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BMC Cancer
Published in: BMC Cancer 1/2023

Open Access 01-12-2023 | Research

Integrated transcriptional analysis reveals macrophage heterogeneity and macrophage-tumor cell interactions in the progression of pancreatic ductal adenocarcinoma

Authors: Kaidi Yang, Tongxin Yang, Jian Yu, Fang Li, Xiang Zhao

Published in: BMC Cancer | Issue 1/2023

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Abstract

Background

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease harboring significant microenvironment heterogeneity, especially for the macrophages. Tumor-associated macrophages (TAMs) orchestrate PDAC malignancy, but their dynamics during disease progression remains poorly understood. There is a pressing need to identify the molecular mechanism underlying tumor-macrophage interactions and thus design novel therapeutic strategies.

Methods

Herein, we developed an insilico computational method incorporating bulk and single-cell transcriptome profiling to characterize macrophage heterogeneity. CellPhoneDB algorithm was applied to infer macrophage-tumor interaction networks, whereas pseudotime trajectory for dissecting cell evolution and dynamics.

Results

We demonstrated myeloid compartment was an interactive hub of tumor microenvironment (TME) essential for PDAC progression. Dimensionality reduction classified seven clusters within the myeloid cells wherein five subsets of macrophages were characterized by diverse cell states and functionality. Remarkably, tissue-resident macrophages and inflammatory monocyte were identified as potential sources of TAMs. Further, we uncovered several ligand-receptor pairs lining tumor cells and macrophages. Among them, HBEGF-CD44, HBEGF-EGFR, LGALS9-CD44, LGALS9-MET, and GRN-EGFR were correlated with worse overall survival. Notably, as in vitro experiments indicated, TAM-derived HBEGF promoted proliferation and invasion of the pancreatic cancer cell line.

Conclusion

Together, our work deciphered a comprehensive single-cell atlas of the macrophage compartment of PDAC and provided novel macrophage-tumor interaction features with potential value in developing targeted immunotherapies and molecular diagnostics for predicting patient outcome.
Appendix
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Literature
1.
2.
McGuigan A, Kelly P, Turkington RC, Jones C, Coleman HG, McCain RS. Pancreatic cancer: a review of clinical diagnosis, epidemiology, treatment and outcomes. World J Gastroenterol. 2018;24(43):4846–61.PubMedPubMedCentralCrossRef
3.
Hruban RH, Petersen GM, Ha PK, Kern SE. Genetics of pancreatic cancer. From genes to families. Surg Oncol Clin N Am. 1998;7(1):1–23.PubMedCrossRef
4.
Singh RR, Goldberg J, Varghese AM, Yu KH, Park W, O’Reilly EM. Genomic profiling in pancreatic ductal adenocarcinoma and a pathway towards therapy individualization: a scoping review. Cancer Treat Rev. 2019;75:27–38.PubMedPubMedCentralCrossRef
5.
Moncada R, Barkley D, Wagner F, Chiodin M, Devlin JC, Baron M, Hajdu CH, Simeone DM, Yanai I. Integrating microarray-based spatial transcriptomics and single-cell RNA-seq reveals tissue architecture in pancreatic ductal adenocarcinomas. Nat Biotechnol. 2020;38(3):333–42.PubMedCrossRef
6.
Zhang Y, Velez-Delgado A, Mathew E, Li D, Mendez FM, Flannagan K, Rhim AD, Simeone DM, Beatty GL. Pasca di Magliano M: myeloid cells are required for PD-1/PD-L1 checkpoint activation and the establishment of an immunosuppressive environment in pancreatic cancer. Gut. 2017;66(1):124–36.PubMedCrossRef
7.
Clark CE, Hingorani SR, Mick R, Combs C, Tuveson DA, Vonderheide RH. Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res. 2007;67(19):9518–27.PubMedCrossRef
8.
Weizman N, Krelin Y, Shabtay-Orbach A, Amit M, Binenbaum Y, Wong RJ, Gil Z. Macrophages mediate gemcitabine resistance of pancreatic adenocarcinoma by upregulating cytidine deaminase. Oncogene. 2014;33(29):3812–9.PubMedCrossRef
9.
10.
Di Caro G, Cortese N, Castino GF, Grizzi F, Gavazzi F, Ridolfi C, Capretti G, Mineri R, Todoric J, Zerbi A, et al. Dual prognostic significance of tumour-associated macrophages in human pancreatic adenocarcinoma treated or untreated with chemotherapy. Gut. 2016;65(10):1710–20.PubMedCrossRef
11.
Hwang WL, Jagadeesh KA, Guo JA, Hoffman HI, Yadollahpour P, Reeves JW, Mohan R, Drokhlyansky E, Van Wittenberghe N, Ashenberg O, et al. Single-nucleus and spatial transcriptome profiling of pancreatic cancer identifies multicellular dynamics associated with neoadjuvant treatment. Nat Genet. 2022;54(8):1178–91.PubMedCrossRef
12.
Cheng S, Li Z, Gao R, Xing B, Gao Y, Yang Y, Qin S, Zhang L, Ouyang H, Du P, et al. A pan-cancer single-cell transcriptional atlas of tumor infiltrating myeloid cells. Cell. 2021;184(3):792–809e723.PubMedCrossRef
13.
Ostuni R, Kratochvill F, Murray PJ, Natoli G. Macrophages and cancer: from mechanisms to therapeutic implications. Trends Immunol. 2015;36(4):229–39.PubMedCrossRef
14.
Zhu Y, Herndon JM, Sojka DK, Kim KW, Knolhoff BL, Zuo C, Cullinan DR, Luo J, Bearden AR, Lavine KJ, et al. Tissue-Resident Macrophages in Pancreatic Ductal Adenocarcinoma Originate from embryonic hematopoiesis and promote Tumor Progression. Immunity. 2017;47(2):323–38. e326.PubMedPubMedCentralCrossRef
15.
Cox N, Pokrovskii M, Vicario R, Geissmann F. Origins, Biology, and Diseases of tissue macrophages. Annu Rev Immunol. 2021;39:313–44.PubMedCrossRef
16.
Gosselin D, Link VM, Romanoski CE, Fonseca GJ, Eichenfield DZ, Spann NJ, Stender JD, Chun HB, Garner H, Geissmann F, et al. Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell. 2014;159(6):1327–40.PubMedPubMedCentralCrossRef
17.
Yona S, Kim KW, Wolf Y, Mildner A, Varol D, Breker M, Strauss-Ayali D, Viukov S, Guilliams M, Misharin A, et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity. 2013;38(1):79–91.PubMedCrossRef
18.
Najafi M, Hashemi Goradel N, Farhood B, Salehi E, Nashtaei MS, Khanlarkhani N, Khezri Z, Majidpoor J, Abouzaripour M, Habibi M, et al. Macrophage polarity in cancer: a review. J Cell Biochem. 2019;120(3):2756–65.PubMedCrossRef
19.
Hosein AN, Huang H, Wang Z, Parmar K, Du W, Huang J, Maitra A, Olson E, Verma U, Brekken RA. Cellular heterogeneity during mouse pancreatic ductal adenocarcinoma progression at single-cell resolution. JCI Insight. 2019;23;5(16):e129212.
20.
Sathe A, Grimes SM, Lau BT, Chen J, Suarez C, Huang RJ, Poultsides G, Ji HP. Single-cell genomic characterization reveals the Cellular reprogramming of the gastric Tumor Microenvironment. Clin Cancer Res. 2020;26(11):2640–53.PubMedPubMedCentralCrossRef
21.
Zhang L, Li Z, Skrzypczynska KM, Fang Q, Zhang W, O’Brien SA, He Y, Wang L, Zhang Q, Kim A, et al. Single-cell analyses inform mechanisms of myeloid-targeted therapies in Colon cancer. Cell. 2020;181(2):442–59. e429.PubMedCrossRef
22.
Peng J, Sun BF, Chen CY, Zhou JY, Chen YS, Chen H, Liu L, Huang D, Jiang J, Cui GS, et al. Single-cell RNA-seq highlights intra-tumoral heterogeneity and malignant progression in pancreatic ductal adenocarcinoma. Cell Res. 2019;29(9):725–38.PubMedPubMedCentralCrossRef
23.
Aibar S, Gonzalez-Blas CB, Moerman T, Huynh-Thu VA, Imrichova H, Hulselmans G, Rambow F, Marine JC, Geurts P, Aerts J, et al. SCENIC: single-cell regulatory network inference and clustering. Nat Methods. 2017;14(11):1083–6.PubMedPubMedCentralCrossRef
24.
Efremova M, Vento-Tormo M, Teichmann SA, Vento-Tormo R. CellPhoneDB: inferring cell-cell communication from combined expression of multi-subunit ligand-receptor complexes. Nat Protoc. 2020;15(4):1484–506.PubMedCrossRef
25.
Sanford DE, Belt BA, Panni RZ, Mayer A, Deshpande AD, Carpenter D, Mitchem JB, Plambeck-Suess SM, Worley LA, Goetz BD, et al. Inflammatory monocyte mobilization decreases patient survival in pancreatic cancer: a role for targeting the CCL2/CCR2 axis. Clin Cancer Res. 2013;19(13):3404–15.PubMedPubMedCentralCrossRef
26.
Kramerova I, Kumagai-Cresse C, Ermolova N, Mokhonova E, Marinov M, Capote J, Becerra D, Quattrocelli M, Crosbie RH, Welch E, et al. Spp1 (osteopontin) promotes TGFbeta processing in fibroblasts of dystrophin-deficient muscles through matrix metalloproteinases. Hum Mol Genet. 2019;28(20):3431–42.PubMedPubMedCentralCrossRef
27.
Mulder K, Patel AA, Kong WT, Piot C, Halitzki E, Dunsmore G, Khalilnezhad S, Irac SE, Dubuisson A, Chevrier M, et al. Cross-tissue single-cell landscape of human monocytes and macrophages in health and disease. Immunity. 2021;54(8):1883–900. e1885.PubMedCrossRef
28.
Xue J, Schmidt SV, Sander J, Draffehn A, Krebs W, Quester I, De Nardo D, Gohel TD, Emde M, Schmidleithner L, et al. Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity. 2014;40(2):274–88.PubMedPubMedCentralCrossRef
29.
Huber R, Pietsch D, Panterodt T, Brand K. Regulation of C/EBPbeta and resulting functions in cells of the monocytic lineage. Cell Signal. 2012;24(6):1287–96.PubMedCrossRef
30.
Zhang X, Wang Y, Yuan J, Li N, Pei S, Xu J, Luo X, Mao C, Liu J, Yu T, et al. Macrophage/microglial Ezh2 facilitates autoimmune inflammation through inhibition of Socs3. J Exp Med. 2018;215(5):1365–82.PubMedPubMedCentralCrossRef
31.
32.
Zhao Y, Ma J, Fan Y, Wang Z, Tian R, Ji W, Zhang F, Niu R. TGF-beta transactivates EGFR and facilitates breast cancer migration and invasion through canonical Smad3 and ERK/Sp1 signaling pathways. Mol Oncol. 2018;12(3):305–21.PubMedPubMedCentralCrossRef
33.
Barkal AA, Weiskopf K, Kao KS, Gordon SR, Rosental B, Yiu YY, George BM, Markovic M, Ring NG, Tsai JM, et al. Engagement of MHC class I by the inhibitory receptor LILRB1 suppresses macrophages and is a target of cancer immunotherapy. Nat Immunol. 2018;19(1):76–84.PubMedCrossRef
34.
Ho WJ, Jaffee EM, Zheng L. The tumour microenvironment in pancreatic cancer - clinical challenges and opportunities. Nat Rev Clin Oncol. 2020;17(9):527–40.PubMedPubMedCentralCrossRef
35.
36.
Ye H, Zhou Q, Zheng S, Li G, Lin Q, Wei L, Fu Z, Zhang B, Liu Y, Li Z, et al. Tumor-associated macrophages promote progression and the Warburg effect via CCL18/NF-kB/VCAM-1 pathway in pancreatic ductal adenocarcinoma. Cell Death Dis. 2018;9(5):453.PubMedPubMedCentralCrossRef
37.
Tekin C, Aberson HL, Waasdorp C, Hooijer GKJ, de Boer OJ, Dijk F, Bijlsma MF, Spek CA. Macrophage-secreted MMP9 induces mesenchymal transition in pancreatic cancer cells via PAR1 activation.Cell Oncol (Dordr). 2020;43(6):1161-1174.
38.
Wang X, Luo G, Zhang K, Cao J, Huang C, Jiang T, Liu B, Su L, Qiu Z. Hypoxic tumor-derived exosomal miR-301a mediates M2 macrophage polarization via PTEN/PI3Kgamma to promote pancreatic Cancer metastasis. Cancer Res. 2018;78(16):4586–98.PubMedCrossRef
39.
Azizi E, Carr AJ, Plitas G, Cornish AE, Konopacki C, Prabhakaran S, Nainys J, Wu K, Kiseliovas V, Setty M, et al. Single-cell map of Diverse Immune Phenotypes in the breast Tumor Microenvironment. Cell. 2018;174(5):1293–1308e1236.PubMedPubMedCentralCrossRef
40.
Muller S, Kohanbash G, Liu SJ, Alvarado B, Carrera D, Bhaduri A, Watchmaker PB, Yagnik G, Di Lullo E, Malatesta M, et al. Single-cell profiling of human gliomas reveals macrophage ontogeny as a basis for regional differences in macrophage activation in the tumor microenvironment. Genome Biol. 2017;18(1):234.PubMedPubMedCentralCrossRef
41.
Kadiyala P, Elhossiny AM, Carpenter ES. Using single cell transcriptomics to elucidate the myeloid compartment in pancreatic Cancer. Front Oncol. 2022;12:881871.PubMedPubMedCentralCrossRef
42.
Liou GY, Doppler H, Necela B, Krishna M, Crawford HC, Raimondo M, Storz P. Macrophage-secreted cytokines drive pancreatic acinar-to-ductal metaplasia through NF-kappaB and MMPs. J Cell Biol. 2013;202(3):563–77.PubMedPubMedCentralCrossRef
43.
Storz P. The crosstalk between acinar cells with Kras mutations and M1-polarized macrophages leads to initiation of pancreatic precancerous lesions. Oncoimmunology. 2015;4(6):e1008794.PubMedPubMedCentralCrossRef
44.
45.
Kumar MP, Du J, Lagoudas G, Jiao Y, Sawyer A, Drummond DC, Lauffenburger DA, Raue A. Analysis of single-cell RNA-Seq identifies cell-cell communication Associated with Tumor characteristics. Cell Rep. 2018;25(6):1458–1468e1454.PubMedPubMedCentralCrossRef
46.
Camp JG, Sekine K, Gerber T, Loeffler-Wirth H, Binder H, Gac M, Kanton S, Kageyama J, Damm G, Seehofer D, et al. Multilineage communication regulates human liver bud development from pluripotency. Nature. 2017;546(7659):533–8.PubMedCrossRef
47.
Rowe GC, Raghuram S, Jang C, Nagy JA, Patten IS, Goyal A, Chan MC, Liu LX, Jiang A, Spokes KC, et al. PGC-1alpha induces SPP1 to activate macrophages and orchestrate functional angiogenesis in skeletal muscle. Circ Res. 2014;115(5):504–17.PubMedPubMedCentralCrossRef
48.
Chen P, Zhao D, Li J, Liang X, Li J, Chang A, Henry VK, Lan Z, Spring DJ, Rao G, et al. Symbiotic macrophage-glioma cell interactions reveal synthetic lethality in PTEN-Null glioma. Cancer Cell. 2019;35(6):868–884e866.PubMedPubMedCentralCrossRef
49.
Zhu Y, Knolhoff BL, Meyer MA, Nywening TM, West BL, Luo J, Wang-Gillam A, Goedegebuure SP, Linehan DC, DeNardo DG. CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res. 2014;74(18):5057–69.PubMedPubMedCentralCrossRef
50.
Zhang Y, Du W, Chen Z, Xiang C. Upregulation of PD-L1 by SPP1 mediates macrophage polarization and facilitates immune escape in lung adenocarcinoma. Exp Cell Res. 2017;359(2):449–57.PubMedCrossRef
51.
Wu C, Thalhamer T, Franca RF, Xiao S, Wang C, Hotta C, Zhu C, Hirashima M, Anderson AC, Kuchroo VK. Galectin-9-CD44 interaction enhances stability and function of adaptive regulatory T cells. Immunity. 2014;41(2):270–82.PubMedPubMedCentralCrossRef
52.
Daley D, Mani VR, Mohan N, Akkad N, Ochi A, Heindel DW, Lee KB, Zambirinis CP, Pandian GSB, Savadkar S, et al. Dectin 1 activation on macrophages by galectin 9 promotes pancreatic carcinoma and peritumoral immune tolerance. Nat Med. 2017;23(5):556–67.PubMedPubMedCentralCrossRef
53.
54.
Sun Q, Zhang Y, Liu M, Ye Z, Yu X, Xu X, Qin Y. Prognostic and diagnostic significance of galectins in pancreatic cancer: a systematic review and meta-analysis. Cancer Cell Int. 2019;19:309.PubMedPubMedCentralCrossRef
55.
Seifert AM, Reiche C, Heiduk M, Tannert A, Meinecke AC, Baier S, von Renesse J, Kahlert C, Distler M, Welsch T, et al. Detection of pancreatic ductal adenocarcinoma with galectin-9 serum levels. Oncogene. 2020;39(15):3102–13.PubMedPubMedCentralCrossRef
56.
Nielsen SR, Quaranta V, Linford A, Emeagi P, Rainer C, Santos A, Ireland L, Sakai T, Sakai K, Kim YS, et al. Macrophage-secreted granulin supports pancreatic cancer metastasis by inducing liver fibrosis. Nat Cell Biol. 2016;18(5):549–60.PubMedPubMedCentralCrossRef
57.
Quaranta V, Rainer C, Nielsen SR, Raymant ML, Ahmed MS, Engle DD, Taylor A, Murray T, Campbell F, Palmer DH, et al. Macrophage-derived Granulin Drives Resistance to Immune Checkpoint Inhibition in metastatic pancreatic Cancer. Cancer Res. 2018;78(15):4253–69.PubMedPubMedCentralCrossRef
58.
Ray KC, Moss ME, Franklin JL, Weaver CJ, Higginbotham J, Song Y, Revetta FL, Blaine SA, Bridges LR, Guess KE, et al. Heparin-binding epidermal growth factor-like growth factor eliminates constraints on activated Kras to promote rapid onset of pancreatic neoplasia. Oncogene. 2014;33(7):823–31.PubMedCrossRef
Metadata
Title
Integrated transcriptional analysis reveals macrophage heterogeneity and macrophage-tumor cell interactions in the progression of pancreatic ductal adenocarcinoma
Authors
Kaidi Yang
Tongxin Yang
Jian Yu
Fang Li
Xiang Zhao
Publication date
01-12-2023
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2023
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-023-10675-y

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