Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Translational Medicine
Published in: Journal of Translational Medicine 1/2024

Open Access 01-12-2024 | Kidney Cancer | Research

Single-cell transcriptome sequencing reveals aberrantly activated inter-tumor cell signaling pathways in the development of clear cell renal cell carcinoma

Authors: Junfeng Zhang, Fuzhong Liu, Wenjia Guo, Xing Bi, Shuai Yuan, Fuerhaiti Shayiti, Ting Pan, Kailing Li, Peng Chen

Published in: Journal of Translational Medicine | Issue 1/2024

Login to get access

Abstract

Background

Aberrant intracellular or intercellular signaling pathways are important mechanisms that contribute to the development and progression of cancer. However, the intercellular communication associated with the development of ccRCC is currently unknown. The purpose of this study was to examine the aberrant tumor cell-to-cell communication signals during the development of ccRCC.

Methods

We conducted an analysis on the scRNA-seq data of 6 ccRCC and 6 normal kidney tissues. This analysis included sub clustering, CNV analysis, single-cell trajectory analysis, cell–cell communication analysis, and transcription factor analysis. Moreover, we performed validation tests on clinical samples using multiplex immunofluorescence.

Results

This study identified eleven aberrantly activated intercellular signaling pathways in tumor clusters from ccRCC samples. Among these, two of the majors signaling molecules, MIF and SPP1, were mainly secreted by a subpopulation of cancer stem cells. This subpopulation demonstrated high expression levels of the cancer stem cell markers POU5F1 and CD44 (POU5F1hiCD44hiE.T), with the transcription factor POU5F1 regulating the expression of SPP1. Further research demonstrated that SPP1 binds to integrin receptors on the surface of target cells and promotes ccRCC development and progression by activating potential signaling mechanisms such as ILK and JAK/STAT.

Conclusion

Aberrantly activated tumor intercellular signaling pathways promote the development and progression of ccRCC. The cancer stem cell subpopulation (POU5F1hiCD44hiE.T) promotes malignant transformation and the development of a malignant phenotype by releasing aberrant signaling molecules and interacting with other tumor cells.
Appendix
Available only for authorised users
Literature
1.
Huang Q, Sun Y, Ma X, Gao Y, Li X, Niu Y, Zhang X, Chang C. Androgen receptor increases hematogenous metastasis yet decreases lymphatic metastasis of renal cell carcinoma. Nat Commun. 2017;8(1):918.PubMedPubMedCentralCrossRef
2.
Ling L, Tan SK, Goh TH, Cheung E, Nurcombe V, van Wijnen AJ, Cool SM. Targeting the heparin-binding domain of fibroblast growth factor receptor 1 as a potential cancer therapy. Mol Cancer. 2015;14:136.PubMedPubMedCentralCrossRef
3.
McRonald FE, Morris MR, Gentle D, Winchester L, Baban D, Ragoussis J, Clarke NW, Brown MD, Kishida T, Yao M, et al. CpG methylation profiling in VHL related and VHL unrelated renal cell carcinoma. Mol Cancer. 2009;8:31.PubMedPubMedCentralCrossRef
4.
Cancer Genome Atlas Research N. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature. 2013;499(7456):43–9.CrossRef
5.
Clark DJ, Dhanasekaran SM, Petralia F, Pan J, Song X, Hu Y, da Veiga Leprevost F, Reva B, Lih TM, Chang HY, et al. Integrated proteogenomic characterization of clear cell renal cell carcinoma. Cell. 2019;179(4):964–83.PubMedPubMedCentralCrossRef
6.
Fu L, Wang G, Shevchuk MM, Nanus DM, Gudas LJ. Generation of a mouse model of von hippel-lindau kidney disease leading to renal cancers by expression of a constitutively active mutant of HIF1α. Can Res. 2011;71(21):6848–56.CrossRef
7.
Xu L, Hu H, Zheng LS, Wang MY, Mei Y, Peng LX, Qiang YY, Li CZ, Meng DF, Wang MD, et al. ETV4 is a theranostic target in clear cell renal cell carcinoma that promotes metastasis by activating the pro-metastatic gene FOSL1 in a PI3K-AKT dependent manner. Cancer Lett. 2020;482:74–89.PubMedCrossRef
8.
Jin S, Guerrero-Juarez CF, Zhang L, Chang I, Ramos R, Kuan CH, Myung P, Plikus MV, Nie Q. Inference and analysis of cell-cell communication using cell chat. Nat Commun. 2021;12(1):1088.PubMedPubMedCentralCrossRef
9.
Trapnell C, Cacchiarelli D, Grimsby J, Pokharel P, Li S, Morse M, Lennon NJ, Livak KJ, Mikkelsen TS, Rinn JL. The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells. Nat Biotechnol. 2014;32(4):381–6.PubMedPubMedCentralCrossRef
10.
Chen Y, Sun Y, Xu Y, Lin WW, Luo Z, Han Z, Liu S, Qi B, Sun C, Go K, et al. Single-cell integration analysis of heterotopic ossification and fibrocartilage developmental lineage: endoplasmic reticulum stress effector Xbp1 transcriptionally regulates the notch signaling pathway to mediate fibrocartilage differentiation. Oxid Med Cell Longev. 2021;2021:7663366.PubMedPubMedCentralCrossRef
11.
Szatanek R, Baran J, Siedlar M, Baj-Krzyworzeka M. Isolation of extracellular vesicles: determining the correct approach (Review). Int J Mol Med. 2015;36(1):11–7.PubMedPubMedCentralCrossRef
12.
Javeed N, Gustafson MP, Dutta SK, Lin Y, Bamlet WR, Oberg AL, Petersen GM, Chari ST, Dietz AB, Mukhopadhyay D. Immunosuppressive CD14(+)HLA-DR(lo/neg) monocytes are elevated in pancreatic cancer and “primed” by tumor-derived exosomes. Oncoimmunology. 2017;6(1):e1252013.PubMedCrossRef
13.
de Visser KE, Joyce JA. The evolving tumor microenvironment: From cancer initiation to metastatic outgrowth. Cancer Cell. 2023;41(3):374–403.PubMedCrossRef
14.
Song G, Shi Y, Zhang M, Goswami S, Afridi S, Meng L, Ma J, Chen Y, Lin Y, Zhang J, et al. Global immune characterization of HBV/HCV-related hepatocellular carcinoma identifies macrophage and T-cell subsets associated with disease progression. Cell Discov. 2020;6(1):90.PubMedPubMedCentralCrossRef
15.
Fuentes P, Sese M, Guijarro PJ, Emperador M, Sanchez-Redondo S, Peinado H, Hummer S, Ramon YCS. ITGB3-mediated uptake of small extracellular vesicles facilitates intercellular communication in breast cancer cells. Nat Commun. 2020;11(1):4261.PubMedCentralCrossRef
16.
17.
Hao Y, Hao S, Andersen-Nissen E, Mauck WM 3rd, Zheng S, Butler A, Lee MJ, Wilk AJ, Darby C, Zager M, et al. Integrated analysis of multimodal single-cell data. Cell. 2021;184(13):3573–87.PubMedPubMedCentralCrossRef
18.
Jerby-Arnon L, Shah P, Cuoco MS, Rodman C, Su MJ, Melms JC, Leeson R, Kanodia A, Mei S, Lin JR, et al. A cancer cell program promotes T cell exclusion and resistance to checkpoint blockade. Cell. 2018;175(4):984–97.PubMedPubMedCentralCrossRef
19.
Liu YM, Ge JY, Chen YF, Liu T, Chen L, Liu CC, Ma D, Chen YY, Cai YW, Xu YY, et al. Combined single-cell and spatial transcriptomics reveal the metabolic evolvement of breast cancer during early dissemination. Adv Sci. 2023;10(6):e2205395.CrossRef
20.
Qiu X, Mao Q, Tang Y, Wang L, Chawla R, Pliner HA, Trapnell C. Reversed graph embedding resolves complex single-cell trajectories. Nat Methods. 2017;14(10):979–82.PubMedPubMedCentralCrossRef
21.
Aibar S, González-Blas CB, Moerman T, Huynh-Thu VA, Imrichova H, Hulselmans G, Rambow F, Marine J-C, Geurts P, Aerts J, et al. SCENIC: single-cell regulatory network inference and clustering. Nat Methods. 2017;14(11):1083–6.PubMedPubMedCentralCrossRef
22.
Bi K, He MX, Bakouny Z, Kanodia A, Napolitano S, Wu J, Grimaldi G, Braun DA, Cuoco MS, Mayorga A, et al. Tumor and immune reprogramming during immunotherapy in advanced renal cell carcinoma. Cancer Cell. 2021;39(5):649–61.PubMedPubMedCentralCrossRef
23.
Sun Z, Chen L, Xin H, Jiang Y, Huang Q, Cillo AR, Tabib T, Kolls JK, Bruno TC, Lafyatis R, et al. A bayesian mixture model for clustering droplet-based single-cell transcriptomic data from population studies. Nat Commun. 2019;10(1):1649.PubMedPubMedCentralCrossRef
24.
Puram SV, Tirosh I, Parikh AS, Patel AP, Yizhak K, Gillespie S, Rodman C, Luo CL, Mroz EA, Emerick KS, et al. Single-cell transcriptomic analysis of primary and metastatic tumor ecosystems in head and neck cancer. Cell. 2017;171(7):1611–24.PubMedPubMedCentralCrossRef
25.
Chui MH. Insights into cancer metastasis from a clinicopathologic perspective: epithelial-mesenchymal transition is not a necessary step. Int J Cancer. 2013;132(7):1487–95.PubMedCrossRef
26.
Choueiri TK, Pal SK, McDermott DF, Morrissey S, Ferguson KC, Holland J, Kaelin WG, Dutcher JP. A phase I study of cabozantinib (XL184) in patients with renal cell cancer. Ann Oncol. 2014;25(8):1603–8.PubMedPubMedCentralCrossRef
27.
28.
29.
Van de Sande B, Flerin C, Davie K, De Waegeneer M, Hulselmans G, Aibar S, Seurinck R, Saelens W, Cannoodt R, Rouchon Q, et al. A scalable SCENIC workflow for single-cell gene regulatory network analysis. Nat Protoc. 2020;15(7):2247–76.PubMedCrossRef
30.
Sharif T, Martell E, Dai C, Kennedy BE, Murphy P, Clements DR, Kim Y, Lee PW, Gujar SA. Autophagic homeostasis is required for the pluripotency of cancer stem cells. Autophagy. 2017;13(2):264–84.PubMedCrossRef
31.
32.
De Franceschi N, Arjonen A, Elkhatib N, Denessiouk K, Wrobel AG, Wilson TA, Pouwels J, Montagnac G, Owen DJ, Ivaska J. Selective integrin endocytosis is driven by interactions between the integrin alpha-chain and AP2. Nat Struct Mol Biol. 2016;23(2):172–9.PubMedPubMedCentralCrossRef
33.
Slack RJ, Macdonald SJF, Roper JA, Jenkins RG, Hatley RJD. Emerging therapeutic opportunities for integrin inhibitors. Nat Rev Drug Discov. 2022;21(1):60–78.PubMedCrossRef
34.
Okada T, Lee AY, Qin LX, Agaram N, Mimae T, Shen Y, O’Connor R, Lopez-Lago MA, Craig A, Miller ML, et al. Integrin-alpha10 dependency identifies RAC and RICTOR as therapeutic targets in high-grade myxofibrosarcoma. Cancer Discov. 2016;6(10):1148–65.PubMedPubMedCentralCrossRef
35.
Pang X, He X, Qiu Z, Zhang H, Xie R, Liu Z, Gu Y, Zhao N, Xiang Q, Cui Y. Targeting integrin pathways: mechanisms and advances in therapy. Signal Transduct Target Ther. 2023;8(1):1.PubMedPubMedCentralCrossRef
36.
Hannigan G, Troussard AA, Dedhar S. Integrin-linked kinase: a cancer therapeutic target unique among its ILK. Nat Rev Cancer. 2005;5(1):51–63.PubMedCrossRef
37.
Saiz N, Williams KM, Seshan VE, Hadjantonakis AK. Asynchronous fate decisions by single cells collectively ensure consistent lineage composition in the mouse blastocyst. Nat Commun. 2016;7:13463.PubMedPubMedCentralCrossRef
38.
Franceschi VR, Nakata PA. Calcium oxalate in plants: formation and function. Annu Rev Plant Biol. 2005;56:41–71.PubMedCrossRef
39.
40.
Luistro L, He W, Smith M, Packman K, Vilenchik M, Carvajal D, Roberts J, Cai J, Berkofsky-Fessler W, Hilton H, et al. Preclinical profile of a potent gamma-secretase inhibitor targeting notch signaling with in vivo efficacy and pharmacodynamic properties. Cancer Res. 2009;69(19):7672–80.PubMedPubMedCentralCrossRef
41.
Qi J, Sun H, Zhang Y, Wang Z, Xun Z, Li Z, Ding X, Bao R, Hong L, Jia W, et al. Single-cell and spatial analysis reveal interaction of FAP(+) fibroblasts and SPP1(+) macrophages in colorectal cancer. Nat Commun. 2022;13(1):1742.PubMedPubMedCentralCrossRef
42.
Deng G, Zeng F, Su J, Zhao S, Hu R, Zhu W, Hu S, Chen X, Yin M. BET inhibitor suppresses melanoma progression via the noncanonical NF-kappaB/SPP1 pathway. Theranostics. 2020;10(25):11428–43.PubMedPubMedCentralCrossRef
43.
Sparkes A, De Baetselier P, Roelants K, De Trez C, Magez S, Van Ginderachter JA, Raes G, Bucala R, Stijlemans B. The non-mammalian MIF superfamily. Immunobiology. 2017;222(3):473–82.PubMedCrossRef
44.
Kindt N, Journe F, Laurent G, Saussez S. Involvement of macrophage migration inhibitory factor in cancer and novel therapeutic targets. Oncol Lett. 2016;12(4):2247–53.PubMedPubMedCentralCrossRef
45.
46.
Lambert SA, Jolma A, Campitelli LF, Das PK, Yin Y, Albu M, Chen X, Taipale J, Hughes TR, Weirauch MT. The human transcription factors. Cell. 2018;172(4):650–65.PubMedCrossRef
47.
Jen J, Tang YA, Lu YH, Lin CC, Lai WW, Wang YC. Oct4 transcriptionally regulates the expression of long non-coding RNAs NEAT1 and MALAT1 to promote lung cancer progression. Mol Cancer. 2017;16(1):104.PubMedPubMedCentralCrossRef
48.
Xu C, Xie D, Yu SC, Yang XJ, He LR, Yang J, Ping YF, Wang B, Yang L, Xu SL, et al. beta-Catenin/POU5F1/SOX2 transcription factor complex mediates IGF-I receptor signaling and predicts poor prognosis in lung adenocarcinoma. Cancer Res. 2013;73(10):3181–9.PubMedCrossRef
49.
Tung CH, Huang MF, Liang CH, Wu YY, Wu JE, Hsu CL, Chen YL, Hong TM. alpha-Catulin promotes cancer stemness by antagonizing WWP1-mediated KLF5 degradation in lung cancer. Theranostics. 2022;12(3):1173–86.PubMedPubMedCentralCrossRef
50.
Fendler A, Bauer D, Busch J, Jung K, Wulf-Goldenberg A, Kunz S, Song K, Myszczyszyn A, Elezkurtaj S, Erguen B, et al. Inhibiting WNT and NOTCH in renal cancer stem cells and the implications for human patients. Nat Commun. 2020;11(1):929.PubMedPubMedCentralCrossRef
51.
Walcher L, Kistenmacher AK, Suo H, Kitte R, Dluczek S, Strauss A, Blaudszun AR, Yevsa T, Fricke S, Kossatz-Boehlert U. Cancer stem cells-origins and biomarkers: perspectives for targeted personalized therapies. Front Immunol. 2020;11:1280.PubMedPubMedCentralCrossRef
52.
Yang L, Shi P, Zhao G, Xu J, Peng W, Zhang J, Zhang G, Wang X, Dong Z, Chen F, et al. Targeting cancer stem cell pathways for cancer therapy. Signal Transduct Target Ther. 2020;5(1):8.PubMedPubMedCentralCrossRef
53.
Ahmed F, Samantasinghar A, Soomro AM, Kim S, Choi KH. A systematic review of computational approaches to understand cancer biology for informed drug repurposing. J Biomed Inform. 2023;142:104373.PubMedCrossRef
54.
Ahmed F, Ho SG, Samantasinghar A, Memon FH, Rahim CSA, Soomro AM, Pratibha Sunildutt N, Kim KH, Choi KH. Drug repurposing in psoriasis, performed by reversal of disease-associated gene expression profiles. Comput Struct Biotechnol J. 2022;20:6097–107.PubMedPubMedCentralCrossRef
55.
Ahmed F, Kang IS, Kim KH, Asif A, Rahim CSA, Samantasinghar A, Memon FH, Choi KH. Drug repurposing for viral cancers: a paradigm of machine learning, deep learning, and virtual screening-based approaches. J Med Virol. 2023;95(4):e28693.PubMedCrossRef
56.
Ahmed F, Soomro AM, Chethikkattuveli Salih AR, Samantasinghar A, Asif A, Kang IS, Choi KH. A comprehensive review of artificial intelligence and network based approaches to drug repurposing in Covid-19. Biomed Pharmacother. 2022;153:113350.PubMedPubMedCentralCrossRef
57.
Ahmed F, Lee JW, Samantasinghar A, Kim YS, Kim KH, Kang IS, Memon FH, Lim JH, Choi KH. SperoPredictor: an integrated machine learning and molecular docking-based drug repurposing framework with use case of COVID-19. Front Public Health. 2022;10:902123.PubMedPubMedCentralCrossRef
58.
Bhattacharya R, Ye XC, Wang R, Ling X, McManus M, Fan F, Boulbes D, Ellis LM. Intracrine VEGF signaling mediates the activity of prosurvival pathways in human colorectal cancer cells. Cancer Res. 2016;76(10):3014–24.PubMedPubMedCentralCrossRef
59.
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):868–84.PubMedPubMedCentralCrossRef
60.
Matsushita H, Yang YM, Pandol SJ, Seki E. Exosome migration inhibitory factor as a marker and therapeutic target for pancreatic cancer. Gastroenterology. 2016;150(4):1033–5.PubMedCrossRef
Metadata
Title
Single-cell transcriptome sequencing reveals aberrantly activated inter-tumor cell signaling pathways in the development of clear cell renal cell carcinoma
Authors
Junfeng Zhang
Fuzhong Liu
Wenjia Guo
Xing Bi
Shuai Yuan
Fuerhaiti Shayiti
Ting Pan
Kailing Li
Peng Chen
Publication date
01-12-2024
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2024
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-023-04818-9

Other articles of this Issue 1/2024

Journal of Translational Medicine 1/2024 Go to the issue

Research

Integrative network analysis suggests prioritised drugs for atopic dermatitis

Correction

Correction: Excitatory neurons in the lateral parabrachial nucleus mediate the interruptive effect of inflammatory pain on a sustained attention task

Research

The microtubule targeting agent ST-401 triggers cell death in interphase and prevents the formation of polyploid giant cancer cells

Research

Fluorinated hydroxyapatite conditions a favorable osteo-immune microenvironment via triggering metabolic shift from glycolysis to oxidative phosphorylation

Research

Engineering PD-1-targeted small protein variants for in vitro diagnostics and in vivo PET imaging

Research

The redox-active defensive Selenoprotein T as a novel stress sensor protein playing a key role in the pathophysiology of heart failure
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine
Image Credits