Pioglitazone-mediated reversal of elevated glucose metabolism in the airway epithelium of mouse lung adenocarcinomas

• Text
• PDF

Abstract

Airway epithelial cells are prone to the damage caused by lung cancer risk factors, such as cigarette smoking. Little is known about surrogate biomarkers in the bronchial airway epithelium that can be used to assess the effect of potential chemoprevention drugs on lung adenocarcinoma formation/progression. Pioglitazone has been suggested as a chemoprevention drug for lung cancer. To study the mechanisms underlying the role of pioglitazone in lung cancer prevention, we performed transcriptome sequencing (RNA-Seq) and found that Kras signaling was repressed by pioglitazone treatment in the airway epithelial cells of mice with lung adenocarcinoma (FDR q = 9.8E-04). It was also found that glucose metabolic pathways were elevated in the airway epithelium of mice with lung adenocarcinomas and inhibited by pioglitazone treatment (FDR q = 0.01). Downregulation of glucose metabolism genes was also observed in lung tumors of mice treated with pioglitazone. The high-risk expression signature of elevated glucose metabolism was associated with poor survival outcome in multiple lung adenocarcinoma patient populations (P values ranging from 1.0E-9 to 5.5E-5). Our results suggest that the role of pioglitazone in preventing lung adenocarcinoma may depend on inhibiting Kras signaling and glucose metabolism, which may serve as biomarkers of agent action in the airway epithelium.

Authors

Donghai Xiong, Jing Pan, Qi Zhang, Eva Szabo, Mark Steven Miller, Ronald A. Lubet, Yian Wang, Ming You

Genomic landscape and evolution of metastatic chromophobe renal cell carcinoma

• Text
• PDF

Abstract

Chromophobe renal cell carcinoma (chRCC) typically shows ~7 chromosome losses (1, 2, 6, 10, 13, 17, and 21) and ~31 exonic somatic mutations, yet carries ~5%–10% metastatic incidence. Since extensive chromosomal losses can generate proteotoxic stress and compromise cellular proliferation, it is intriguing how chRCC, a tumor with extensive chromosome losses and a low number of somatic mutations, can develop lethal metastases. Genomic features distinguishing metastatic from nonmetastatic chRCC are unknown. An integrated approach, including whole-genome sequencing (WGS), targeted ultradeep cancer gene sequencing, and chromosome analyses (FACETS, OncoScan, and FISH), was performed on 79 chRCC patients including 38 metastatic (M-chRCC) cases. We demonstrate that TP53 mutations (58%), PTEN mutations (24%), and imbalanced chromosome duplication (ICD, duplication of ≥ 3 chromosomes) (25%) were enriched in M-chRCC. Reconstruction of the subclonal composition of paired primary-metastatic chRCC tumors supports the role of TP53, PTEN, and ICD in metastatic evolution. Finally, the presence of these 3 genomic features in primary tumors of both The Cancer Genome Atlas kidney chromophobe (KICH) (n = 64) and M-chRCC (n = 35) cohorts was associated with worse survival. In summary, our study provides genomic insights into the metastatic progression of chRCC and identifies TP53 mutations, PTEN mutations, and ICD as high-risk features.

Authors

Jozefina Casuscelli, Nils Weinhold, Gunes Gundem, Lu Wang, Emily C. Zabor, Esther Drill, Patricia I. Wang, Gouri J. Nanjangud, Almedina Redzematovic, Amrita M. Nargund, Brandon J. Manley, Maria E. Arcila, Nicholas M. Donin, John C. Cheville, R. Houston Thompson, Allan J. Pantuck, Paul Russo, Emily H. Cheng, William Lee, Satish K. Tickoo, Irina Ostrovnaya, Chad J. Creighton, Elli Papaemmanuil, Venkatraman E. Seshan, A. Ari Hakimi, James J. Hsieh

Macrophage infiltration and genetic landscape of undifferentiated uterine sarcomas

• Text
• PDF

Abstract

Endometrial stromal tumors include translocation-associated low- and high-grade endometrial stromal sarcomas (ESS) and highly malignant undifferentiated uterine sarcomas (UUS). UUS is considered a poorly defined group of aggressive tumors and is often seen as a diagnosis of exclusion after ESS and leiomyosarcoma (LMS) have been ruled out. We performed a comprehensive analysis of gene expression, copy number variation, point mutations, and immune cell infiltrates in the largest series to date of all major types of uterine sarcomas to shed light on the biology of UUS and to identify potential novel therapeutic targets. We show that UUS tumors have a distinct molecular profile from LMS and ESS. Gene expression and immunohistochemical analyses revealed the presence of high numbers of tumor-associated macrophages (TAMs) in UUS, which makes UUS patients suitable candidates for therapies targeting TAMs. Our results show a high genomic instability of UUS and downregulation of several TP53-mediated tumor suppressor genes, such as NDN, CDH11, and NDRG4. Moreover, we demonstrate that UUS carry somatic mutations in several oncogenes and tumor suppressor genes implicated in RAS/PI3K/AKT/mTOR, ERBB3, and Hedgehog signaling.

Authors

Joanna Przybyl, Magdalena Kowalewska, Anna Quattrone, Barbara Dewaele, Vanessa Vanspauwen, Sushama Varma, Sujay Vennam, Aaron M. Newman, Michal Swierniak, Elwira Bakuła-Zalewska, Janusz A. Siedlecki, Mariusz Bidzinski, Jan Cools, Matt van de Rijn, Maria Debiec-Rychter

CXCL13-producing T_FH cells link immune suppression and adaptive memory in human breast cancer

• Text
• PDF

Abstract

T follicular helper cells (TFH cells) are important regulators of antigen-specific B cell responses. The B cell chemoattractant CXCL13 has recently been linked with TFH cell infiltration and improved survival in human cancer. Although human TFH cells can produce CXCL13, their immune functions are currently unknown. This study presents data from human breast cancer, advocating a role for tumor-infiltrating CXCL13-producing (CXCR5–) TFH cells, here named TFHX13 cells, in promoting local memory B cell differentiation. TFHX13 cells potentially trigger tertiary lymphoid structure formation and thereby generate germinal center B cell responses at the tumor site. Follicular DCs are not potent CXCL13 producers in breast tumor tissues. We used the TFH cell markers PD-1 and ICOS to identify distinct effector and regulatory CD4+ T cell subpopulations in breast tumors. TFHX13 cells are an important component of the PD-1hiICOSint effector subpopulation and coexpanded with PD-1hiICOSintFOXP3hi Tregs. IL2 deprivation induces CXCL13 expression in vitro with a synergistic effect from TGFβ1, providing insight into TFHX13 cell differentiation in response to Treg accumulation, similar to conventional TFH cell responses. Our data suggest that human TFHX13 cell differentiation may be a key factor in converting Treg-mediated immune suppression to de novo activation of adaptive antitumor humoral responses in the chronic inflammatory breast cancer microenvironment.

Authors

Chunyan Gu-Trantien, Edoardo Migliori, Laurence Buisseret, Alexandre de Wind, Sylvain Brohée, Soizic Garaud, Grégory Noël, Luan Dang C.V., Jean-Nicolas Lodewyckx, Céline Naveaux, Hugues Duvillier, Stanislas Goriely, Denis Larsimont, Karen Willard-Gallo

Insulin supplementation attenuates cancer-induced cardiomyopathy and slows tumor disease progression

• Text
• PDF

Abstract

Advanced cancer induces fundamental changes in metabolism and promotes cardiac atrophy and heart failure. We discovered systemic insulin deficiency in cachectic cancer patients. Similarly, mice with advanced B16F10 melanoma (B16F10-TM) or colon 26 carcinoma (C26-TM) displayed decreased systemic insulin associated with marked cardiac atrophy, metabolic impairment, and function. B16F10 and C26 tumors decrease systemic insulin via high glucose consumption, lowering pancreatic insulin production and producing insulin-degrading enzyme. As tumor cells consume glucose in an insulin-independent manner, they shift glucose away from cardiomyocytes. Since cardiomyocytes in both tumor models remained insulin responsive, low-dose insulin supplementation by subcutaneous implantation of insulin-releasing pellets improved cardiac glucose uptake, atrophy, and function, with no adverse side effects. In addition, by redirecting glucose to the heart in addition to other organs, the systemic insulin treatment lowered glucose usage by the tumor and thereby decreased tumor growth and volume. Insulin corrected the cancer-induced reduction in cardiac Akt activation and the subsequent overactivation of the proteasome and autophagy. Thus, cancer-induced systemic insulin depletion contributes to cardiac wasting and failure and may promote tumor growth. Low-dose insulin supplementation attenuates these processes and may be supportive in cardio-oncologic treatment concepts.

Authors

James T. Thackeray, Stefan Pietzsch, Britta Stapel, Melanie Ricke-Hoch, Chun-Wei Lee, Jens P. Bankstahl, Michaela Scherr, Jörg Heineke, Gesine Scharf, Arash Haghikia, Frank M. Bengel, Denise Hilfiker-Kleiner

Nicotinamide metabolism regulates glioblastoma stem cell maintenance

• Text
• PDF

Abstract

Metabolic dysregulation promotes cancer growth through not only energy production, but also epigenetic reprogramming. Here, we report that a critical node in methyl donor metabolism, nicotinamide N-methyltransferase (NNMT), ranked among the most consistently overexpressed metabolism genes in glioblastoma relative to normal brain. NNMT was preferentially expressed by mesenchymal glioblastoma stem cells (GSCs). NNMT depletes S-adenosyl methionine (SAM), a methyl donor generated from methionine. GSCs contained lower levels of methionine, SAM, and nicotinamide, but they contained higher levels of oxidized nicotinamide adenine dinucleotide (NAD⁺) than differentiated tumor cells. In concordance with the poor prognosis associated with DNA hypomethylation in glioblastoma, depletion of methionine, a key upstream methyl group donor, shifted tumors toward a mesenchymal phenotype and accelerated tumor growth. Targeting NNMT expression reduced cellular proliferation, self-renewal, and in vivo tumor growth of mesenchymal GSCs. Supporting a mechanistic link between NNMT and DNA methylation, targeting NNMT reduced methyl donor availability, methionine levels, and unmethylated cytosine, with increased levels of DNA methyltransferases, DNMT1 and DNMT3A. Supporting the clinical significance of these findings, NNMT portended poor prognosis for glioblastoma patients. Collectively, our findings support NNMT as a GSC-specific therapeutic target in glioblastoma by disrupting oncogenic DNA hypomethylation.

Authors

Jinkyu Jung, Leo J.Y. Kim, Xiuxing Wang, Qiulian Wu, Tanwarat Sanvoranart, Christopher G. Hubert, Briana C. Prager, Lisa C. Wallace, Xun Jin, Stephen C. Mack, Jeremy N. Rich

Transcriptional dissection of melanoma identifies a high-risk subtype underlying TP53 family genes and epigenome deregulation

• Text
• PDF

Abstract

BACKGROUND. Melanoma is a heterogeneous malignancy. We set out to identify the molecular underpinnings of high-risk melanomas, those that are likely to progress rapidly, metastasize, and result in poor outcomes.

METHODS. We examined transcriptome changes from benign states to early-, intermediate-, and late-stage tumors using a set of 78 treatment-naive melanocytic tumors consisting of primary melanomas of the skin and benign melanocytic lesions. We utilized a next-generation sequencing platform that enabled a comprehensive analysis of protein-coding and -noncoding RNA transcripts.

RESULTS. Gene expression changes unequivocally discriminated between benign and malignant states, and a dual epigenetic and immune signature emerged defining this transition. To our knowledge, we discovered previously unrecognized melanoma subtypes. A high-risk primary melanoma subset was distinguished by a 122-epigenetic gene signature (“epigenetic” cluster) and TP53 family gene deregulation (TP53, TP63, and TP73). This subtype associated with poor overall survival and showed enrichment of cell cycle genes. Noncoding repetitive element transcripts (LINEs, SINEs, and ERVs) that can result in immunostimulatory signals recapitulating a state of “viral mimicry” were significantly repressed. The high-risk subtype and its poor predictive characteristics were validated in several independent cohorts. Additionally, primary melanomas distinguished by specific immune signatures (“immune” clusters) were identified.

CONCLUSION. The TP53 family of genes and genes regulating the epigenetic machinery demonstrate strong prognostic and biological relevance during progression of early disease. Gene expression profiling of protein-coding and -noncoding RNA transcripts may be a better predictor for disease course in melanoma. This study outlines the transcriptional interplay of the cancer cell’s epigenome with the immune milieu with potential for future therapeutic targeting.

FUNDING. National Institutes of Health (CA154683, CA158557, CA177940, CA087497-13), Tisch Cancer Institute, Melanoma Research Foundation, the Dow Family Charitable Foundation, and the Icahn School of Medicine at Mount Sinai.

Authors

Brateil Badal, Alexander Solovyov, Serena Di Cecilia, Joseph Minhow Chan, Li-Wei Chang, Ramiz Iqbal, Iraz T. Aydin, Geena S. Rajan, Chen Chen, Franco Abbate, Kshitij S. Arora, Antoine Tanne, Stephen B. Gruber, Timothy M. Johnson, Douglas R. Fullen, Leon Raskin, Robert Phelps, Nina Bhardwaj, Emily Bernstein, David T. Ting, Georg Brunner, Eric E. Schadt, Benjamin D. Greenbaum, Julide Tok Celebi

β-catenin and PI3Kδ inhibition expands precursor Th17 cells with heightened stemness and antitumor activity

• Text
• PDF

Abstract

ICOS costimulation generates Th17 cells with durable memory responses to tumor. Herein, we found that ICOS induces PI3K/p110δ/Akt and Wnt/β-catenin pathways in Th17 cells. Coinhibiting PI3Kδ and β-catenin altered the biological fate of Th17 cells. Th17 cells inhibited of both pathways expressed less RORγt, which, in turn, reduced their ability to secrete IL-17. Unexpectedly, these cells were more effective (than uninhibited cells) at regressing tumor when infused into mice, leading to long-term curative responses. PI3Kδ inhibition expanded precursor Th17 cells with a central memory phenotype that expressed nominal regulatory properties (low FoxP3), while β-catenin inhibition enhanced Th17 multifunctionality in vivo. Remarkably, upon TCR restimulation, RORγt and IL-17 rebounded in Th17 cells treated with PI3Kδ and β-catenin inhibitors. Moreover, these cells regained β-catenin, Tcf7, and Akt expression, licensing them to secrete heightened IL-2, persist, and eradicate solid tumors without help from endogenous NK and CD8 T cells. This finding shines a light on ways to repurpose FDA-approved drugs to augment T cell–based cancer immunotherapies.

Authors

Kinga Majchrzak, Michelle H. Nelson, Jacob S. Bowers, Stefanie R. Bailey, Megan M. Wyatt, John M. Wrangle, Mark P. Rubinstein, Juan C. Varela, Zihai Li, Richard A. Himes, Sherine S.L. Chan, Chrystal M. Paulos

First-in-human trial of multikinase VEGF inhibitor regorafenib and anti-EGFR antibody cetuximab in advanced cancer patients

• Text
• PDF

Abstract

BACKGROUND. The combination of multikinase VEGF inhibitor regorafenib and anti-EGFR antibody cetuximab overcomes intrinsic and acquired resistance in both EGFR-sensitive and EGFR-resistant preclinical models of colorectal cancer (CRC).

METHODS. Utilizing a standard 3+3 design, a phase I study was designed to determine safety, maximum tolerated dose (MTD), and dose-limiting toxicities (DLTs) of the regorafenib plus cetuximab combination among patients with advanced cancer including CRC. Comprehensive genomic profiling was performed on the exceptional responder.

RESULTS. Among the 27 patients enrolled the median age was 54 years. None of 19 patients treated at dose level 1 (cetuximab i.v. 200 mg/m² followed by 150 mg/m² weekly + regorafenib 80 mg daily) experienced a DLT, and 2 of 5 patients treated at dose level 2 (cetuximab i.v. 200 mg/m² followed by 150 mg/m² weekly + regorafenib 120 mg daily) experienced a DLT (grade 3 thrombocytopenia [n = 1] and grade 3 intra-abdominal bleed [n = 1]). Most common adverse events were grade 1 or 2 rash (20 patients). Of 24 evaluable patients, 11 (46%) patients had clinical benefit (stable disease > 6 cycles or partial response [PR]) (CRC n = 8, one patient each with head and neck cancer, carcinoma of unknown primary, and glioblastoma). A CRC patient, who progressed on anti-EGFR and regorafenib, achieved a PR (46% decrease per RECIST v1.1) lasting 15 months. Genomic profiling of an exceptional responder with response for over 27 cycles revealed hypermutated genotype with microsatellite instability (MSI).

CONCLUSION. Regorafenib 80 mg daily plus cetuximab 200 mg/m² loading dose, followed by 150 mg/m² every week is the MTD/recommended phase II dose. The combination demonstrated early signals of activity in wild-type CRC, including 1 exceptional responder with MSI high.

TRIAL REGISTRATION. clinicaltrials.gov NCT02095054

FUNDING. The University of Texas MD Anderson Cancer Center is supported by the NIH Cancer Center Support Grant CA016672. This work was supported in part by the Cancer Prevention Research Institute of Texas grant RP110584 and National Center for Advancing Translational Sciences grant UL1 TR000371 (Center for Clinical and Translational Sciences).

Authors

Vivek Subbiah, Muhammad Rizwan Khawaja, David S. Hong, Behrang Amini, Jiang Yungfang, Hui Liu, Adrienne Johnson, Alexa B. Schrock, Siraj M. Ali, James X. Sun, David Fabrizio, Sarina Piha-Paul, Siqing Fu, Apostolia M. Tsimberidou, Aung Naing, Filip Janku, Daniel D. Karp, Michael Overman, Cathy Eng, Scott Kopetz, Funda Meric-Bernstam, Gerald S. Falchook

Physiologically activated mammary fibroblasts promote postpartum mammary cancer

• Text
• PDF

Abstract

Women diagnosed with breast cancer within 5 years of childbirth have poorer prognosis than nulliparous or pregnant women. Weaning-induced breast involution is implicated, as the collagen-rich, immunosuppressive microenvironment of the involuting mammary gland is tumor promotional in mice. To investigate the role of mammary fibroblasts, isolated mammary PDGFRα⁺ cells from nulliparous and postweaning mice were assessed for activation phenotype and protumorigenic function. Fibroblast activation during involution was evident by increased expression of fibrillar collagens, lysyl oxidase, Tgfb1, and Cxcl12 genes. The ability of mammary tumors to grow in an isogenic, orthotopic transplant model was increased when tumor cells were coinjected with involution-derived compared with nulliparous-derived mammary fibroblasts. Mammary tumors in the involution-fibroblast group had increased Ly6C⁺ monocytes at the tumor border, and decreased CD8⁺ T cell infiltration and tumor cell death. Ibuprofen treatment suppressed involution-fibroblast activation and tumor promotional capacity, concurrent with decreases in tumor Ly6C⁺ monocytes, and increases in intratumoral CD8⁺ T cell infiltration, granzyme levels, and tumor cell death. In total, our data identify a COX/prostaglandin E2 (PGE2)–dependent activated mammary fibroblast within the involuting mammary gland that displays protumorigenic, immunosuppressive activity, identifying fibroblasts as potential targets for the prevention and treatment of postpartum breast cancer.

Authors

Qiuchen Guo, Jessica Minnier, Julja Burchard, Kami Chiotti, Paul Spellman, Pepper Schedin