Multiomic characterization of pancreatic cancer-associated macrophage polarization reveals deregulated metabolic programs driven by the GM-CSF-PI3K pathway
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Abstract
The pancreatic ductal adenocarcinoma microenvironment is composed of a variety of cell types and marked by extensive fibrosis and inflammation. Tumor-associated macrophages (TAMs) are abundant, and they are important mediators of disease progression and invasion. TAMs are polarized in situ to a tumor promoting and immunosuppressive phenotype via cytokine signaling and metabolic crosstalk from malignant epithelial cells and other components of the tumor microenvironment. However, the specific distinguishing features and functions of TAMs remain poorly defined. Here, we generated tumor-educated macrophages (TEMs) in vitro and performed detailed, multiomic characterization (i.e., transcriptomics, proteomics, metabolomics). Our results reveal unique genetic and metabolic signatures of TEMs, the veracity of which were queried against our in-house single-cell RNA sequencing dataset of human pancreatic tumors. This analysis identified expression of novel, metabolic TEM markers in human pancreatic TAMs, including ARG1, ACLY, and TXNIP. We then utilized our TEM model system to study the role of mutant Kras signaling in cancer cells on TEM polarization. This revealed an important role for granulocyte–macrophage colony-stimulating factor (GM-CSF) and lactate on TEM polarization, molecules released from cancer cells in a mutant Kras-dependent manner. Lastly, we demonstrate that GM-CSF dysregulates TEM gene expression and metabolism through PI3K–AKT pathway signaling. Collectively, our results define new markers and programs to classify pancreatic TAMs, how these are engaged by cancer cells, and the precise signaling pathways mediating polarization.
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Deoxycytidine can also be released from CAFs.
“Deoxycytidine can also be released from CAFs259”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [259]
Both TAM- and CAF-released deoxycytidine inhibit gemcitabine efficacy through molecular competition at deoxycytidine kinase.
“both TAM and CAF-released deoxycytidine act to inhibit the efficacy of gemcitabine through molecular competition at deoxycytidine kinase258,259”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [259]
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Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625 · see citing works
Siegel, R. L., Miller, K. D., & Jemal, A. (2020) · CA: A Cancer Journal for Clinicians · doi:10.3322/caac.21590 · Cited by 20,444 · see citing works
Szklarczyk, D., Gable, A. L., Lyon, D., Junge, A., Wyder, S., Huerta-Cepas, J., Simonovic, M., Doncheva, N. T., Morris, J. H., Bork, P., et al. (2019) · Nucleic Acids Research · doi:10.1093/nar/gky1131 · Cited by 17,749 · see citing works
Mootha, V. K., Lindgren, C. M., Eriksson, K.-F., Subramanian, A., Sihag, S., Lehar, J., Puigserver, P., Carlsson, E., Ridderstråle, M., Laurila, E., et al. (2003) · Nature Genetics · doi:10.1038/ng1180 · Cited by 10,197 · see citing works
Macrophage Diversity Enhances Tumor Progression and Metastasis
Qian, B., & Pollard, J. W. (2010) · Cell · doi:10.1016/j.cell.2010.03.014 · Cited by 5,208 · see citing works
Metabolic regulation of gene expression by histone lactylation
Zhang, D., Tang, Z., Huang, H., Zhou, G., Cui, C., Weng, Y., Liu, W., Kim, S., Lee, S., Perez-Neut, M., et al. (2019) · Nature · doi:10.1038/s41586-019-1678-1 · Cited by 4,371 · see citing works
MetaboAnalyst 5.0: narrowing the gap between raw spectra and functional insights
Pang, Z., Chong, J., Zhou, G., Morais, D. A. D. L., Chang, L., Barrette, M., Gauthier, C., Jacques, P., Li, S., & Xia, J. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab382 · Cited by 3,972 · see citing works
Gene set knowledge discovery with enrichr
Xie, Z., Bailey, A., Kuleshov, M. V., Clarke, D. J. B., Evangelista, J. E., Jenkins, S. L., Lachmann, A., Wojciechowicz, M. L., Kropiwnicki, E., Jagodnik, K. M., et al. (2021) · Current Protocols · doi:10.1002/cpz1.90 · Cited by 3,451 · see citing works
Functional Polarization of Tumour-Associated Macrophages by Tumour-Derived Lactic Acid
Colegio, O. R., Chu, N.-Q., Szabo, A. L., Chu, T., Rhebergen, A. M., Jairam, V., Cyrus, N., Brokowski, C. E., Eisenbarth, S. C., Phillips, G. M., et al. (2014) · Nature · doi:10.1038/nature13490 · Cited by 3,046 · see citing works
Murray, P. J. (2017) · Annual Review of Physiology · doi:10.1146/annurev-physiol-022516-034339 · Cited by 2,981 · see citing works
MSFragger: ultrafast and comprehensive peptide identification in mass spectrometry–based proteomics
Kong, A. T., Leprevost, F. D. V., Avtonomov, D. M., Mellacheruvu, D., & Nesvizhskii, A. I. (2017) · Nature Methods · doi:10.1038/nmeth.4256 · Cited by 2,344 · see citing works
Self-citationEMT and Dissemination Precede Pancreatic Tumor Formation
Rhim, A. D., Mirek, E. T., Aiello, N. M., Maitra, A., Bailey, J. M., McAllister, F., Reichert, M., Beatty, G. L., Rustgi, A. K., Vonderheide, R. H., et al. (2012) · Cell · doi:10.1016/j.cell.2011.11.025 · Cited by 2,136 · see citing works
Jha, A. K., Huang, S. C.-C., Sergushichev, A., Lampropoulou, V., Ivanova, Y., Loginicheva, E., Chmielewski, K., Stewart, K. M., Ashall, J., Everts, B., et al. (2015) · Immunity · doi:10.1016/j.immuni.2015.02.005 · Cited by 2,066 · see citing works
Orecchioni, M., Ghosheh, Y., Pramod, A. B., & Ley, K. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01084 · Cited by 2,063 · see citing works
Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism
Ying, H., Kimmelman, A. C., Lyssiotis, C. A., Hua, S., Chu, G. C., Fletcher-Sananikone, E., Locasale, J. W., Son, J., Zhang, H., Coloff, J. L., et al. (2012) · Cell · doi:10.1016/j.cell.2012.01.058 · Cited by 2,043 · see citing works
Self-citationZhu, Y., Knolhoff, B. L., Meyer, M. A., Nywening, T. M., West, B. L., Luo, J., Wang-Gillam, A., Goedegebuure, S. P., Linehan, D. C., & DeNardo, D. G. (2014) · Cancer Research · doi:10.1158/0008-5472.can-13-3723 · Cited by 1,324 · see citing works
The Pancreas Cancer Microenvironment
Feig, C., Gopinathan, A., Neesse, A., Chan, D. S., Cook, N., & Tuveson, D. A. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-3114 · Cited by 1,316 · see citing works
Bayne, L. J., Beatty, G. L., Jhala, N., Clark, C. E., Rhim, A. D., Stanger, B. Z., & Vonderheide, R. H. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.04.025 · Cited by 947 · see citing works
Kamphorst, J. J., Nofal, M., Commisso, C., Hackett, S. R., Lu, W., Grabocka, E., Vander Heiden, M. G., Miller, G., Drebin, J. A., Bar-Sagi, D., et al. (2015) · Cancer Research · doi:10.1158/0008-5472.can-14-2211 · Cited by 893 · see citing works
Zhu, Y., Herndon, J. M., Sojka, D. K., Kim, K.-W., Knolhoff, B. L., Zuo, C., Cullinan, D. R., Luo, J. R., Bearden, A. R., Lavine, K. J., et al. (2017) · Immunity · doi:10.1016/j.immuni.2017.07.014 · Cited by 799 · see citing works
Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice
Collins, M. A., Bednar, F., Zhang, Y., Brisset, J.-C., Galbán, S., Galbán, C. J., Rakshit, S., Flannagan, K. S., Adsay, N. V., & Pasca di Magliano, M. (2012) · Journal of Clinical Investigation · doi:10.1172/jci59227 · Cited by 770 · see citing works
Self-citationOncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia
Pylayeva-Gupta, Y., Lee, K. E., Hajdu, C. H., Miller, G., & Bar-Sagi, D. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.04.024 · Cited by 721 · see citing works
Cancer-related inflammation: Common themes and therapeutic opportunities
Balkwill, F. R., & Mantovani, A. (2011) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2011.12.005 · Cited by 685 · see citing works
AMPK-Dependent Degradation of TXNIP upon Energy Stress Leads to Enhanced Glucose Uptake via GLUT1
Wu, N., Zheng, B., Shaywitz, A. J., Dagon, Y., Tower, C., Bellinger, G., Shen, C., Wen, J., Asara, J. M., McGraw, T. E., et al. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.01.035 · Cited by 665 · see citing works
Philosopher: a versatile toolkit for shotgun proteomics data analysis
Leprevost, F. D. V., Haynes, S. E., Avtonomov, D. M., Chang, H.-Y., Shanmugam, A. K., Mellacheruvu, D., Kong, A. T., & Nesvizhskii, A. I. (2020) · Nature Methods · doi:10.1038/s41592-020-0912-y · Cited by 618 · see citing works
Self-citationATP-Citrate Lyase: A Key Player in Cancer Metabolism
Zaidi, N., Swinnen, J. V., & Smans, K. A. (2012) · Cancer Research · doi:10.1158/0008-5472.can-11-4112 · Cited by 549 · see citing works
Multimodal mapping of the tumor and peripheral blood immune landscape in human pancreatic cancer
Steele, N. G., Carpenter, E. S., Kemp, S. B., Sirihorachai, V. R., The, S., Delrosario, L., Lazarus, J., Amir, E.-A. D., Gunchick, V., Espinoza, C. E., et al. (2020) · Nature Cancer · doi:10.1038/s43018-020-00121-4 · Cited by 546 · see citing works
Self-citationEvidence for a gamma-interferon receptor that regulates macrophage tumoricidal activity.
Celada, A., Gray, P. W., Rinderknecht, E., & Schreiber, R. D. (1984) · The Journal of Experimental Medicine · doi:10.1084/jem.160.1.55 · Cited by 465 · see citing works
Akt-mTORC1 signaling regulates Acly to integrate metabolic input to control of macrophage activation
Covarrubias, A. J., Aksoylar, H., Yu, J., Snyder, N. W., Worth, A. J., Iyer, S. S., Wang, J., Ben‐Sahra, I., Byles, V., Polynne-Stapornkul, T., et al. (2016) · eLife · doi:10.7554/elife.11612 · Cited by 455 · see citing works
Self-citationMacrophage-Released Pyrimidines Inhibit Gemcitabine Therapy in Pancreatic Cancer
Halbrook, C. J., Pontious, C., Kovalenko, I., Lapienyte, L., Dreyer, S., Lee, H.-J., Thurston, G., Zhang, Y., Lazarus, J., Sajjakulnukit, P., et al. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.02.001 · Cited by 419 · see citing works
Self-citationThe CCL5/CCR5 Axis in Cancer Progression
Aldinucci, D., Borghese, C., & Casagrande, N. (2020) · Cancers · doi:10.3390/cancers12071765 · Cited by 413 · see citing works
Zhang, Y., Lazarus, J., Steele, N. G., Yan, W., Lee, H.-J., Nwosu, Z. C., Halbrook, C. J., Menjivar, R. E., Kemp, S. B., Sirihorachai, V. R., et al. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-0958 · Cited by 385 · see citing works
Self-citationOncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation
Tape, C. J., Ling, S., Dimitriadi, M., McMahon, K. M., Worboys, J. D., Leong, H. S., Norrie, I. C., Miller, C. J., Poulogiannis, G., Lauffenburger, D. A., et al. (2016) · Cell · doi:10.1016/j.cell.2016.03.029 · Cited by 369 · see citing works
Zhang, Y., Velez-Delgado, A., Mathew, E., Li, D., Mendez, F., Flannagan, K., Rhim, A. D., Simeone, D. M., Beatty, G. L., & di Magliano, M. P. (2016) · Gut · doi:10.1136/gutjnl-2016-312078 · Cited by 338 · see citing works
Self-citationBeatty, G. L., Winograd, R., Evans, R. A., Long, K. B., Luque, S. L., Lee, J. W., Clendenin, C. J., Gladney, W. L., Knoblock, D. M., Guirnalda, P. D., et al. (2015) · Gastroenterology · doi:10.1053/j.gastro.2015.04.010 · Cited by 293 · see citing works
Fibroblast Heterogeneity in the Pancreatic Tumor Microenvironment
Helms, E. J., Oñate, M. K., & Sherman, M. H. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-1353 · Cited by 283 · see citing works
Caro, G. D., Cortese, N., Castino, G. F., Grizzi, F., Gavazzi, F., Ridolfi, C., Capretti, G. L., Mineri, R., Todoric, J., Zerbi, A., et al. (2015) · Gut · doi:10.1136/gutjnl-2015-309193 · Cited by 275 · see citing works
Arg1 expression defines immunosuppressive subsets of tumor-associated macrophages
Arlauckas, S., Garren, S. B., Garris, C. S., Kohler, R., Oh, J., Pittet, M., & Weissleder, R. (2018) · Theranostics · doi:10.7150/thno.26888 · Cited by 273 · see citing works
Candido, J. B., Morton, J. P., Bailey, P., Campbell, A. D., Karim, S. A., Jamieson, T., Lapienyte, L., Gopinathan, A., Clark, W., McGhee, E. J., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.03.131 · Cited by 224 · see citing works
Samuvel, D. J., Sundararaj, K. P., Nareika, A., Lopes-Virella, M. F., & Huang, Y. Q. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0802059 · Cited by 220 · see citing works
Binnemars‐Postma, K., Bansal, R., Storm, G., & Prakash, J. (2017) · The FASEB Journal · doi:10.1096/fj.201700629r · Cited by 186 · see citing works
Lactate and IL6 define separable paths of inflammatory metabolic adaptation
Dichtl, S., Lindenthal, L., Zeitler, L., Behnke, K., Schlösser, D., Strobl, B., Scheller, J., Kasmi, K. C. E., & Murray, P. J. (2021) · Science Advances · doi:10.1126/sciadv.abg3505 · Cited by 163 · see citing works
Lehtonen, A., Matikainen, S., Miettinen, M., & Julkunen, I. (2002) · Journal of Leukocyte Biology · doi:10.1189/jlb.71.3.511 · Cited by 151 · see citing works
Acidity promotes tumour progression by altering macrophage phenotype in prostate cancer
El-Kenawi, A., Gatenbee, C., Robertson‐Tessi, M., Bravo, R., Dhillon, J., Balagurunathan, Y., Berglund, A., Vishvakarma, N. K., Ibrahim‐Hashim, A., Choi, J. W., et al. (2019) · British Journal of Cancer · doi:10.1038/s41416-019-0542-2 · Cited by 147 · see citing works
Djomehri, S. I., Gonzalez, M. E., Leprevost, F. D. V., Tekula, S. R., Chang, H.-Y., White, M. J., Cimino‐Mathews, A., Burman, B., Basrur, V., Argani, P., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-15283-z · Cited by 144 · see citing works
Self-citationGM-CSF-Dependent Inflammatory Pathways
Hamilton, J. A. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02055 · Cited by 141 · see citing works
Macrophage ATP citrate lyase deficiency stabilizes atherosclerotic plaques
Baardman, J., Verberk, S. G. S., van der Velden, S., Gijbels, M. J., van Roomen, C. P. A. A., Sluimer, J. C., Broos, J. Y., Griffith, G. R., Prange, K. H. M., van Weeghel, M., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-20141-z · Cited by 127 · see citing works
Zhan, Y., Lew, A. M., & Chopin, M. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02679 · Cited by 87 · see citing works
Lee, H., Kremer, D. M., Sajjakulnukit, P., Zhang, L., & Lyssiotis, C. A. (2019) · Metabolomics · doi:10.1007/s11306-019-1564-8 · Cited by 81 · see citing works
Self-citationChen, J., Huang, J., Luo, B., Dong, S., Wang, R., Jiang, Z., Xie, Y.-K., Yi, W., Wen, G., & Zhong, J. (2019) · Cancer Science · doi:10.1111/cas.13931 · Cited by 70 · see citing works
Strategies for discovering novel pancreatic cancer biomarkers
Chan, A., Diamandis, E. P., & Blasutig, I. M. (2012) · Journal of Proteomics · doi:10.1016/j.jprot.2012.09.025 · Cited by 59 · see citing works
Jost, M. M., Ninci, E., Meder, B., Kempf, C., van Royen, N., Hua, J., Berger, B. J., Hoefer, I. E., Modolell, M., & Buschmann, I. R. (2003) · The FASEB Journal · doi:10.1096/fj.03-0071fje · Cited by 59 · see citing works
Park, M.-Y., Lim, B.-G., Kim, S., Sohn, H., Kim, S., & Kim, T. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00183 · Cited by 57 · see citing works
Lee, H., Jedrychowski, M. P., Vinayagam, A., Wu, N., Shyh‐Chang, N., Hu, Y., Min-Wen, C., Moore, J. K., Asara, J. M., Lyssiotis, C. A., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.06.074 · Cited by 49 · see citing works
Self-citationPancreatic Fibroblast Heterogeneity: From Development to Cancer
Garcia, P. E., Scales, M. K., Allen, B. L., & di Magliano, M. P. (2020) · Cells · doi:10.3390/cells9112464 · Cited by 46 · see citing works
Tumor-associated macrophage polarization promotes the progression of esophageal carcinoma
Yuan, X., Li, Y., Zhang, A. Z., Jiang, C. H., Li, F. P., Xie, Y., Li, J. F., Liang, W. H., Zhang, H. J., Liu, C. X., et al. (2020) · Aging · doi:10.18632/aging.202201 · Cited by 42 · see citing works
Thudium, K. E., Wollenberg, L. A., Mavis, C. K., Czuczman, M. S., Fetterly, G. J., & Hernandez‐Ilizaliturri, F. J. (2012) · Cancer Research · doi:10.1158/1538-7445.am2012-3709 · Cited by 8 · see citing works
Flagged first, then by citations
1 of the 58 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Pancreatic cancer: Advances and challenges
Halbrook, C. J., Lyssiotis, C. A., Pasca di Magliano, M., & Maitra, A. (2023) · Cell · doi:10.1016/j.cell.2023.02.014 · Cited by 1,321 · see citing works
Self-citationTherapeutic targeting of tumour myeloid cells
Barry, S. T., Gabrilovich, D. I., Sansom, O. J., Campbell, A. D., & Morton, J. P. (2023) · Nature Reviews Cancer · doi:10.1038/s41568-022-00546-2 · Cited by 305 · see citing works
Current and future immunotherapeutic approaches in pancreatic cancer treatment
Farhangnia, P., Khorramdelazad, H., Nickho, H., & Delbandi, A. (2024) · Journal of Hematology & Oncology · doi:10.1186/s13045-024-01561-6 · Cited by 247 · see citing works
Arginase 1 is a key driver of immune suppression in pancreatic cancer
Menjivar, R. E., Nwosu, Z. C., Du, W., Donahue, K. L., Hong, H. S., Espinoza, C. E., Brown, K. L., Velez-Delgado, A., Yan, W., Lima, F., et al. (2023) · eLife · doi:10.7554/elife.80721 · Cited by 180 · see citing works
Self-citationLinking macrophage metabolism to function in the tumor microenvironment
Jin, R., Neufeld, L. A., & McGaha, T. L. (2025) · Nature Cancer · doi:10.1038/s43018-025-00909-2 · Cited by 173 · see citing works
Barriers and opportunities for gemcitabine in pancreatic cancer therapy
Beutel, A. K., & Halbrook, C. J. (2023) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00331.2022 · Cited by 150 · see citing works
Self-citationQian, Y., Yin, Y., Zheng, X., Liu, Z., & Wang, X. (2024) · Biomarker Research · doi:10.1186/s40364-023-00549-7 · Cited by 115 · see citing works
Halbrook, C. J., Thurston, G., Boyer, S., Anaraki, C., Jiménez, J. A., McCarthy, A., Steele, N. G., Kerk, S. A., Hong, H. S., Lin, L., et al. (2022) · Nature Cancer · doi:10.1038/s43018-022-00463-1 · Cited by 80 · see citing works
Self-citationDeng, J., Pan, T., Liu, Z., McCarthy, C., Vicencio, J. M., Cao, L., Alfano, G., Suwaidan, A. A., Yin, M., Beatson, R., et al. (2023) · British Journal of Cancer · doi:10.1038/s41416-023-02442-4 · Cited by 76 · see citing works
Li, X., Peng, X., Zhang, C., Bai, X., Li, Y., Chen, G., Guo, H., He, W., Zhou, X., & Gou, X. (2022) · Advanced Science · doi:10.1002/advs.202202993 · Cited by 51 · see citing works
The immunometabolic ecosystem in cancer
Bantug, G. R., & Hess, C. (2023) · Nature Immunology · doi:10.1038/s41590-023-01675-y · Cited by 51 · see citing works
Macrophage-derived SHP-2 inhibits the metastasis of colorectal cancer via Tie2-PI3K signals
Wu, X., Guan, S., Lu, Y., XUE, J., Yu, X., Zhang, Q., Wang, X., & LI, T. (2023) · Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics · doi:10.32604/or.2023.028657 · Cited by 41 · see citing works
Yang, S., Wang, M., Hua, Y., Li, J., Zheng, H., Cui, M., Huang, N., Liu, Q., & Liao, Q. (2024) · Cancer Letters · doi:10.1016/j.canlet.2024.216610 · Cited by 43 · see citing works
Emergency myelopoiesis in solid cancers
Aliazis, K., Yenyuwadee, S., Phikulsod, P., & Boussiotis, V. A. (2024) · British Journal of Haematology · doi:10.1111/bjh.19656 · Cited by 32 · see citing works
Liu, R., Li, J., Liu, L., Wang, W., & Jia, J. (2024) · Cancer Pathogenesis and Therapy · doi:10.1016/j.cpt.2024.07.004 · Cited by 31 · see citing works
He, X., Wang, L., Li, H., Liu, Y., Tong, C., Xie, C., Yan, X., Luo, D., & Xiong, X. (2023) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjad025 · Cited by 26 · see citing works
The 2023 Report on the Proteome from the HUPO Human Proteome Project
Omenn, G. S., Lane, L., Overall, C. M., Lindskog, C., Pineau, C., Packer, N. H., Cristea, I. M., Weintraub, S. T., Orchard, S. E., Roehrl, M. H. A., et al. (2024) · Journal of Proteome Research · doi:10.1021/acs.jproteome.3c00591 · Cited by 26 · see citing works
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Filiberti, S., Russo, M., Lonardi, S., Bugatti, M., Vermi, W., Tournier, C., & Giurisato, E. (2022) · Biomedicines · doi:10.3390/biomedicines10112709 · Cited by 22 · see citing works
TNFR1 signaling promotes pancreatic tumor growth by limiting dendritic cell number and function
Alam, M. S., Gaida, M. M., Witzel, H. R., Otsuka, S., Abbasi, A. J., Guerin, T. M., Abdelmaksoud, A. A., Wong, N. W., Cam, M., Kozlov, S., et al. (2024) · Cell Reports Medicine · doi:10.1016/j.xcrm.2024.101696 · Cited by 21 · see citing works
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Zou, J. P., Wang, S., Zhang, Y., Tian, W., Mai, G., Xu, Y., Xiao, W., Graves, E. E., & Wu, F. (2025) · Chinese Journal of Cancer Research · doi:10.21147/j.issn.1000-9604.2025.03.12 · Cited by 20 · see citing works
Self-citationLin, H.-J. L., Liu, Y., Caroland, K. P., & Lin, J. (2023) · Cancers · doi:10.3390/cancers15133507 · Cited by 19 · see citing works
Gelbach, P. E., & Finley, S. D. (2023) · iScience · doi:10.1016/j.isci.2023.107569 · Cited by 16 · see citing works
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Szczepanski, J. M., Rudolf, M. A., & Shi, J. (2024) · Cancers · doi:10.3390/cancers16040794 · Cited by 13 · see citing works
Early cellular and molecular signatures correlate with severity of West Nile virus infection
Lee, H., Zhao, Y., Fleming, I., Mehta, S. S., Wang, X., Wyk, B. V., Ronca, S. E., Kang, H. A., Chou, C., Fatou, B., et al. (2023) · iScience · doi:10.1016/j.isci.2023.108387 · Cited by 11 · see citing works
Self-citationMetabolic Reprogramming of Breast Tumor-Educated Macrophages Revealed by NMR Metabolomics
Dias, A. S., Almeida, C. R., Helguero, L. A., & Duarte, I. F. (2023) · Cancers · doi:10.3390/cancers15041211 · Cited by 11 · see citing works
Fu, Y., Li, M., Wu, S., Wang, J., & Wang, S. (2026) · Cell Death and Disease · doi:10.1038/s41419-026-08685-2 · Cited by 10 · see citing works
Precision immune regulation in KRAS-mutated cancers: the final piece of the puzzle?
Fu, S., Ma, J., Cai, C., Tan, J., Deng, X., Shen, H., Zeng, S., Chen, Y., & Han, Y. (2025) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-025-03444-1 · Cited by 11 · see citing works
Zhu, T., Wu, X., Liao, Y., Yan, Y., Yu, M., Wang, L., & Xia, Q. (2023) · Clinical Cancer Bulletin · doi:10.1007/s44272-023-00005-5 · Cited by 8 · see citing works
MIRTH: Metabolite Imputation via Rank-Transformation and Harmonization
Freeman, B., Jaro, S., Park, T., Keene, S. M., Tansey, W., & Reznik, E. (2022) · Genome biology · doi:10.1186/s13059-022-02738-3 · Cited by 9 · see citing works
The Long Noncoding RNA Gm9866/Nuclear Factor-κB Axis Promotes Macrophage Polarization
Liao, X., Ruan, X., Chen, X., Zheng, B., Wu, X., Deng, Z., Yang, Z., Wang, F., Qin, S., & Jiang, H. (2023) · Mediators of Inflammation · doi:10.1155/2023/9991916 · Cited by 7 · see citing works
Diabetic Ferroptosis and Pancreatic Cancer: Foe or Friend?
Li, L., Yu, X., Gao, L., Cheng, L., Sun, B., & Wang, G. (2022) · Antioxidants and Redox Signaling · doi:10.1089/ars.2022.0101 · Cited by 7 · see citing works
García‐Domínguez, M. (2025) · Life · doi:10.3390/life15111737 · Cited by 6 · see citing works
Bahng, I. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1713123 · Cited by 6 · see citing works
Systematic analysis of TREM2 and its carcinogenesis in pancreatic cancer
Zheng, W., Yu, W., Hua, R., He, J., Wu, N., Tian, S., Huang, W., & Qin, L. (2024) · Translational Cancer Research · doi:10.21037/tcr-24-201 · Cited by 6 · see citing works
Advancement of single-cell sequencing for clinical diagnosis and treatment of pancreatic cancer
Zhang, K., Chen, Y., Zhu, J., Ge, X., Wu, J., Xu, P., & Yao, J. J. (2023) · Frontiers in Medicine · doi:10.3389/fmed.2023.1213136 · Cited by 6 · see citing works
Sheinin, M., Mondal, S., & Pahan, K. (2023) · Cancers · doi:10.3390/cancers15245796 · Cited by 6 · see citing works
Dual-Specificity Phosphatases in Regulation of Tumor-Associated Macrophage Activity
Patysheva, M. R., Prostakishina, E. A., Budnitskaya, A. A., Дмитриевна, Б. О., & Kzhyshkowska, J. G. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242417542 · Cited by 5 · see citing works
Wang, M., Yang, X., Zhang, Q., Qiu, Y., Qu, J., Xu, H., & Li, Q. (2025) · Phytomedicine · doi:10.1016/j.phymed.2025.157325 · Cited by 3 · see citing works
Foglia, B., Nurcis, J., Signorini, M., & Cannito, S. (2026) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2026.1823145 · Cited by 3 · see citing works
GOT1 Inhibition Induces Extracellular Matrix Remodeling in Pancreatic Cancer
Curvello, R., Hauser, S., Seifert, M., Barlow, C. K., Steele, J. R., Salisbury, E., Croagh, D. G., Stok, K. S., Taubenberger, A. V., Schittenhelm, R. B., et al. (2026) · Advanced Science · doi:10.1002/advs.202516578 · Cited by 4 · see citing works
Liu, Z., Zhang, Y., & Wu, C. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.115664 · Cited by 2 · see citing works
Self-citationMachine learning identifies 6-gene signature in peripheral blood for pancreatic cancer diagnosis
Carrillo‐Pérez, F., Caba, O., Jiménez‐Luna, C., Ortuño, F. M., Castillo-Secilla, D., Herrera, L. J., Prados, J. C., & Rojas, I. (2025) · Heliyon · doi:10.1016/j.heliyon.2025.e43138 · Cited by 2 · see citing works
New insights into the ACLY-mediated metabolic and epigenetic interplay in macrophages
Yuan, L., Wang, T., Song, Y., 郭鹏, Zhu, Y., Cao, Y., Song, B., & Yu, Z. (2026) · Journal of Enzyme Inhibition and Medicinal Chemistry · doi:10.1080/14756366.2026.2689852 · Cited by 1 · see citing works
FAM53B promotes pancreatic ductal adenocarcinoma metastasis by regulating macrophage M2 polarization
Pei, X., Cai, M., Jiang, D., Chen, S.-H., Wang, Q., Lu, H., & Lu, Y. (2024) · World Journal of Gastrointestinal Oncology · doi:10.4251/wjgo.v16.i4.1479 · Cited by 1 · see citing works
Carrillo‐Pérez, F., Caba, O., Jiménez‐Luna, C., Ortuño, F. M., Castillo-Secilla, D., Herrera, L. J., Prados, J. C., & Rojas, I. (2023) · Research Square · doi:10.21203/rs.3.rs-3067425/v1
Chen, Z., Guan, D., Wang, Y., & Gou, Y. (2025) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2025.06.004
Zhang, Y., Kadiyala, P., Yan, W., Brown, K. L., Avritt, F. R., Donahue, K. L., Procario, M. C., Okoye, J. O., Giridharan, T., Elhossiny, A. M., et al. (2026) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-25-1300
Self-citationKalli, M., Stylianou, C., Georgiou, S., Voutouri, C., Michael, C., Kyriakou, S., Himonas, E., Mpekris, F., Tornovsky-Babeay, S., Egudkin, A., et al. (2026) · Cellular and Molecular Bioengineering · doi:10.1007/s12195-026-00912-2
Shen, S., Chen, K., Li, L., Jiang, M., Jia, Y., Bai, X., Zeng, Z., Ma, C., Dang, Y., Hu, K., et al. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1799536
孙宏实, Wang, J., Xie, Z., Yang, Z., & Yang, T. (2026) · Journal of Physiology and Biochemistry · doi:10.1007/s13105-026-01230-x
Hou, Y., & Tan, Z. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1942345
- Authors
- Boyer, S., Lee, H.-J., Steele, N., Zhang, L., Sajjakulnukit, P., Andren, A., Ward, M. H., Singh, R., Basrur, V., Zhang, Y., Nesvizhskii, A. I., Pasca di Magliano, M., Halbrook, C. J., & Lyssiotis, C. A.
- Affiliations
- University of Michigan (US)
- University of California, Irvine (US)
- Department of Surgery, University of Michigan
- Corresponding author
- Lee, Ho-Joon
- Halbrook, Christopher J
- Lyssiotis, Costas A
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2022-02-14
- Volume
- 11
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC8843093
- OpenAlex
- W4220853254
- Cited by
- 56
- References
- 58
- Citations by year
- 2026: 10 · 2025: 9 · 2024: 11 · 2023: 19 · 2022: 7
- FWCI
- 4.39
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Cancer Institute (R50CA232985, U24CA210967, U01CA224145, P30CA046592, F32CA228328, K99/R00CA241357, P30CA062203, R37CA237421, R01CA248160, R01CA244931, K99CA26315401)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK034933, DK097153)
- National Pancreas Foundation (NPF-5615796)
- V Foundation for Cancer Research (V2021-026)
- Sky Foundation
- Charles Woodson Research Fund
- UM Pediatric Brain Tumor Initiative
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Psychiatry and Mental health › Cancer, Stress, Anesthesia, and Immune Response
- Keywords
- pancreatic ductal adenocarcinoma, tumor-associated macrophages, macrophage polarization, GM-CSF, PI3K/Akt signaling, tumor microenvironment, cancer metabolism, lactate, Arg1, ATP citrate lyase, TXNIP, metabolic crosstalk, immunosuppression
- MeSH terms
- Tumor-Associated Macrophages, Animals, Cell Transformation, Neoplastic, Humans, Mice, Inbred C57BL, Pancreatic Neoplasms, Transcription Factors, Signal Transduction, Granulocyte-Macrophage Colony-Stimulating Factor, Gene Expression Profiling, Proteomics, Cell Line, Tumor, Mice, Metabolic Networks and Pathways, Metabolomics
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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