation of tumor cells across an intact endothelium. Cancer Res; 77(22); 6453–61. ©2017 AACR.
Data from Multiscale Modeling of Inflammation-Induced Tumorigenesis Reveals Competing Oncogenic and Oncoprotective Roles for Inflammation
Authors: Guo Yucheng , Nie Qing , MacLean Adam L. , Li Yanda , Lei Jinzhi , Li Shao
Published: March 2023

Abstract
Chronic inflammation is a serious risk factor for cancer; however, the routes from inflammation to cancer are poorly understood. On the basis of the processes implicated by frequently mutated genes associated with inflammation and cancer in three organs (stomach, colon, and liver) extracted from the Gene Expression Omnibus, The Cancer Genome Atlas, and Gene Ontology databases, we present a multiscale model of the long-term evolutionary dynamics leading from inflammation to tumorigenesis. The model incorporates cross-talk among interactions on several scales, including responses to DNA damage, gene mutation, cell-cycle behavior, population dynamics, inflammation, and metabolism-immune balance. Model simulations revealed two stages of inflammation-induced tumorigenesis: a precancerous state and tumorigenesis. The precancerous state was mainly caused by mutations in the cell proliferation pathway; the transition from the precancerous to tumorigenic states was induced by mutations in pathways associated with apoptosis, differentiation, and metabolism-immune balance. We identified opposing effects of inflammation on tumorigenesis. Mild inflammation removed cells with DNA damage through DNA damage-induced cell death, whereas severe inflammation accelerated accumulation of mutations and hence promoted tumorigenesis. These results provide insight into the evolutionary dynamics of inflammation-induced tumorigenesis and highlight the combinatorial effects of inflammation and metabolism-immune balance. This approach establishes methods for quantifying cancer risk, for the discovery of driver pathways in inflammation-induced tumorigenesis, and has direct relevance for early detection and prevention and development of new treatment regimes. Cancer Res; 77(22); 6429–41. ©2017 AACR.
Data from Secretory Autophagy in Cancer-Associated Fibroblasts Promotes Head and Neck Cancer Progression and Offers a Novel Therapeutic Target
Authors: New Jacob , Arnold Levi , Ananth Megha , Alvi Sameer , Thornton Mackenzie , Werner Lauryn , Tawfik Ossama , Dai Hongying , Shnayder Yelizaveta , Kakarala Kiran , Tsue Terance T. , Girod Douglas A. , Ding Wen-Xing , Anant Shrikant , Thomas Sufi Mary
Published: March 2023

Abstract
Despite therapeutic advancements, there has been little change in the survival of patients with head and neck squamous cell carcinoma (HNSCC). Recent results suggest that cancer-associated fibroblasts (CAF) drive progression of this disease. Here, we report that autophagy is upregulated in HNSCC-associated CAFs, where it is responsible for key pathogenic contributions in this disease. Autophagy is fundamentally involved in cell degradation, but there is emerging evidence that suggests it is also important for cellular secretion. Thus, we hypothesized that autophagy-dependent secretion of tumor-promoting factors by HNSCC-associated CAFs may explain their role in malignant development. In support of this hypothesis, we observed a reduction in CAF-facilitated HNSCC progression after blocking CAF autophagy. Studies of cell growth media conditioned after autophagy blockade revealed levels of secreted IL6, IL8, and other cytokines were modulated by autophagy. Notably, when HNSCC cells were cocultured with normal fibroblasts, they upregulated autophagy through IL6, IL8, and basic fibroblast growth factor. In a mouse xenograft model of HNSCC, pharmacologic inhibition of Vps34, a key mediator of autophagy, enhanced the antitumor efficacy of cisplatin. Our results establish an oncogenic function for secretory autophagy in HNSCC stromal cells that promotes malignant progression. Cancer Res; 77(23); 6679–91. ©2017 AACR.
Data from Differential PI3Kδ Signaling in CD4+ T-cell Subsets Enables Selective Targeting of T Regulatory Cells to Enhance Cancer Immunotherapy
Authors: Ahmad Shamim , Abu-Eid Rasha , Shrimali Rajeev , Webb Mason , Verma Vivek , Doroodchi Atbin , Berrong Zuzana , Samara Raed , Rodriguez Paulo C. , Mkrtichyan Mikayel , Khleif Samir N.
Published: March 2023

Abstract
To modulate T-cell function for cancer therapy, one challenge is to selectively attenuate regulatory but not conventional CD4+ T-cell subsets [regulatory T cell (Treg) and conventional T cell (Tconv)]. In this study, we show how a functional dichotomy in Class IA PI3K isoforms in these two subsets of CD4+ T cells can be exploited to target Treg while leaving Tconv intact. Studies employing isoform-specific PI3K inhibitors and a PI3Kδ-deficient mouse strain revealed that PI3Kα and PI3Kβ were functionally redundant with PI3Kδ in Tconv. Conversely, PI3Kδ was functionally critical in Treg, acting there to control T-cell receptor signaling, cell proliferation, and survival. Notably, in a murine model of lung cancer, coadministration of a PI3Kδ-specific inhibitor with a tumor-specific vaccine decreased numbers of suppressive Treg and increased numbers of vaccine-induced CD8 T cells within the tumor microenvironment, eliciting potent antitumor efficacy. Overall, our results offer a mechanistic rationale to employ PI3Kδ inhibitors to selectively target Treg and improve cancer immunotherapy. Cancer Res; 77(8); 1892–904. ©2017 AACR.
Data from Granzyme B PET Imaging as a Predictive Biomarker of Immunotherapy Response
Authors: Larimer Benjamin M. , Wehrenberg-Klee Eric , Dubois Frank , Mehta Anila , Kalomeris Taylor , Flaherty Keith , Boland Genevieve , Mahmood Umar
Published: March 2023

Abstract
While cancer immunotherapy can produce dramatic responses, only a minority of patients respond to treatment. Reliable response biomarkers are needed to identify responders, and conventional imaging modalities have not proved adequate. Here, we provide a preclinical proof of concept for the use of granzyme B, a downstream effector of tumoral cytotoxic T cells, as an early biomarker for tumors responding to immunotherapy. We designed novel PET imaging probes for the murine and human granzyme B isoforms that specifically and quantitatively bind granzyme B. Immunotherapy-treated mice were imaged prior to therapy-induced tumor volume reduction. Imaging distinguished treated responders from nonresponders with excellent predictive ability. To assess the clinical value of a granzyme B imaging paradigm, biopsy specimens from melanoma patients on checkpoint inhibitor therapy were analyzed. A marked differential in granzyme B expression was observed between treated responders and nonresponders. Additionally, our human probe was able to specifically detect granzyme B expression in human samples, providing a clear candidate for clinical application. Overall, our results suggest granzyme B PET imaging can serve as a quantitatively useful predictive biomarker for efficacious responses to cancer immunotherapy. Cancer Res; 77(9); 2318–27. ©2017 AACR.
Data from TLR4-Mediated Inflammation Promotes KSHV-Induced Cellular Transformation and Tumorigenesis by Activating the STAT3 Pathway
Authors: Gruffaz Marion , Vasan Karthik , Tan Brandon , Ramos da Silva Suzane , Gao Shou-Jiang
Published: March 2023

Abstract
Toll-like receptors (TLR) are conserved immune sensors mediating antimicrobial and antitumoral responses, but recent evidence implicates them in promoting carcinogenesis in certain cancers. Kaposi sarcoma is caused by infection of Kaposi sarcoma–associated herpesvirus (KSHV) and is characterized by uncontrolled neoangiogenesis and inflammation. Here, we show that TLR4 is upregulated in KSHV-infected spindle tumor cells in human Kaposi sarcoma lesions. In a model of KSHV-induced cellular transformation, KSHV upregulated expression of TLR4, its adaptor MyD88, and coreceptors CD14 and MD2. KSHV induction of TLR4 was mediated by multiple viral miRNAs. Importantly, the TLR4 pathway was activated constitutively in KSHV-transformed cells, resulting in chronic induction of IL6, IL1β, and IL18. Accordingly, IL6 mediated constitutive activation of the STAT3 pathway, an essential event for uncontrolled cellular proliferation and transformation. TLR4 stimulation with lipopolysaccharides or live bacteria enhanced tumorigenesis while TLR4 antagonist CLI095 inhibited it. These results highlight an essential role of the TLR4 pathway and chronic inflammation in KSHV-induced tumorigenesis, which helps explain why HIV-infected patients, who frequently suffer from opportunistic bacterial infections and metabolic complications, frequently develop Kaposi sarcoma. Cancer Res; 77(24); 7094–108. ©2017 AACR.
Data from Tumor-Associated Neutrophils and Macrophages Promote Gender Disparity in Hepatocellular Carcinoma in Zebrafish
Authors: Yan Chuan , Yang Qiqi , Gong Zhiyuan
Published: March 2023

Abstract
Hepatocellular carcinoma (HCC) occurs more frequently and aggressively in men than women, but the mechanistic basis of this gender disparity is obscure. Chronic inflammation is a major etiologic factor in HCC, so we investigated the role of cortisol in gender discrepancy in a zebrafish model of HCC. Inducible expression of oncogenic KrasV12 in hepatocytes of transgenic zebrafish resulted in accelerated liver tumor progression in males. These tumors were more heavily infiltrated with tumor-associated neutrophils (TAN) and tumor-associated macrophages (TAM) versus females, and they both showed protumor gene expression and promoted tumor progression. Interestingly, the adrenal hormone cortisol was predominantly produced in males to induce Tgfb1 expression, which functioned as an attractant for TAN and TAM. Inhibition of cortisol signaling in males, or increase of cortisol level in females, decreased or increased the numbers of TAN and TAM, respectively, accompanied by corresponding changes in protumor molecular expression. Higher levels of cortisol, TGFB1, and TAN/TAM infiltration in males were also confirmed in human pre-HCC and HCC samples, features that positively correlated in human patients. These results identify increased cortisol production and TAN/TAM infiltration as primary factors in the gender disparity of HCC development in both fish and human. Cancer Res; 77(6); 1395–407. ©2017 AACR.
Data from RUNX1 Upregulation by Cytotoxic Drugs Promotes Apoptosis
Authors: Speidel Daniel , Wellbrock Jasmin , Abas Melissa
Published: March 2023

Abstract
Mutations in the RUNX1 gene have been associated with chemotherapy resistance and poor prognosis in patients with acute myeloid leukemia (AML), T-cell acute lymphoblastic leukemia, and myelodysplastic syndromes. However, the underlying mechanisms connecting RUNX1 to the success of therapy remain elusive. Here we explore the hypothesis that RUNX1 is directly involved in the response of hematopoietic cells to cytotoxic agents. RUNX1 was upregulated posttranscriptionally by cytotoxic agents in C57BL/6 mice in vivo and hematopoietic cell lines. Upregulation was also seen in primary human AML cells after treatment with cytarabine in vitro. Upon overexpression, RUNX1 restricted proliferation, promoted apoptosis, and augmented the DNA damage response. This unknown activity of RUNX1 required an intact runt homology domain (RHD), a domain where most leukemia-associated point mutations cluster. Consistent with this, two RHD-defective RUNX1 proteins lacked any antiproliferative or apoptotic activity, and RHD-defective (K83N, N109D) mutant RUNX1 conferred resistance to ionizing radiation when overexpressed in Ba/F3 cells under certain conditions. Our experiments reveal a novel function of RUNX1 and offer an explanation for the link between RUNX1 mutations and chemotherapy and radiation resistance. Moreover, these data suggest that pharmacologic modulation of RUNX1 might be an attractive new approach to treat hematologic malignancies. Cancer Res; 77(24); 6818–24. ©2017 AACR.
Data from Basophils Promote Tumor Rejection via Chemotaxis and Infiltration of CD8+ T Cells
Authors: Sektioglu Ibrahim M. , Carretero Rafael , Bulbuc Nadja , Bald Tobias , Tüting Thomas , Rudensky Alexander Y. , Hämmerling Günter J.
Published: March 2023

Abstract
Elevated numbers of regulatory T cells (Treg) in patient tumors are known to inhibit efficient antitumor T-cell responses. To study the mechanisms controlling tumor rejection, we assessed different mouse models for Treg depletion. In Foxp3DTR knock-in mice, about 99% Treg depletion was achieved, resulting in complete rejection of transplanted HCmel12 melanomas in a CD8+ T-cell–dependent way. In contrast, about 90% Treg depletion obtained in BAC transgenic Foxp3.LuciDTR4 mice failed to induce complete rejection of HCmel12 melanomas, demonstrating that residual Tregs were able to control CD8+ T-cell responses against the tumor. Ninety-nine percent of Treg depletion provoked drastic changes in the tumor microenvironment, such as strong infiltration of CD8+ T cells and basophils. Intratumoral basophils enhanced CD8+ T-cell infiltration via production of chemokines CCL3 and CCL4; antibody-based blocking of these chemokines inhibited CD8+ T-cell infiltration. Therapeutic induction of basophilia by IL3/anti-IL3 antibody complexes, combined with transfer of CD8+ T cells, resulted in enhanced T-cell infiltration and tumor rejection. Our study identifies a critical role basophils play in tumor rejection and that this role can be exploited for therapeutic intervention. Cancer Res; 77(2); 291–302. ©2016 AACR.
Data from Proliferating EpCAM-Positive Ductal Cells in the Inflamed Liver Give Rise to Hepatocellular Carcinoma
Authors: Matsumoto Tomonori , Takai Atsushi , Eso Yuji , Kinoshita Kazuo , Manabe Toshiaki , Seno Hiroshi , Chiba Tsutomu , Marusawa Hiroyuki
Published: March 2023

Abstract
Hepatocellular carcinoma (HCC) originates from regenerating liver cells with genetic alterations in chronically inflamed liver. Ductal cells and hepatocytes proliferate for liver regeneration, and proliferating ductal cells (PDC) derived from bile ductules have long been considered putative liver stem/progenitor cells and candidate cellular origins of HCC. The potential of PDC as tumor-originating cells, however, remains controversial in contrast to accumulating evidence that HCC originates from hepatocytes. Here, we demonstrate that PDCs expressing the established surface and cancer stem cell marker EpCAM give rise to HCC in inflamed liver. EpCAM-expressing PDCs were specifically labeled in newly developed EpcamCreERT2 mice and traced in a chemically induced liver injury model. Stepwise accumulation of genetic alterations in EpCAM-positive cells was induced by the mutagenesis activity of activation-induced cytidine deaminase using conditional transgenic mice. Lineage-tracing experiments revealed that labeled PDC differentiated into cholangiocytes, but not into hepatocytes, in the chemically damaged liver. Nevertheless, EpCAM-positive PDC with genetic alterations gave rise to HCC after 8 months of chemical administration. PDC-derived HCC showed histologic characteristics of concomitant ductule-like structures resembling human cholangiolocellular carcinoma (CLC) and exhibited serial transitions from PDC-like CLC cells to hepatocyte-like HCC cells. The Wnt signaling pathway was specifically upregulated in the CLC components of PDC-derived HCC. Our findings provide direct experimental evidence that EpCAM-expressing PDC could be a cellular origin of HCC, suggesting the existence of stem/progenitor-derived hepatocarcinogenesis. Cancer Res; 77(22); 6131–43. ©2017 AACR.
Data from Radiation-Induced Enhancement of Antitumor T-cell Immunity by VEGF-Targeted 4-1BB Costimulation
Authors: Schrand Brett , Verma Bhavna , Levay Agata , Patel Shradha , Castro Iris , Benaduce Ana Paula , Brenneman Randall , Umland Oliver , Yagita Hideo , Gilboa Eli , Ishkanian Adrian
Published: March 2023

Abstract
Radiotherapy can elicit systemic immune control of local tumors and distant nonirradiated tumor lesions, known as the abscopal effect. Although this effect is enhanced using checkpoint blockade or costimulatory antibodies, objective responses remain suboptimal. As radiotherapy can induce secretion of VEGF and other stress products in the tumor microenvironment, we hypothesized that targeting immunomodulatory drugs to such products will not only reduce toxicity but also broaden the scope of tumor-targeted immunotherapy. Using an oligonucleotide aptamer platform, we show that radiation-induced VEGF-targeted 4-1BB costimulation potentiated both local tumor control and abscopal responses with equal or greater efficiency than 4-1BB, CTLA-4, or PD1 antibodies alone. Although 4-1BB and CTLA-4 antibodies elicited organ-wide inflammatory responses and tissue damage, VEGF-targeted 4-1BB costimulation produced no observable toxicity. These findings suggest that radiation-induced tumor-targeted immunotherapy can improve the therapeutic index and extend the reach of immunomodulatory agents. Cancer Res; 77(6); 1310–21. ©2017 AACR.
Data from Biallelic Dicer1 Loss Mediated by aP2-Cre Drives Angiosarcoma
Authors: Hanna Jason A. , Drummond Catherine J. , Garcia Matthew R. , Go Jonathan C. , Finkelstein David , Rehg Jerold E. , Hatley Mark E.
Published: March 2023

Abstract
Angiosarcoma is an aggressive vascular sarcoma with an extremely poor prognosis. Because of the relative rarity of this disease, its molecular drivers and optimal treatment strategies are obscure. DICER1 is an RNase III endoribonuclease central to miRNA biogenesis, and germline DICER1 mutations result in a cancer predisposition syndrome, associated with an increased risk of many tumor types. Here, we show that biallelic Dicer1 deletion with aP2-Cre drives aggressive and metastatic angiosarcoma independent of other genetically engineered oncogenes or tumor suppressor loss. Angiosarcomas in aP2-Cre;Dicer1Flox/- mice histologically and genetically resemble human angiosarcoma. miR-23 target genes, including the oncogenes Ccnd1 as well as Adam19, Plau, and Wsb1 that promote invasiveness and metastasis, were enriched in mouse and human angiosarcoma. These studies illustrate that Dicer1 can function as a traditional loss-of-function tumor suppressor gene, and they provide a fully penetrant animal model for the study of angiosarcoma development and metastasis. Cancer Res; 77(22); 6109–18. ©2017 AACR.
Data from Paxillin Binding to the Cytoplasmic Domain of CD103 Promotes Cell Adhesion and Effector Functions for CD8+ Resident Memory T Cells in Tumors
Authors: Gauthier Ludiane , Corgnac Stéphanie , Boutet Marie , Gros Gwendoline , Validire Pierre , Bismuth Georges , Mami-Chouaib Fathia
Published: March 2023

Abstract
CD8+/CD103+ tissue-resident memory T cells (TRM cells) accumulate in several human solid tumors, where they have been associated with a favorable prognosis. However, the role of CD103, the α subunit of the integrin αEβ7 (also known as CD103), in the retention and functions of these TRM is undefined. In this report, we investigated the role of CD103 cytoplasmic domain and the focal adhesion-associated protein paxillin (Pxn) in downstream signaling and functional activities triggered through αE/CD103 chain. Binding to immobilized recombinant (r)E-cadherin-Fc of CD103 integrin expressed on tumor-specific CTL clones promotes phosphorylation of Pxn and Pyk2 and binding of Pxn to the αE/CD103 subunit tail. Inhibition of Pxn phosphorylation by the Src inhibitor saracatinib or its knockdown via shRNA dramatically altered adhesion and spreading of freshly isolated CD8+/CD103+ lung tumor–infiltrating lymphocytes and CD103+ tumor-specific CTL clones. Inhibition of Pxn phosphorylation with saracatinib in these CTL clones also severely compromised their functional activities toward autologous tumor cells. Using Jurkat T cells as a model to study CD103 integrin activation, we demonstrated a key role of serine residue S1163 of the αE chain intracellular domain in polarization of CD103 and recruitment of lysosomes and Pxn at the contact zone of T lymphocytes with rE-cadherin-Fc–coated beads. Overall, our results show how Pxn binding to the CD103 cytoplasmic tail triggers αEβ7 integrin outside-in signaling that promotes CD8+ T-cell migratory behavior and effector functions. These results also explain the more favorable prognosis associated with retention of TRM cells in the tumor microenvironment. Cancer Res; 77(24); 7072–82. ©2017 AACR.
Data from Enriching the Housing Environment for Mice Enhances Their NK Cell Antitumor Immunity via Sympathetic Nerve–Dependent Regulation of NKG2D and CCR5
Authors: Song Yanfang , Gan Yu , Wang Qing , Meng Zihong , Li Guohua , Shen Yuling , Wu Yufeng , Li Peiying , Yao Ming , Gu Jianren , Tu Hong
Published: March 2023

Abstract
Mice housed in an enriched environment display a tumor-resistant phenotype due to eustress stimulation. However, the mechanisms underlying enriched environment–induced protection against cancers remain largely unexplained. In this study, we observed a significant antitumor effect induced by enriched environment in murine pancreatic cancer and lung cancer models. This effect remained intact in T/B lymphocyte-deficient Rag1−/− mice, but was nearly eliminated in natural killer (NK) cell–deficient Beige mice or in antibody-mediated NK-cell–depleted mice, suggesting a predominant role of NK cells in enriched environment–induced tumor inhibition. Exposure to enriched environment enhanced NK-cell activity against tumors and promoted tumoral infiltration of NK cells. Enriched environment increased the expression levels of CCR5 and NKG2D (KLRK1) in NK cells; blocking their function effectively blunted the enriched environment–induced enhancement of tumoral infiltration and cytotoxic activity of NK cells. Moreover, blockade of β-adrenergic signaling or chemical sympathectomy abolished the effects of enriched environment on NK cells and attenuated the antitumor effect of enriched environment. Taken together, our results provide new insight into the mechanism by which eustress exerts a beneficial effect against cancer. Cancer Res; 77(7); 1611–22. ©2017 AACR.
Data from CBX8 Exhibits Oncogenic Activity via AKT/β-Catenin Activation in Hepatocellular Carcinoma
Authors: Zhang Chris Zhiyi , Chen Shi-Lu , Wang Chun-Hua , He Yang-Fan , Yang Xia , Xie Dan , Yun Jing-Ping
Published: March 2023

Abstract
Deregulation of polycomb proteins influences the development and progression of hepatocellular carcinoma. Here we show that chromobox 8 (CBX8) expression is increased in hepatocellular carcinoma and correlates with poor outcome in two independent cohorts containing a total of 879 cases. Ectopic expression of CBX8 facilitated tumor growth and metastasis, whereas CBX8 silencing suppressed these effects. CBX8 efficiently activated AKT/β-catenin signaling via upregulation of the transcription factor EGR1 and miR-365-3p in a noncanonical manner: CBX8 directly bound the EGR1 promoter to enhance its activity. In the nucleus, CBX8 also interacted with EGR1 to prevent its degradation. Furthermore, CBX8 increased the transcription of miR-365a-3p, which promoted the nuclear localization of β-catenin by targeting the 3′-UTR ZNRF1. Inhibiting either EGR1 or miR-365a-3p partially rescued CBX8-mediated malignant phenotypes. In clinical samples, CBX8 expression closely correlated with EGR1, miR-365a-3p, and nuclear β-catenin. Collectively, our results show that CBX8 functions as an oncogene to upregulate EGR1 and miR-365-3p to stimulate the AKT/β-catenin pathway. This newly identified signaling axis may suggest new therapeutic strategies against hepatocellular carcinoma.

Significance: Elucidation of a key new element of the β-catenin signaling pathway in liver cancer may suggest new therapeutic targets. Cancer Res; 78(1); 51–63. ©2017 AACR.
Data from ESE3 Inhibits Pancreatic Cancer Metastasis by Upregulating E-Cadherin
Authors: Zhao Tiansuo , Jiang Wenna , Wang Xiuchao , Wang Hongwei , Zheng Chen , Li Yang , Sun Yan , Huang Chongbiao , Han Zhi-bo , Yang Shengyu , Jia Zhiliang , Xie Keping , Ren He , Hao Jihui
Published: March 2023

Abstract
The ETS family transcription factor ESE3 is a crucial element in differentiation and development programs for many epithelial tissues. Here we report its role as a tumor suppressor in pancreatic cancer. We observed drastically lower ESE3 expression in pancreatic ductal adenocarcinomas (PDAC) compared with adjacent normal pancreatic tissue. Reduced expression of ESE3 in PDAC correlated closely with an increase in lymph node metastasis and vessel invasion and a decrease in relapse-free and overall survival in patients. In functional experiments, downregulating the expression of ESE3 promoted PDAC cell motility and invasiveness along with metastasis in an orthotopic mouse model. Mechanistic studies in PDAC cell lines, the orthotopic mouse model, and human PDAC specimens demonstrated that ESE3 inhibited PDAC metastasis by directly upregulating E-cadherin expression at the level of its transcription. Collectively, our results establish ESE3 as a negative regulator of PDAC progression and metastasis by enforcing E-cadherin upregulation. Cancer Res; 77(4); 874–85. ©2016 AACR.
Data from RelB Expression Determines the Differential Effects of Ascorbic Acid in Normal and Cancer Cells
Authors: Wei Xiaowei , Xu Yong , Xu Fang Fang , Chaiswing Luksana , Schnell David , Noel Teresa , Wang Chi , Chen Jinfei , St. Clair Daret K. , St. Clair William H.
Published: March 2023

Abstract
Cancer cells typically experience higher oxidative stress than normal cells, such that elevating pro-oxidant levels can trigger cancer cell death. Although pre-exposure to mild oxidative agents will sensitize cancer cells to radiation, this pre-exposure may also activate the adaptive stress defense system in normal cells. Ascorbic acid is a prototype redox modulator that when infused intravenously appears to kill cancers without injury to normal tissues; however, the mechanisms involved remain elusive. In this study, we show how ascorbic acid kills cancer cells and sensitizes prostate cancer to radiation therapy while also conferring protection upon normal prostate epithelial cells against radiation-induced injury. We found that the NF-κB transcription factor RelB is a pivotal determinant in the differential radiosensitization effects of ascorbic acid in prostate cancer cells and normal prostate epithelial cells. Mechanistically, high reactive oxygen species concentrations suppress RelB in cancer cells. RelB suppression decreases expression of the sirtuin SIRT3 and the powerful antioxidant MnSOD, which in turn increases oxidative and metabolic stresses in prostate cancer cells. In contrast, ascorbic acid enhances RelB expression in normal cells, improving antioxidant and metabolic defenses against radiation injury. In addition to showing how RelB mediates the differential effects of ascorbic acid on cancer and normal tissue radiosensitivities, our work also provides a proof of concept for the existence of redox modulators that can improve the efficacy of radiotherapy while protecting against normal tissue injury in cancer settings. Cancer Res; 77(6); 1345–56. ©2017 AACR.
Data from The NCX1/TRPC6 Complex Mediates TGFβ-Driven Migration and Invasion of Human Hepatocellular Carcinoma Cells
Authors: Xu Jingyu , Yang Yuan , Xie Rui , Liu Jilong , Nie Xubiao , An Jiaxing , Wen Guorong , Liu Xuemei , Jin Hai , Tuo Biguang
Published: March 2023

Abstract
TGFβ plays an important role in the progression and metastasis of hepatocellular carcinoma (HCC), yet the cellular and molecular mechanisms underlying this role are not completely understood. In this study, we investigated the roles of Na+/Ca2+ exchanger 1 (NCX1) and canonical transient receptor potential channel 6 (TRPC6) in regulating TGFβ in human HCC. In HepG2 and Huh7 cells, TGFβ-stimulated intracellular Ca2+ increases through NCX1 and TRPC6 and induced the formation of a TRPC6/NCX1 molecular complex. This complex-mediated Ca2+ signaling regulated the effect of TGFβ on the migration, invasion, and intrahepatic metastasis of human HCC cells in nude mice. TGFβ upregulated TRPC6 and NCX1 expression, and there was a positive feedback between TRPC6/NCX1 signaling and Smad signaling. Expression of both TRPC6 and NCX1 were markedly increased in native human HCC tissues, and their expression levels positively correlated with advancement of HCC in patients. These data reveal the role of the TRPC6/NCX1 molecular complex in HCC and in regulating TGFβ signaling, and they implicate TRPC6 and NCX1 as potential targets for therapy in HCC.

Significance: TGFβ induces the formation and activation of a TRPC6/NCX1 molecular complex, which mediates the effects of TGFβ on the migration, invasion, and intrahepatic metastasis of HCC. Cancer Res; 78(10); 2564–76. ©2018 AACR.
Data from Interferon-γ Signaling in Melanocytes and Melanoma Cells Regulates Expression of CTLA-4
Authors: Mo Xuan , Zhang Hanghang , Preston Sarah , Martin Kayla , Zhou Bo , Vadalia Nish , Gamero Ana M. , Soboloff Jonathan , Tempera Italo , Zaidi M. Raza
Published: March 2023

Abstract
CTLA4 is a cell surface receptor on T cells that functions as an immune checkpoint molecule to enforce tolerance to cognate antigens. Anti–CTLA4 immunotherapy is highly effective at reactivating T-cell responses against melanoma, which is postulated to be due to targeting CTLA4 on T cells. Here, we report that CTLA4 is also highly expressed by most human melanoma cell lines, as well as in normal human melanocytes. Interferon-γ (IFNG) signaling activated the expression of the human CTLA4 gene in a melanocyte and melanoma cell–specific manner. Mechanistically, IFNG activated CTLA4 expression through JAK1/2-dependent phosphorylation of STAT1, which bound a specific gamma-activated sequence site on the CTLA4 promoter, thereby licensing CBP/p300-mediated histone acetylation and local chromatin opening. In melanoma cell lines, elevated baseline expression relied upon constitutive activation of the MAPK pathway. Notably, RNA-seq analyses of melanoma specimens obtained from patients who had received anti–CTLA4 immunotherapy (ipilimumab) showed upregulation of an IFNG-response gene expression signature, including CTLA4 itself, which correlated significantly with durable response. Taken together, our results raise the possibility that CTLA4 targeting on melanoma cells may contribute to the clinical immunobiology of anti–CTLA4 responses.

Significance: These findings show that human melanoma cells express high levels of the immune checkpoint molecule CTLA4, with important possible implications for understanding how anti-CTLA4 immunotherapy mediates its therapeutic effects. Cancer Res; 78(2); 436–50. ©2017 AACR.
Data from Small-Molecule Inhibition of Axl Targets Tumor Immune Suppression and Enhances Chemotherapy in Pancreatic Cancer
Authors: Ludwig Kathleen F. , Du Wenting , Sorrelle Noah B. , Wnuk-Lipinska Katarzyna , Topalovski Mary , Toombs Jason E. , Cruz Victoria H. , Yabuuchi Shinichi , Rajeshkumar N.V. , Maitra Anirban , Lorens James B. , Brekken Rolf A.
Published: March 2023

Abstract
Activation of the receptor tyrosine kinase Axl is associated with poor outcomes in pancreatic cancer (PDAC), where it coordinately mediates immune evasion and drug resistance. Here, we demonstrate that the selective Axl kinase inhibitor BGB324 targets the tumor–immune interface to blunt the aggressive traits of PDAC cells in vitro and enhance gemcitibine efficacy in vivo. Axl signaling stimulates the TBK1–NFκB pathway and innate immune suppression in the tumor microenvironment. In tumor cells, BGB324 treatment drove epithelial differentiation, expression of nucleoside transporters affecting gemcitabine response, and an immune stimulatory microenvironment. Our results establish a preclinical mechanistic rationale for the clinical development of Axl inhibitors to improve the treatment of PDAC patients.

Significance: These results establish a preclinical mechanistic rationale for the clinical development of AXL inhibitors to improve the treatment of PDAC patients. Cancer Res; 78(1); 246–55. ©2017 AACR.
Data from AMPK–Akt Double-Negative Feedback Loop in Breast Cancer Cells Regulates Their Adaptation to Matrix Deprivation
Authors: Saha Manipa , Kumar Saurav , Bukhari Shoiab , Balaji Sai A. , Kumar Prashant , Hindupur Sravanth K. , Rangarajan Annapoorni
Published: March 2023

Abstract
Cell detachment from the extracellular matrix triggers anoikis. Disseminated tumor cells must adapt to survive matrix deprivation, while still retaining the ability to attach at secondary sites and reinitiate cell division. In this study, we elucidate mechanisms that enable reversible matrix attachment by breast cancer cells. Matrix deprival triggered AMPK activity and concomitantly inhibited AKT activity by upregulating the Akt phosphatase PHLPP2. The resultant pAMPKhigh/pAktlow state was critical for cell survival in suspension, as PHLPP2 silencing also increased anoikis while impairing autophagy and metastasis. In contrast, matrix reattachment led to Akt-mediated AMPK inactivation via PP2C-α-mediated restoration of the pAkthigh/pAMPKlow state. Clinical specimens of primary and metastatic breast cancer displayed an Akt-associated gene expression signature, whereas circulating breast tumor cells displayed an elevated AMPK-dependent gene expression signature. Our work establishes a double-negative feedback loop between Akt and AMPK to control the switch between matrix-attached and matrix-detached states needed to coordinate cell growth and survival during metastasis.

Significance: These findings reveal a molecular switch that regulates cancer cell survival during metastatic dissemination, with the potential to identify targets to prevent metastasis in breast cancer. Cancer Res; 78(6); 1497–510. ©2018 AACR.
Data from miR-508 Defines the Stem-like/Mesenchymal Subtype in Colorectal Cancer
Authors: Yan Ting-Ting , Ren Lin-Lin , Shen Chao-Qin , Wang Zhen-Hua , Yu Ya-Nan , Liang Qian , Tang Jia-Yin , Chen Ying-Xuan , Sun Dan-Feng , Zgodzinski Witold , Majewski Marek , Radwan Piotr , Kryczek Ilona , Zhong Ming , Chen Jinxian , Liu Qiang , Zou Weiping , Chen Hao-Yan , Hong Jie , Fang Jing-Yuan
Published: March 2023

Abstract
Colorectal cancer includes an invasive stem-like/mesenchymal subtype, but its genetic drivers, functional, and clinical relevance are uncharacterized. Here we report the definition of an altered miRNA signature defining this subtype that includes a major genomic loss of miR-508. Mechanistic investigations showed that this miRNA affected the expression of cadherin CDH1 and the transcription factors ZEB1, SALL4, and BMI1. Loss of miR-508 in colorectal cancer was associated with upregulation of the novel hypoxia-induced long noncoding RNA AK000053. Ectopic expression of miR-508 in colorectal cancer cells blunted epithelial-to-mesenchymal transition (EMT), stemness, migration, and invasive capacity in vitro and in vivo. In clinical colorectal cancer specimens, expression of miR-508 negatively correlated with stemness and EMT-associated gene expression and positively correlated with patient survival. Overall, our results showed that miR-508 is a key functional determinant of the stem-like/mesenchymal colorectal cancer subtype and a candidate therapeutic target for its treatment.

Significance: These results define a key functional determinant of a stem-like/mesenchymal subtype of colorectal cancers and a candidate therapeutic target for its treatment. Cancer Res; 78(7); 1751–65. ©2018 AACR.
Data from S-Nitrosylation of cIAP1 Switches Cancer Cell Fate from TNFα/TNFR1-Mediated Cell Survival to Cell Death
Authors: Romagny Sabrina , Bouaouiche Sarra , Lucchi Géraldine , Ducoroy Patrick , Bertoldo Jean B. , Terenzi Hernan , Bettaieb Ali , Plenchette Stéphanie
Published: March 2023

Abstract
TNFα is a prominent proinflammatory cytokine and a critical mediator for the development of many types of cancer such as breast, colon, prostate, cervical, skin, liver, and chronic lymphocytic leukemia. Binding of TNFα to TNFR1 can lead to divergent signaling pathways promoting predominantly NF-κB activation but also cell death. We report here that the nitric oxide (NO) donor glyceryl trinitrate (GTN) converts TNFα, generated from immune cells or cancer cells stimulated by chemotherapy, into a prodeath mediator in colon and mammary cancer cells. GTN-mediated S-nitrosylation of cIAP1 on cysteines 571 and 574 inhibited its E3 ubiquitin ligase activity, which in turn reduced Lys63-linked ubiquitination of RIP1 and initiated assembly of a death complex. These findings provide insights into how NO can harness advantageous aspects of inflammation in cancer and provide new therapeutic strategies.

Significance: Combination of an NO donor with chemotherapeutic drug–induced TNFα represents a potentially valuable anticancer strategy. Cancer Res; 78(8); 1948–57. ©2018 AACR.
Data from Distinct TP63 Isoform-Driven Transcriptional Signatures Predict Tumor Progression and Clinical Outcomes
Authors: Abbas Hussein A. , Bui Ngoc Hoang Bao , Rajapakshe Kimal , Wong Justin , Gunaratne Preethi , Tsai Kenneth Y. , Coarfa Cristian , Flores Elsa R.
Published: March 2023

Abstract
TP63 is required to maintain stem cell pluripotency and suppresses the metastatic potential of cancer cells through multiple mechanisms. These functions are differentially regulated by individual isoforms, necessitating a deeper understanding of how the distinct transcriptional programs controlled by these isoforms affect cancer progression and outcomes. In this study, we conducted a pan-cancer analysis of The Cancer Genome Atlas to identify transcriptional networks regulated by TAp63 and ΔNp63 using transcriptomes derived from epidermal cells of TAp63−/− and ΔNp63−/− mice. Analysis of 17 cancer developmental and 27 cancer progression signatures revealed a consistent tumor suppressive pattern for TAp63. In contrast, we identified pleiotropic roles for ΔNp63 in tumor development and found that its regulation of Lef1 was crucial for its oncogenic role. ΔNp63 performed a distinctive role as suppressor of tumor progression by cooperating with TAp63 to modulate key biological pathways, principally cell-cycle regulation, extracellular matrix remodeling, epithelial-to-mesenchymal transition, and the enrichment of pluripotent stem cells. Importantly, these TAp63 and ΔNp63 signatures prognosticated progression and survival, even within specific stages, in bladder and renal carcinomas as well as low-grade gliomas. These data describe a novel approach for understanding transcriptional activities of TP63 isoforms across a large number of cancer types, potentially enabling identification of patient subsets most likely to benefit from therapies predicated on manipulating specific TP63 isoforms.

Significance: Transcriptomic analyses of patient samples and murine knockout models highlight the prognostic role of several critical mechanisms of tumor suppression that are regulated by TP63. Cancer Res; 78(2); 451–62. ©2017 AACR.
Data from Comparative Transcriptome Analysis Quantifies Immune Cell Transcript Levels, Metastatic Progression, and Survival in Osteosarcoma
Authors: Scott Milcah C. , Temiz Nuri A. , Sarver Anne E. , LaRue Rebecca S. , Rathe Susan K. , Varshney Jyotika , Wolf Natalie K. , Moriarity Branden S. , O'Brien Timothy D. , Spector Logan G. , Largaespada David A. , Modiano Jaime F. , Subramanian Subbaya , Sarver Aaron L.
Published: March 2023

Abstract
Overall survival of patients with osteosarcoma (OS) has improved little in the past three decades, and better models for study are needed. OS is common in large dog breeds and is genetically inducible in mice, making the disease ideal for comparative genomic analyses across species. Understanding the level of conservation of intertumor transcriptional variation across species and how it is associated with progression to metastasis will enable us to more efficiently develop effective strategies to manage OS and to improve therapy. In this study, transcriptional profiles of OS tumors and cell lines derived from humans (n = 49), mice (n = 103), and dogs (n = 34) were generated using RNA sequencing. Conserved intertumor transcriptional variation was present in tumor sets from all three species and comprised gene clusters associated with cell cycle and mitosis and with the presence or absence of immune cells. Further, we developed a novel gene cluster expression summary score (GCESS) to quantify intertumor transcriptional variation and demonstrated that these GCESS values associated with patient outcome. Human OS tumors with GCESS values suggesting decreased immune cell presence were associated with metastasis and poor survival. We validated these results in an independent human OS tumor cohort and in 15 different tumor data sets obtained from The Cancer Genome Atlas. Our results suggest that quantification of immune cell absence and tumor cell proliferation may better inform therapeutic decisions and improve overall survival for OS patients.

Significance: This study offers new tools to quantify tumor heterogeneity in osteosarcoma, identifying potentially useful prognostic biomarkers for metastatic progression and survival in patients. Cancer Res; 78(2); 326–37. ©2017 AACR.