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Publications

Indica Labs / Publications

Automated Analysis of Lymphocytic Infiltration, Tumor Budding, and Their Spatial Relationship Improves Prognostic Accuracy in Colorectal Cancer

Ines P. Nearchou, Kate Lillard, Christos G. Gavriel, Hideki Ueno, David J. Harrison, and Peter D. Caie Cancer Immunology Research| Published March 7, 2019 | DOI 10.1158/2326-6066.CIR-18-0377 Both immune profiling and tumor budding significantly correlate with colorectal cancer patient outcome but are traditionally reported independently. This study evaluated the association and interaction between lymphocytic infiltration and tumor budding, coregistered on a single slide, in order to determine a more precise prognostic algorithm for patients with stage II colorectal cancer. Multiplexed immunofluorescence and...

Peroxisome Proliferator-Activated Receptor g2 Controls the Rate of Adipose Tissue Lipid Storage and Determines Metabolic Flexibility

Sam Virtue, Kasparas Petkevicius, Jose Maria Moreno-Navarrete, Benjamin Jenkins, Daniel Hart, Martin Dale, Albert Koulman, Jose Manuel Fernandez-Real, and Antonio Vidal-Puig Cell Reports| Published August 21st, 2018 | DOI https://doi.org/10.1073/pnas.1721418115 One understudied function of white adipose tissue (AT) is its role in postprandial lipid buffering. In this study, we demonstrate that mice lacking the adipose tissue-specific transcription factor peroxisome proliferator activated receptor g2 (PPARg2) exhibit a defect in their rate of adipose tissue lipid storage. Impaired adipose tissue storage rate reduces metabolic flexibility,...

FOXM1 contributes to treatment failure in acute myeloid leukemia

Irum Khan, Marianna Halasi, Anand Patel, Rachael Schultz, Nandini Kalakota, Yi-Hua Chen, Nathan Aardsma, Li Liu, John D. Crispino, Nadim Mahmud, Olga Frankfurt, and Andrei L. Gartel JCI Insight | Published August 9th, 2018 | DOI https://doi.org/10.1172/jci.insight.121583 Acute myeloid leukemia (AML) patients with NPM1 mutations demonstrate a superior response to standard chemotherapy treatment. Our previous work has shown that these favorable outcomes are linked to the cytoplasmic relocalization and inactivation of FOXM1 driven by mutated NPM1. Here, we went on to confirm the important...

Mice harboring the human SLC30A8 R138X loss-of-function mutation have increased insulin secretory capacity

Sandra Kleiner, Daniel Gomez, Bezawit Megra, Erqian Na, Ramandeep Bhavsar, Katie Cavino, Yurong Xin, Jose Rojas, Giselle Dominguez-Gutierrez, Brian Zambrowicz, Gaelle Carrat, Pauline Chabosseau, Ming Hu, Andrew J. Murphy, George D. Yancopoulos, Guy A. Rutter, and Jesper Gromada PNAS | Published July 23rd, 2018 | DOI https://doi.org/10.1073/pnas.1721418115 SLC30A8 encodes a zinc transporter that is primarily expressed in the pancreatic islets of Langerhans. In β-cells it transports zinc into insulin-containing secretory granules. Loss-of-function (LOF) mutations in SLC30A8 protect against type 2 diabetes in humans. In this study, we generated a knockin mouse model carrying one of the most common human LOF mutations for SLC30A8, R138X....

Digital image analysis improves precision of PD‐L1 scoring in cutaneous melanoma

Viktor H. Koelzer, Aline Gisler, Jonathan C. Hanhart, Johannes Griss, Stephan N. Wagner, Niels Willi, Gieri Cathomas, Melanie Sachs, Werner Kempf, Daniela S. Thommen, Kirsten D. Mertz Nature Medicine | First published April 16th, 2018 | DOI https://doi.org/10.1111/his.13528 Abstract Aims Immune checkpoint inhibitors have become a successful treatment in metastatic melanoma. The high response rates in a subset of patients suggest that a sensitive companion diagnostic test is required. The predictive value of programmed death ligand 1 (PD‐L1) staining in melanoma has been questioned due to...

A transcriptionally and functionally distinct PD-1+ CD8+ T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade

Daniela S. Thommen, Viktor H. Koelzer, Petra Herzig, Andreas Roller, Marcel Trefny, Sarah Dimeloe, Anna Kiialainen, Jonathan Hanhart, Catherine Schill, Christoph Hess, Spasenija Savic Prince, Mark Wiese, Didier Lardinois, Ping-Chih Ho, Christian Klein, Vaios Karanikas, Kirsten D. Mertz, Ton N. Schumacher & Alfred Zippelius Nature Medicine | Published June 11th, 2018 | DOI https://doi.org/10.1038/s41591-018-0057-z Abstract Evidence from mouse chronic viral infection models suggests that CD8+T cell subsets characterized by distinct expression levels of the receptor PD-1 diverge in their state of exhaustion and potential for...

The neurotrophic tyrosine kinase receptor TrkA and its ligand NGF are increased in squamous cell carcinomas of the lung

Fangfang Gao, Nathan Griffin, Sam Faulkner, Christopher W. Rowe, Lily Williams, Severine Roselli, Rick F. Thorne, Aysha Ferdoushi, Phillip Jobling, Marjorie M. Walker & Hubert Hondermarck Scientific Reports | Published May 25th, 2018 | DOI https://doi.org/10.1038/s41598-018-26408-2 Abstract The neurotrophic tyrosine kinase receptor TrkA (NTRK1) and its ligand nerve growth factor (NGF) are emerging promoters of tumor progression. In lung cancer, drugs targeting TrkA are in clinical trials, but the clinicopathological significance of TrkA and NGF, as well as that of the precursor proNGF, the...

Diet-Induced Growth Is Regulated via Acquired Leptin Resistance and Engages a Pomc-Somatostatin-Growth Hormone Circuit

Heiko Löhr, Simon Hess, Mafalda M.A. Pereira, Philip Reinoß, Sandra Leibold, Christel Schenkel, Claudia M. Wunderlich, Peter Kloppenburg, Jens C. Brüning, Matthias Hammerschmidt5,'Correspondence information about the author Matthias Hammerschmidt Cell Reports , 2018 DOI: https://doi.org/10.1016/j.celrep.2018.04.018 Abstract Anorexigenic pro-opiomelanocortin (Pomc)/alpha-melanocyte stimulating hormone (αMSH) neurons of the hypothalamic melanocortin system function as key regulators of energy homeostasis, also controlling somatic growth across different species. However, the mechanisms of melanocortin-dependent growth control still remain ill-defined. Here, we reveal a thus-far-unrecognized structural and functional connection between Pomc neurons and...

T-cell Localization, Activation, and Clonal Expansion in Human Pancreatic Ductal Adenocarcinoma

Ingunn M. Stromnes, Ayaka Hulbert, Robert H. Pierce, Philip D. Greenberg and Sunil R. Hingorani Cancer Immunology Research , 2017 DOI: 10.1158/2326-6066.CIR-16-0322 Abstract Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy resistant to most therapies, including immune checkpoint blockade. To elucidate mechanisms of immunotherapy resistance, we assessed immune parameters in resected human PDA. We demonstrate significant interpatient variability in T-cell number, localization, and phenotype. CD8+ T cells, Foxp3+ regulatory T cells, and PD-1+ and PD-L1+ cells were preferentially enriched in tertiary lymphoid structures that were found in most tumors compared with stroma and tumor cell nests. Tumors containing...

PD-1 Blockade Induces Responses by Inhibiting Adaptive Immune Resistance

Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, Chmielowski B, Spasic M, Henry G, Ciobanu V, West AN, Carmona M, Kivork C, Seja E, Cherry G, Gutierrez AJ, Grogan TR, Mateus C, Tomasic G, Glaspy JA, Emerson RO, Robins H, Pierce RH, Elashoff DA, Robert C, Ribas A. Nature. 2014 Nov 27;515(7528):568-71 Therapies that target the programmed death-1 (PD-1) receptor have shown unprecedented rates of durable clinical responses in patients with various cancer types. One mechanism by which cancer...

The R-enantiomer of ketorolac delays mammary tumor development in mouse mammary tumor virus-polyoma middle T antigen (MMTV-PyMT) mice

Amanda S. Peretti, Dayna Dominguez, Martha M. Grimes, Helen J. Hathaway, Eric R. Prossnitz, Melanie R. Rivera, Angela Wandinger-Ness, Donna F. Kusewitt, & Laurie G. Hudson The American Journal of Pathology, 2017 https://doi.org/10.1016/j.ajpath.2017.10.018 Abstract Epidemiologic studies report improved breast cancer survival in women receiving ketorolac (Toradol®) for post-operative pain relief compared to other analgesics. Ketorolac is a racemic drug. The S-enantiomer inhibits cyclooxygenases; R-ketorolac is a selective inhibitor of the small GTPases Ras-related C3 botulinum toxin substrate 1 (Rac1) and cell division control protein...

High levels of tumor-associated neutrophils are associated with improved overall survival in patients with stage II colorectal cancer

Ryan S. Berry, Meng-Jun Xiong, Alissa Greenbaum, Parisa Mortaji, Robert A. Nofchissey, Fred Schultz, Cathleen Martinez, Li Luo, Katherine T. Morris, & Joshua A. Hanson PLoS ONE, December 2017 https://doi.org/10.1371/journal.pone.0188799 Abstract Conflicting reports regarding whether high tumor-associated neutrophils (TAN) are associated with outcomes in colorectal cancer (CRC) exist. Previous investigators have counted TAN using non-neutrophil-specific immunohistochemistry (IHC) stains. We examined whether TAN levels as determined by multi-field manual counting would predict prognosis. IRB approval was obtained and two pathologists, blinded to stage/outcome, counted TAN...

Association of HIV Status With Local Immune Response to Anal Squamous Cell Carcinoma

Elizabeth L. Yanik, Genevieve J. Kaunitz, Tricia R. Cottrell, Farah Succaria, Tracee L. McMiller, Maria L. Ascierto, Jessica Esandrio, Haiying Xu, Aleksandra Ogurtsova, Toby Cornish, Evan J. Lipson, Suzanne L. Topalian, Eric A. Engels, & Janis M. Taube JAMA Oncology, July 2017 doi:10.1001/jamaoncol.2017.0115 Abstract Importance  The programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) pathway play an important immunosuppressive role in cancer and chronic viral infection, and have been effectively targeted in cancer therapy. Anal squamous cell carcinoma (SCC) is associated with...

Cross-Platform Comparison of Computer-assisted Image Analysis Quantification of In Situ mRNA Hybridization in Investigative Pathology.

Timothy R. Holzer, Jeffrey C. Hanson, Erin M. Wray, Jason A. Bailey, Kim R. Kennedy, Patrick R. Finnegan, Aejaz Nasir, & Kelly M. Credille Applied Immunohistochemistry &  Molecular Morphology, July 2017 doi: 10.1097/PAI.0000000000000542 Abstract Although availability of automated platforms has proliferated, there is no standard practice for computer-assisted generation of scores for mRNA in situ hybridization (ISH) visualized by brightfield microscopic imaging on tissue sections. To address this systematically, an ISH for peptidylprolyl isomerase B (PPIB) (cyclophilin B) mRNA was optimized and applied to...

A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma

Donald M. O’Rourke, MacLean P. Nasrallah, Arati Desai, Jan J. Melenhorst, Keith Mansfield, Jennifer J. D. Morrissette, Maria Martinez-Lage, Steven Brem, Eileen Maloney, Angela Shen, Randi Isaacs, Suyash Mohan, Gabriela Plesa, Simon F. Lacey, Jean-Marc Navenot, Zhaohui Zheng, Bruce L. Levine, Hideho Okada, Carl H. June, Jennifer L. Brogdon and Marcela V. Maus, Science Translational Medicine, July 2017 DOI: 10.1126/scitranslmed.aaa0984 Abstract We conducted a first-in-human study of intravenous delivery of a single dose of autologous T cells redirected to the epidermal growth factor receptor...

Plant-based vaccines for oral delivery of type 1 diabetes-related autoantigens: Evaluating oral tolerance mechanisms and disease prevention in NOD mice

Amanda L. Posgai, Clive H. Wasserfall, Kwang-Chul Kwon, Henry Daniell, Desmond A. Schatz, & Mark A. Atkinson Scientific Reports, February 2017 doi:10.1038/srep42372 Abstract Autoantigen-specific immunological tolerance represents a central objective for prevention of type 1 diabetes (T1D). Previous studies demonstrated mucosal antigen administration results in expansion of Foxp3+ and LAP+ regulatory T cells (Tregs), suggesting oral delivery of self-antigens might represent an effective means for modulating autoimmune disease. Early preclinical experiments using the non-obese diabetic (NOD) mouse model reported mucosal administration of T1D-related autoantigens...

Molecular Pathways: Mucins and Drug Delivery in Cancer

Chinthalapally V. Rao, Naveena B. Janakiram, and Altaf Mohammed Clinical Cancer Research, February 2017 DOI: 10.1158/1078-0432.CCR-16-0862 Abstract Over the past few decades, clinical and preclinical studies have clearly demonstrated the role of mucins in tumor development. It is well established that mucins form a barrier impeding drug access to target sites, leading to cancer chemoresistance. Recently gained knowledge regarding core enzyme synthesis has opened avenues to explore the possibility of disrupting mucin synthesis to improve drug efficacy. Cancer cells exploit aberrant mucin synthesis to...

Glucagon receptor inhibition normalizes blood glucose in severe insulin-resistant mice

Haruka Okamotoa, Katie Cavinoa, Erqian Naa, Elizabeth Krumma, Sun Y. Kima, Xiping Chenga, Andrew J. Murphya, George D. Yancopoulosa, and Jesper Gromadaa PNAS January 23, 2017, doi:10.1073/pnas.1621069114 Abstract Inactivating mutations in the insulin receptor results in extreme insulin resistance. The resulting hyperglycemia is very difficult to treat, and patients are at risk for early morbidity and mortality from complications of diabetes. We used the insulin receptor antagonist S961 to induce severe insulin resistance, hyperglycemia, and ketonemia in mice. Using this model, we show...

Angptl4 does not control hyperglucagonemia or α-cell hyperplasia following glucagon receptor inhibition

Haruka Okamotoa, Katie Cavinoa, Erqian Naa, Elizabeth Krumma, Steven Kima, Panayiotis E. Stevisa, Joyce Harpa, Andrew J. Murphya, George D. Yancopoulosa, and Jesper Gromadaa PNAS January 31, 2017, doi:10.1073/pnas.1620989114  Abstract Genetic disruption or pharmacologic inhibition of glucagon signaling effectively lowers blood glucose but results in compensatory glucagon hypersecretion involving expansion of pancreatic α-cell mass. Ben-Zvi et al. recently reported that angiopoietin-like protein 4 (Angptl4) links glucagon receptor inhibition to hyperglucagonemia and α-cell proliferation [Ben-Zvi et al. (2015) Proc Natl Acad Sci USA 112:15498–15503]....

Neutrophils dominate the immune cell composition in non-small cell lung cancer

Julia Kargl, Stephanie E. Busch, Grace H. Y. Yang, Kyoung-Hee Kim, Mark L. Hanke, Heather E. Metz, Jesse J. Hubbard, Sylvia M. Lee, David K. Madtes, Martin W. McIntosh & A. McGarry Houghton Nature Communications 8, Article number: 14381, February 2017 Abstract The response rate to immune checkpoint inhibitor therapy for non-small-cell lung cancer (NSCLC) is just 20%. To improve this figure, several early phase clinical trials combining novel immunotherapeutics with immune checkpoint blockade have been initiated. Unfortunately, these trials have been designed without a...

Weight Perturbation Alters Leptin Signal Transduction in a Region-Specific Manner throughout the Brain

Michael V. Morabito, Yann Ravussin, Bridget R. Mueller, Alicja A. Skowronski, Kazuhisa Watanabe, Kylie S. Foo, Samuel X. Lee, Anders Lehmann, Stephan Hjorth, Lori M. Zeltser, Charles A. LeDuc, Rudolph L. Leibel PLOS One, January 20, 2017 Abstract Diet-induced obesity (DIO) resulting from consumption of a high fat diet (HFD) attenuates normal neuronal responses to leptin and may contribute to the metabolic defense of an acquired higher body weight in humans; the molecular bases for the persistence of this defense are unknown. We measured the...

Acetate Recapturing by Nuclear Acetyl-CoA Synthetase 2 Prevents Loss of Histone Acetylation during Oxygen and Serum Limitation

Vinay Bulusu, Sergey Tumanov, Evdokia Michalopoulou, Niels J. van den Broek, Gillian MacKay, Colin Nixon, Sandeep Dhayade, Zachary T. Schug, Johan Vande Voorde, Karen Blyth, Eyal Gottlieb, Alexei Vazquez, Jurre J. Kamphorst Cell Reports January 2017 Volume 18, Issue 3  Abstract Acetyl-CoA is a key metabolic intermediate with an important role in transcriptional regulation. The nuclear-cytosolic acetyl-CoA synthetase 2 (ACSS2) was found to sustain the growth of hypoxic tumor cells. It generates acetyl-CoA from acetate, but exactly which pathways it supports is not fully...

Differential Cytokine Gene Expression in Granulomas from Lungs and Lymph Nodes of Cattle Experimentally Infected with Aerosolized Mycobacterium bovis

Mitchell V. Palmer , Tyler C. Thacker ,W. Ray Waters Abstract The hallmark lesion of tuberculosis in humans and animals is the granuloma. The granuloma represents a distinct host cellular immune response composed of epithelioid macrophages, lymphocytes, and multinucleated giant cells, often surrounding a caseous necrotic core. Within the granuloma, host-pathogen interactions determine disease outcome. Factors within the granulomas such as cytokines and chemokines drive cell recruitment, activity, function and ultimately the success or failure of the host’s ability to control infection....

Use of the Fluidigm C1 platform for RNA sequencing of single mouse pancreatic islet cells

Yurong Xin, Jinrang Kim, Min Ni, Yi Wei, Haruka Okamoto, Joseph Lee, Christina Adler, Katie Cavino, Andrew J. Murphy, George D. Yancopoulos, Hsin Chieh Lin, and Jesper Gromada PNAS March 2016 vol. 113 no. 12 Abstract This study provides an assessment of the Fluidigm C1 platform for RNA sequencing of single mouse pancreatic islet cells. The system combines microfluidic technology and nanoliter-scale reactions. We sequenced 622 cells, allowing identification of 341 islet cells with high-quality gene expression profiles. The cells clustered into populations of α-cells (5%), β-cells (92%), δ-cells (1%), and pancreatic polypeptide...

Phosphorylation of calcium/calmodulin-stimulated protein kinase II at T286 enhances invasion and migration of human breast cancer cells

Mengna Chi, Hamish Evans, Jackson Gilchrist, Jack Mayhew, Alexander Hoffman, Elizabeth Ann Pearsall, Helen Jankowski, Joshua Stephen Brzozowski & Kathryn Anne Skelding Scientific Reports | Published September 8th, 2016 | DOI: 10.1038/srep33132 Calcium/calmodulin-stimulated protein kinase II (CaMKII) is a multi-functional kinase that controls a range of cellular functions, including proliferation, differentiation and apoptosis. The biological properties of CaMKII are regulated by multi-site phosphorylation. However, the role that CaMKII phosphorylation plays in cancer cell metastasis has not been examined. We demonstrate herein that...

Cutaneous wound healing through paradoxical MAPK activation by BRAF inhibitors

Helena Escuin-Ordinas, Shuoran Li, Michael W. Xie, Lu Sun, Willy Hugo, Rong Rong Huang, Jiang Jiao, Felipe Meira de-Faria, Susan Realegeno, Paige Krystofinski, Ariel Azhdam, Sara Marie D. Komenan, Mohammad Atefi, Begona Comin-Aunduix, Matteo Pellegrini, Alistar J Cochran, Robert Modlin, Harvey R Herschman, Roger S. Lo, William H. McBride, Tatiana Segura and Antoni Ribas Nature Communications | Published August 1st, 2016 | DOI: 10.1038/ncomms12348 BRAF inhibitors are highly effective therapies for the treatment of BRAFV600-mutated melanoma, with the main toxicity being a variety...

Exacerbated Experimental Colitis in TNFAIP8-Deficient Mice

Sun H, Lou Y, Porturas T, Morrissey S, Luo G, Qi J, Ruan Q, Shi S, Chen YH. J Immunol. 2015 Jun 15;194(12):5736-42. The TNF-α-induced protein 8 (TNFAIP8 or TIPE) is a risk factor for cancer and bacterial infection, and its expression is upregulated in a number of human cancers. However, its physiologic and pathologic functions are unclear. In this study, we describe the generation of TIPE-deficient mice and their increased sensitivity to colonic inflammation. TIPE-deficient mice were generated by germ...

Nerve fibers infiltrate the tumor microenvironment and are associated with nerve growth factor production and lymph node invasion in breast cancer

Pundavela J, Roselli S1, Faulkner S, Attia J, Scott RJ, Thorne RF, Forbes JF, Bradshaw RA, Walker MM, Jobling P, Hondermarck H. Mol Oncol. 2015 May 14. pii: S1574-7891(15)00115-5. Infiltration of the tumor microenvironment by nerve fibers is an understudied aspect of breast carcinogenesis. In this study, the presence of nerve fibers was investigated in a cohort of 369 primary breast cancers (ductal carcinomas in situ, invasive ductal and lobular carcinomas) by immunohistochemistry for the neuronal marker PGP9.5. Isolated nerve fibers (axons)...

ANGPTL8/betatrophin does not control pancreatic beta cell expansion

Gusarova V, Alexa CA, Na E, Stevis PE, Xin Y, Bonner-Weir S, Cohen JC, Hobbs HH, Murphy AJ, Yancopoulos GD, Gromada J. Cell. 2014 Oct 23;159(3):691-6. Recently, it was reported that angiopoietin-like protein 8 (ANGPTL8) was the long-sought "betatrophin" that could control pancreatic beta cell proliferation. However, studies of Angptl8(?/?) mice revealed profound reduction of triglyceride levels, but no abnormalities in glucose homeostasis. We now report that Angptl8(?/?) mice undergo entirely normal beta cell expansion in response to insulin resistance resulting from...

Islet-1 is essential for pancreatic beta cell function

Ediger BN, Du A, Liu J, Hunter CS, Walp ER, Schug J, Kaestner KH, Stein R, Stoffers DA, May CL. Diabetes. 2014 Dec;63(12):4206-17. Islet-1 (Isl-1) is essential for the survival and ensuing differentiation of pancreatic endocrine progenitors. Isl-1 remains expressed in all adult pancreatic endocrine lineages; however, its specific function in the postnatal pancreas is unclear. Here we determine whether Isl-1 plays a distinct role in the postnatal β-cell by performing physiological and morphometric analyses of a tamoxifen-inducible, β-cell-specific Isl-1 loss-of-function mouse:...

G-protein-independent coupling of MC4R to Kir7.1 in hypothalamic neurons

Ghamari-Langroudi M, Digby GJ, Sebag JA, Millhauser GL, Palomino R, Matthews R, Gillyard T, Panaro BL, Tough IR, Cox HM, Denton JS, Cone RD. Nature. 2015 Apr 2;520(7545):94-8. The regulated release of anorexigenic α-melanocyte stimulating hormone (α-MSH) and orexigenic Agouti-related protein (AgRP) from discrete hypothalamic arcuate neurons onto common target sites in the central nervous system has a fundamental role in the regulation of energy homeostasis. Both peptides bind with high affinity to the melanocortin-4 receptor (MC4R); existing data show that α-MSH...

Glucagon Receptor Blockade With a Human Antibody Normalizes Blood Glucose in Diabetic Mice and Monkeys

Okamoto H, Kim J, Aglione J1, Lee J, Cavino K, Na E1, Rafique A, Kim JH, Harp J, Valenzuela DM, Yancopoulos GD, Murphy AJ, Gromada J. Endocrinology. 2015 Aug;156(8):2781-94. Antagonizing glucagon action represents an attractive therapeutic option for reducing hepatic glucose production in settings of hyperglycemia where glucagon excess plays a key pathophysiological role. We therefore generated REGN1193, a fully human monoclonal antibody that binds and inhibits glucagon receptor (GCGR) signaling in vitro. REGN1193 administration to diabetic ob/ob and diet-induced obese...