Griffin Hartmann

All Publications

• Convergent olfactory circuits for courtship in Drosophila revealed by ds-Tango. bioRxiv : the preprint server for biology Fisher, J. D., Crown, A. M., Sorkaç, A., Martinez-Machado, S., Snell, N. J., Vishwanath, N., Monje, S., Vo, A., Wu, A. H., Moșneanu, R. A., Okoro, A. M., Savaş, D., Nkera, B., Iturralde, P., Kumari, A., Chou-Freed, C., Hartmann, G. G., Talay, M., Barnea, G. 2024

  Abstract

  Animals exhibit sex-specific behaviors that are governed by sexually dimorphic circuits. One such behavior in male Drosophila melanogaster, courtship, is regulated by various sensory modalities, including olfaction. Here, we reveal how sexually dimorphic olfactory pathways in male flies converge at the third-order, onto lateral horn output neurons, to regulate courtship. To achieve this, we developed ds-Tango, a modified version of the monosynaptic tracing and manipulation tool trans-Tango. In ds-Tango, two distinct configurations of trans-Tango are positioned in series, thus providing selective genetic access not only to the monosynaptic partners of starter neurons but also to their disynaptic connections. Using ds-Tango, we identified a node of convergence for three sexually dimorphic olfactory pathways. Silencing this node results in deficits in sex recognition of potential partners. Our results identify lateral horn output neurons required for proper courtship behavior in male flies and establish ds-Tango as a tool for disynaptic circuit tracing.

  View details for DOI 10.1101/2024.10.23.619891

  View details for PubMedID 39484479

  View details for PubMedCentralID PMC11527207

• Small-cell lung cancer neuronal features and their implications for tumor progression, metastasis, and therapy. Molecular cancer research : MCR Hartmann, G. G., Sage, J. 2024

  Abstract

  Small-cell lung cancer (SCLC) is an epithelial neuroendocrine form of lung cancer for which survival rates remain dismal and new therapeutic approaches are greatly needed. Key biological features of SCLC tumors include fast growth and widespread metastasis, as well as rapid resistance to treatment. Similar to pulmonary neuroendocrine cells, SCLC cells have traits of both hormone-producing cells and neurons. Here we specifically discuss the neuronal features of SCLC. We consider how neuronal G-protein-coupled receptors (GPCRs) and other neuronal molecules on the surface of SCLC cells can contribute to the growth of SCLC tumors and serve as therapeutic targets in SCLC. We also review recent evidence for the role of neuronal programs expressed by SCLC cells in the fast proliferation, migration, and metastasis of these cells. We further highlight how these neuronal programs may be particularly relevant for the development of brain metastases, and how they can assist SCLC cells to functionally interact with neurons and astrocytes. A greater understanding of the molecular and cellular neuronal features of SCLC is likely to uncover new vulnerabilities in SCLC cells, which may help develop novel therapeutic approaches. More generally, the epithelial-to-neuronal transition (ENT) observed during tumor progression in SCLC and other cancer types can contribute significantly to tumor development and response to therapy.

  View details for DOI 10.1158/1541-7786.MCR-24-0265

  View details for PubMedID 38912893

• An engineered interleukin-11 decoy cytokine inhibits receptor signaling and proliferation in lung adenocarcinoma. Bioengineering & translational medicine McIntosh, B. J., Hartmann, G. G., Yamada-Hunter, S. A., Liu, P., Williams, C. F., Sage, J., Cochran, J. R. 2023; 8 (6): e10573

  Abstract

  The cytokine interleukin (IL)-11 has been shown to play a role in promoting fibrosis and cancer, including lung adenocarcinoma, garnering interest as an attractive target for therapeutic intervention. We used combinatorial methods to engineer an IL-11 variant that binds with higher affinity to the IL-11 receptor and stimulates enhanced receptor-mediated cell signaling. Introduction of two additional point mutations ablates IL-11 ligand/receptor association with the gp130 coreceptor signaling complex, resulting in a high-affinity receptor antagonist. Unlike wild-type IL-11, this engineered variant potently blocks IL-11-mediated cell signaling and slows tumor growth in a mouse model of lung cancer. Our approach highlights a strategy where native ligands can be engineered and exploited to create potent receptor antagonists.

  View details for DOI 10.1002/btm2.10573

  View details for PubMedID 38023717

  View details for PubMedCentralID PMC10658506

• INTERNAL CAROTID INJECTION MODEL OF BRAIN METASTASIS DESCRIBES LEPTOMENINGEAL DISEASE Chernikova, S., Tsau, S., Wang, Y., Hartmann, G., Polyak, D., Bhambhvani, H., Kolluru, S., Thy Trinh, Casey, K., Johnson, E., Connolly, I., Recht, L., Ahn, G., Nagpal, S., Quake, S., Brown, J., Gephart, M. OXFORD UNIV PRESS INC. 2023

  View details for Web of Science ID 001115245401387

• Glioma synapses recruit mechanisms of adaptive plasticity. Nature Taylor, K. R., Barron, T., Hui, A., Spitzer, A., Yalcin, B., Ivec, A. E., Geraghty, A. C., Hartmann, G. G., Arzt, M., Gillespie, S. M., Kim, Y. S., Maleki Jahan, S., Zhang, H., Shamardani, K., Su, M., Ni, L., Du, P. P., Woo, P. J., Silva-Torres, A., Venkatesh, H. S., Mancusi, R., Ponnuswami, A., Mulinyawe, S., Keough, M. B., Chau, I., Aziz-Bose, R., Tirosh, I., Suva, M. L., Monje, M. 2023

  Abstract

  The role of the nervous system in the regulation of cancer is increasingly appreciated. In gliomas, neuronal activity drives tumour progression through paracrine signalling factors such as neuroligin-3 and brain-derived neurotrophic factor1-3 (BDNF), and also through electrophysiologically functional neuron-to-glioma synapses mediated by AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors4,5. The consequent glioma cell membrane depolarization drives tumour proliferation4,6. In the healthy brain, activity-regulated secretion of BDNF promotes adaptive plasticity of synaptic connectivity7,8 and strength9-15. Here we show that malignant synapses exhibit similar plasticity regulated by BDNF. Signalling through the receptor tropomyosin-related kinase B16 (TrkB) to CAMKII, BDNF promotes AMPA receptor trafficking to the glioma cell membrane, resulting in increased amplitude of glutamate-evoked currents in the malignant cells. Linking plasticity of glioma synaptic strength to tumour growth, graded optogenetic control of glioma membrane potential demonstrates that greater depolarizing current amplitude promotes increased glioma proliferation. This potentiation of malignant synaptic strength shares mechanistic features with synaptic plasticity17-22 that contributes to memory and learning in the healthy brain23-26. BDNF-TrkB signalling also regulates the number of neuron-to-glioma synapses. Abrogation of activity-regulated BDNF secretion from the brain microenvironment or loss of glioma TrkB expression robustly inhibits tumour progression. Blocking TrkB genetically or pharmacologically abrogates these effects of BDNF on glioma synapses and substantially prolongs survival in xenograft models of paediatric glioblastoma and diffuse intrinsic pontine glioma. Together, these findings indicate that BDNF-TrkB signalling promotes malignant synaptic plasticity and augments tumour progression.

  View details for DOI 10.1038/s41586-023-06678-1

  View details for PubMedID 37914930

• Crosstalk between small-cell lung cancer cells and astrocytes mimics brain development to promote brain metastasis. Nature cell biology Qu, F., Brough, S. C., Michno, W., Madubata, C. J., Hartmann, G. G., Puno, A., Drainas, A. P., Bhattacharya, D., Tomasich, E., Lee, M. C., Yang, D., Kim, J., Peiris-Pagès, M., Simpson, K. L., Dive, C., Preusser, M., Toland, A., Kong, C., Das, M., Winslow, M. M., Pasca, A. M., Sage, J. 2023

  Abstract

  Brain metastases represent an important clinical problem for patients with small-cell lung cancer (SCLC). However, the mechanisms underlying SCLC growth in the brain remain poorly understood. Here, using intracranial injections in mice and assembloids between SCLC aggregates and human cortical organoids in culture, we found that SCLC cells recruit reactive astrocytes to the tumour microenvironment. This crosstalk between SCLC cells and astrocytes drives the induction of gene expression programmes that are similar to those found during early brain development in neurons and astrocytes. Mechanistically, the brain development factor Reelin, secreted by SCLC cells, recruits astrocytes to brain metastases. These astrocytes in turn promote SCLC growth by secreting neuronal pro-survival factors such as SERPINE1. Thus, SCLC brain metastases grow by co-opting mechanisms involved in reciprocal neuron-astrocyte interactions during brain development. Targeting such developmental programmes activated in this cancer ecosystem may help prevent and treat brain metastases.

  View details for DOI 10.1038/s41556-023-01241-6

  View details for PubMedID 37783795

  View details for PubMedCentralID 6602095

• An engineered interleukin-1 decoy cytokine inhibits receptor signaling and proliferation in lung adenocarcinoma BIOENGINEERING & TRANSLATIONAL MEDICINE McIntosh, B. J., Hartmann, G. G., Yamada-Hunter, S. A., Liu, P., Williams, C. F., Sage, J., Cochran, J. R. 2023

  View details for DOI 10.1002/btm2.10573

  View details for Web of Science ID 001031916000001

• GLIOMA SYNAPSES RECRUIT MECHANISMS OF ADAPTIVE PLASTICITY Taylor, K., Barron, T., Zhang, H., Hui, A., Hartmann, G., Ni, L., Venkatesh, H., Du, P., Mancusi, R., Yalcin, B., Chau, I., Ponnuswami, A., Aziz-Bose, R., Monje, M. OXFORD UNIV PRESS INC. 2022: 25

  View details for Web of Science ID 000888571000100

• Complex representation of taste quality by second-order gustatory neurons in Drosophila CURRENT BIOLOGY Snell, N. J., Fisher, J. D., Hartmann, G. G., Zolyomi, B., Talay, M., Barnea, G. 2022; 32 (17): 3758-+

  Abstract

  Sweet and bitter compounds excite different sensory cells and drive opposing behaviors. However, it remains unclear how sweet and bitter tastes are represented by the neural circuits linking sensation to behavior. To investigate this question in Drosophila, we devised trans-Tango(activity), a strategy for calcium imaging of second-order gustatory projection neurons based on trans-Tango, a genetic transsynaptic tracing technique. We found spatial overlap between the projection neuron populations activated by sweet and bitter tastants. The spatial representation of bitter tastants in the projection neurons was consistent, while that of sweet tastants was heterogeneous. Furthermore, we discovered that bitter tastants evoke responses in the gustatory receptor neurons and projection neurons upon both stimulus onset and offset and that bitter offset and sweet onset excite overlapping second-order projections. These findings demonstrate an unexpected complexity in the representation of sweet and bitter tastants by second-order neurons of the gustatory circuit.

  View details for DOI 10.1016/j.cub.2022.07.048

  View details for Web of Science ID 000863328700001

  View details for PubMedID 35973432

  View details for PubMedCentralID PMC9474709

• Coordination of two enhancers drives expression of olfactory trace amine-associated receptors NATURE COMMUNICATIONS Fei, A., Wu, W., Tan, L., Tang, C., Xu, Z., Huo, X., Bao, H., Kong, Y., Johnson, M., Hartmann, G., Talay, M., Yang, C., Riegler, C., Herrera, K. J., Engert, F., Xie, X., Barnea, G., Liberles, S. D., Yang, H., Li, Q. 2021; 12 (1): 3798

  Abstract

  Olfactory sensory neurons (OSNs) are functionally defined by their expression of a unique odorant receptor (OR). Mechanisms underlying singular OR expression are well studied, and involve a massive cross-chromosomal enhancer interaction network. Trace amine-associated receptors (TAARs) form a distinct family of olfactory receptors, and here we find that mechanisms regulating Taar gene choice display many unique features. The epigenetic signature of Taar genes in TAAR OSNs is different from that in OR OSNs. We further identify that two TAAR enhancers conserved across placental mammals are absolutely required for expression of the entire Taar gene repertoire. Deletion of either enhancer dramatically decreases the expression probabilities of different Taar genes, while deletion of both enhancers completely eliminates the TAAR OSN populations. In addition, both of the enhancers are sufficient to drive transgene expression in the partially overlapped TAAR OSNs. We also show that the TAAR enhancers operate in cis to regulate Taar gene expression. Our findings reveal a coordinated control of Taar gene choice in OSNs by two remote enhancers, and provide an excellent model to study molecular mechanisms underlying formation of an olfactory subsystem.

  View details for DOI 10.1038/s41467-021-23823-4

  View details for Web of Science ID 000665041200004

  View details for PubMedID 34145235

  View details for PubMedCentralID PMC8213717

• MALIGNANT SYNAPTIC PLASTICITY IN PEDIATRIC HIGH-GRADE GLIOMAS Taylor, K., Barron, T., Hartmann, G., Zhang, H., Hui, A., Gillespie, S., Monje, M. OXFORD UNIV PRESS INC. 2021: 21

  View details for DOI 10.1093/neuonc/noab090.085

  View details for Web of Science ID 000671540600086

• Emergence of a High-Plasticity Cell State during Lung Cancer Evolution CANCER CELL Marjanovic, N., Hofree, M., Chan, J. E., Canner, D., Wu, K., Trakala, M., Hartmann, G. G., Smith, O. C., Kim, J. Y., Evans, K., Hudson, A., Ashenberg, O., Porter, C. M., Bejnood, A., Subramanian, A., Pitter, K., Yan, Y., Delorey, T., Phillips, D. R., Shah, N., Chaudhary, O., Tsankov, A., Hollmann, T., Rekhtman, N., Massion, P. P., Poirier, J. T., Mazutis, L., Li, R., Lee, J., Amon, A., Rudin, C. M., Jacks, T., Regev, A., Tammela, T. 2020; 38 (2): 229-+

  Abstract

  Tumor evolution from a single cell into a malignant, heterogeneous tissue remains poorly understood. Here, we profile single-cell transcriptomes of genetically engineered mouse lung tumors at seven stages, from pre-neoplastic hyperplasia to adenocarcinoma. The diversity of transcriptional states increases over time and is reproducible across tumors and mice. Cancer cells progressively adopt alternate lineage identities, computationally predicted to be mediated through a common transitional, high-plasticity cell state (HPCS). Accordingly, HPCS cells prospectively isolated from mouse tumors and human patient-derived xenografts display high capacity for differentiation and proliferation. The HPCS program is associated with poor survival across human cancers and demonstrates chemoresistance in mice. Our study reveals a central principle underpinning intra-tumoral heterogeneity and motivates therapeutic targeting of the HPCS.

  View details for DOI 10.1016/j.ccell.2020.06.012

  View details for Web of Science ID 000559591600011

  View details for PubMedID 32707077

  View details for PubMedCentralID PMC7745838

• Transsynaptic Mapping of Second-Order Taste Neurons in Flies by trans-Tango NEURON Talay, M., Richman, E. B., Snell, N. J., Hartmann, G. G., Fisher, J. D., Sorkac, A., Santoyo, J. F., Chou-Freed, C., Nair, N., Johnson, M., Szymanski, J. R., Barnea, G. 2017; 96 (4): 783-+

  Abstract

  Mapping neural circuits across defined synapses is essential for understanding brain function. Here we describe trans-Tango, a technique for anterograde transsynaptic circuit tracing and manipulation. At the core of trans-Tango is a synthetic signaling pathway that is introduced into all neurons in the animal. This pathway converts receptor activation at the cell surface into reporter expression through site-specific proteolysis. Specific labeling is achieved by presenting a tethered ligand at the synapses of genetically defined neurons, thereby activating the pathway in their postsynaptic partners and providing genetic access to these neurons. We first validated trans-Tango in the Drosophila olfactory system and then implemented it in the gustatory system, where projections beyond the first-order receptor neurons are not fully characterized. We identified putative second-order neurons within the sweet circuit that include projection neurons targeting known neuromodulation centers in the brain. These experiments establish trans-Tango as a flexible platform for transsynaptic circuit analysis.

  View details for DOI 10.1016/j.neuron.2017.10.011

  View details for Web of Science ID 000415310800011

  View details for PubMedID 29107518

  View details for PubMedCentralID PMC5693608