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 Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2024

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

Single-cell deconvolution algorithms analysis unveils autocrine IL11-mediated resistance to docetaxel in prostate cancer via activation of the JAK1/STAT4 pathway

Authors: Bisheng Cheng, Lingfeng Li, Tianlong Luo, Qiong Wang, Yong Luo, Shoumin Bai, Kaiwen Li, Yiming Lai, Hai Huang

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2024

Login to get access

Abstract

Background

Docetaxel resistance represents a significant obstacle in the treatment of prostate cancer. The intricate interplay between cytokine signalling pathways and transcriptional control mechanisms in cancer cells contributes to chemotherapeutic resistance, yet the underlying molecular determinants remain only partially understood. This study elucidated a novel resistance mechanism mediated by the autocrine interaction of interleukin-11 (IL-11) and its receptor interleukin-11 receptor subunit alpha(IL-11RA), culminating in activation of the JAK1/STAT4 signalling axis and subsequent transcriptional upregulation of the oncogene c-MYC.

Methods

Single-cell secretion profiling of prostate cancer organoid was analyzed to determine cytokine production profiles associated with docetaxel resistance.Analysis of the expression pattern of downstream receptor IL-11RA and enrichment of signal pathway to clarify the potential autocrine mechanism of IL-11.Next, chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) was performed to detect the nuclear localization and DNA-binding patterns of phosphorylated STAT4 (pSTAT4). Coimmunoprecipitation and reporter assays were utilized to assess interaction between pSTAT4 and the cotranscription factor CREB-binding protein (CBP) as well as their role in c-MYC transcriptional activity.

Results

Autocrine secretion of IL-11 was markedly increased in docetaxel-resistant prostate cancer cells. IL-11 stimulation resulted in robust activation of JAK1/STAT4 signalling. Upon activation, pSTAT4 translocated to the nucleus and associated with CBP at the c-MYC promoter region, amplifying its transcriptional activity. Inhibition of the IL-11/IL-11RA interaction or disruption of the JAK1/STAT4 pathway significantly reduced pSTAT4 nuclear entry and its binding to CBP, leading to downregulation of c-MYC expression and restoration of docetaxel sensitivity.

Conclusion

Our findings identify an autocrine loop of IL-11/IL-11RA that confers docetaxel resistance through the JAK1/STAT4 pathway. The pSTAT4-CBP interaction serves as a critical enhancer of c-MYC transcriptional activity in prostate cancer cells. Targeting this signalling axis presents a potential therapeutic strategy to overcome docetaxel resistance in advanced prostate cancer.

Graphical Abstract

Appendix
Available only for authorised users
Literature
1.
Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73(1):17–48.CrossRefPubMed
2.
Van den Broeck T, Joniau S, Everaerts W. Adjuvant Docetaxel in Nonmetastatic Prostate Cancer: The King Is Dead, Long Live the King! Eur Urol. 2023;84(2):164–5.CrossRefPubMed
3.
Vale CL, Fisher DJ, Godolphin PJ, Rydzewska LH, Boher JM, Burdett S, Chen YH, Clarke NW, Fizazi K, Gravis G, et al. Which patients with metastatic hormone-sensitive prostate cancer benefit from docetaxel: a systematic review and meta-analysis of individual participant data from randomised trials. Lancet Oncol. 2023;24(7):783–97.CrossRefPubMed
4.
Cheng B, Huang H. Expanding horizons in overcoming therapeutic resistance in castration-resistant prostate cancer: targeting the androgen receptor-regulated tumor immune microenvironment. Cancer Biol Med. 2023;20(8):568–74.PubMedPubMedCentral
5.
Rizzo M. Mechanisms of docetaxel resistance in prostate cancer: The key role played by miRNAs. Biochim Biophys Acta Rev Cancer. 2021;1875(1):188481.CrossRefPubMed
6.
Hashemi M, Zandieh MA, Talebi Y, Rahmanian P, Shafiee SS, Nejad MM, Babaei R, Sadi FH, Rajabi R, Abkenar ZO, et al. Paclitaxel and docetaxel resistance in prostate cancer: Molecular mechanisms and possible therapeutic strategies. Biomed Pharmacother. 2023;160:114392.CrossRefPubMed
7.
8.
Gabai Y, Assouline B, Ben-Porath I. Senescent stromal cells: roles in the tumor microenvironment. Trends Cancer. 2023;9(1):28–41.CrossRefPubMed
9.
Clancy JW, D’Souza-Schorey C. Tumor-Derived Extracellular Vesicles: Multifunctional Entities in the Tumor Microenvironment. Annu Rev Pathol. 2023;18:205–29.CrossRefPubMed
10.
Zhao D, Zhang J, Zhang L, Wu Q, Wang Y, Zhang W, Xiao Y, Chen J, Zhan Q. PAFR/Stat3 axis maintains the symbiotic ecosystem between tumor and stroma to facilitate tumor malignancy. Acta Pharm Sin B. 2023;13(2):694–708.CrossRefPubMed
11.
Onnis B, Fer N, Rapisarda A, Perez VS, Melillo G. Autocrine production of IL-11 mediates tumorigenicity in hypoxic cancer cells. J Clin Invest. 2013;123(4):1615–29.CrossRefPubMedPubMedCentral
12.
Chen Y, Wang L, Huang S, Ke J, Wang Q, Zhou Z, Chang W. Lutein attenuates angiotensin II- induced cardiac remodeling by inhibiting AP-1/IL-11 signaling. Redox Biol. 2021;44:102020.CrossRefPubMedPubMedCentral
13.
Huynh J, Baloyan D, Chisanga D, Shi W, O’Brien M, Afshar-Sterle S, Alorro M, Pang L, Williams DS, Parslow AC, et al. Host IL11 Signaling Suppresses CD4(+) T cell-Mediated Antitumor Responses to Colon Cancer in Mice. Cancer Immunol Res. 2021;9(7):735–47.CrossRefPubMed
14.
Lian B, Pei YC, Jiang YZ, Xue MZ, Li DQ, Li XG, Zheng YZ, Liu XY, Qiao F, Sun WL, et al. Truncated HDAC9 identified by integrated genome-wide screen as the key modulator for paclitaxel resistance in triple-negative breast cancer. Theranostics. 2020;10(24):11092–109.CrossRefPubMedPubMedCentral
15.
Zhao X, Guo B, Sun W, Yu J, Cui L. Targeting Squalene Epoxidase Confers Metabolic Vulnerability and Overcomes Chemoresistance in HNSCC. Adv Sci (Weinh). 2023;10(27):e2206878.CrossRefPubMed
16.
Shin DH, Jo JY, Choi M, Kim KH, Bae YK, Kim SS. Oncogenic KRAS mutation confers chemoresistance by upregulating SIRT1 in non-small cell lung cancer. Exp Mol Med. 2023;55(10):2220–37.CrossRefPubMedPubMedCentral
17.
Fatma H, Maurya SK, Siddique HR. Epigenetic modifications of c-MYC: Role in cancer cell reprogramming, progression and chemoresistance. Semin Cancer Biol. 2022;83:166–76.CrossRefPubMed
18.
Caforio M, Sorino C, Iacovelli S, Fanciulli M, Locatelli F, Folgiero V. Recent advances in searching c-Myc transcriptional cofactors during tumorigenesis. J Exp Clin Cancer Res. 2018;37(1):239.CrossRefPubMedPubMedCentral
19.
Zhou Q, Chen X, He H, Peng S, Zhang Y, Zhang J, Cheng L, Liu S, Huang M, Xie R, et al. WD repeat domain 5 promotes chemoresistance and Programmed Death-Ligand 1 expression in prostate cancer. Theranostics. 2021;11(10):4809–24.CrossRefPubMedPubMedCentral
20.
Cheng B, Tang C, Xie J, Zhou Q, Luo T, Wang Q, Huang H. Cuproptosis illustrates tumor micro-environment features and predicts prostate cancer therapeutic sensitivity and prognosis. Life Sci. 2023;325:121659.CrossRefPubMed
21.
Zhou Q, Li K, Lai Y, Yao K, Wang Q, Zhan X, Peng S, Cai W, Yao W, Zang X, et al. B7 score and T cell infiltration stratify immune status in prostate cancer. J Immunother Cancer. 2021;9(8):e002455.
22.
Zhang J, Zhou Q, Xie K, Cheng L, Peng S, Xie R, Liu L, Zhang Y, Dong W, Han J, et al. Targeting WD repeat domain 5 enhances chemosensitivity and inhibits proliferation and programmed death-ligand 1 expression in bladder cancer. J Exp Clin Cancer Res. 2021;40(1):203.CrossRefPubMedPubMedCentral
23.
Wang H, Li N, Liu Q, Guo J, Pan Q, Cheng B, Xu J, Dong B, Yang G, Yang B, et al. Antiandrogen treatment induces stromal cell reprogramming to promote castration resistance in prostate cancer. Cancer Cell. 2023;41(7):1345–62.CrossRefPubMed
24.
Cheng B, Li L, Wu Y, Luo T, Tang C, Wang Q, Zhou Q, Wu J, Lai Y, Zhu D, et al. The key cellular senescence related molecule RRM2 regulates prostate cancer progression and resistance to docetaxel treatment. Cell Biosci. 2023;13(1):211.CrossRefPubMedPubMedCentral
25.
Cheng B, Lai Y, Huang H, Peng S, Tang C, Chen J, Luo T, Wu J, He H, Wang Q, et al. MT1G, an emerging ferroptosis-related gene: A novel prognostic biomarker and indicator of immunotherapy sensitivity in prostate cancer. Environ Toxicol. 2023;39(2):927–41.
26.
Wang Q, Cheng B, Singh S, Tao Y, Xie Z, Qin F, Shi X, Xu J, Hu C, Tan W, Li H, Huang H. A protein-encoding CCDC7 circular RNA inhibits the progression of prostate cancer by up-regulating FLRT3. NPJ Precis Oncol. 2024;8:11.
27.
Saout JR, Lecuyer G, Leonard S, Evrard B, Kammerer-Jacquet SF, Noel L, Khene ZE, Mathieu R, Brunot A, Rolland AD, et al. Single-cell Deconvolution of a Specific Malignant Cell Population as a Poor Prognostic Biomarker in Low-risk Clear Cell Renal Cell Carcinoma Patients. Eur Urol. 2023;83(5):441–51.CrossRefPubMed
28.
Zhang YS, Xin DE, Wang Z, Peng W, Zeng Y, Liang J, Xu M, Chen N, Zhang J, Yue J, et al. Acetylation licenses Th1 cell polarization to constrain Listeria monocytogenes infection. Cell Death Differ. 2022;29(11):2303–15.CrossRefPubMedPubMedCentral
29.
Zhang M, Fu Z, Tian D, Liu E, Dai J, Wang L. Investigation of the interaction between CREB-binding protein and STAT4/STAT6. Mol Biol Rep. 2011;38(7):4805–11.CrossRefPubMed
30.
Nelson EA, Walker SR, Li W, Liu XS, Frank DA. Identification of human STAT5-dependent gene regulatory elements based on interspecies homology. J Biol Chem. 2006;281(36):26216–24.CrossRefPubMed
31.
O’Sullivan A, Chang HC, Yu Q, Kaplan MH. STAT4 is required for interleukin-12-induced chromatin remodeling of the CD25 locus. J Biol Chem. 2004;279(8):7339–45.CrossRefPubMed
32.
33.
Cheng A, Holland SM. Anti-cytokine autoantibodies: mechanistic insights and disease associations. Nat Rev Immunol. 2023;19. Online ahead of print.
34.
35.
Cao LL, Kagan JC. Targeting innate immune pathways for cancer immunotherapy. Immunity. 2023;56(10):2206–17.CrossRefPubMed
36.
Palcau AC, Canu V, Donzelli S, Strano S, Pulito C, Blandino G. CircPVT1: a pivotal circular node intersecting Long Non-Coding-PVT1 and c-MYC oncogenic signals. Mol Cancer. 2022;21(1):33.CrossRefPubMedPubMedCentral
37.
38.
Xiao J, Sun F, Wang YN, Liu B, Zhou P, Wang FX, Zhou HF, Ge Y, Yue TT, Luo JH, et al. UBC9 deficiency enhances immunostimulatory macrophage activation and subsequent antitumor T cell response in prostate cancer. J Clin Invest. 2023;133(4):e158352.
39.
Wang QW, Sun LH, Zhang Y, Wang Z, Zhao Z, Wang ZL, Wang KY, Li GZ, Xu JB, Ren CY, et al. MET overexpression contributes to STAT4-PD-L1 signaling activation associated with tumor-associated, macrophages-mediated immunosuppression in primary glioblastomas. J Immunother Cancer. 2021;9(10):e002451.
40.
Kye YC, Lee GW, Lee SW, Ju YJ, Kim HO, Yun CH, Cho JH. STAT1 maintains naive CD8(+) T cell quiescence by suppressing the type I IFN-STAT4-mTORC1 signaling axis. Sci Adv. 2021;7(36):g8764.ADSCrossRef
41.
Pan MS, Wang H, Ansari KH, Li XP, Sun W, Fan YZ. Gallbladder cancer-associated fibroblasts promote vasculogenic mimicry formation and tumor growth in gallbladder cancer via upregulating the expression of NOX4, a poor prognosis factor, through IL-6-JAK-STAT3 signal pathway. J Exp Clin Cancer Res. 2020;39(1):234.CrossRefPubMedPubMedCentral
42.
43.
Soler MF, Abaurrea A, Azcoaga P, Araujo AM, Caffarel MM. New perspectives in cancer immunotherapy: targeting IL-6 cytokine family. J Immunother Cancer. 2023;11(11):e007530.
44.
Li M, Chi X, Wang Y, Setrerrahmane S, Xie W, Xu H. Trends in insulin resistance: insights into mechanisms and therapeutic strategy. Signal Transduct Target Ther. 2022;7(1):216.CrossRefPubMedPubMedCentral
45.
Raj S, Kesari KK, Kumar A, Rathi B, Sharma A, Gupta PK, Jha SK, Jha NK, Slama P, Roychoudhury S, et al. Molecular mechanism(s) of regulation(s) of c-MET/HGF signaling in head and neck cancer. Mol Cancer. 2022;21(1):31.CrossRefPubMedPubMedCentral
46.
Fan J, To K, Chen ZS, Fu L. ABC transporters affects tumor immune microenvironment to regulate cancer immunotherapy and multidrug resistance. Drug Resist Updat. 2023;66:100905.CrossRefPubMed
Metadata
Title
Single-cell deconvolution algorithms analysis unveils autocrine IL11-mediated resistance to docetaxel in prostate cancer via activation of the JAK1/STAT4 pathway
Authors
Bisheng Cheng
Lingfeng Li
Tianlong Luo
Qiong Wang
Yong Luo
Shoumin Bai
Kaiwen Li
Yiming Lai
Hai Huang
Publication date
01-12-2024
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2024
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-024-02962-8

Other articles of this Issue 1/2024

Journal of Experimental & Clinical Cancer Research 1/2024 Go to the issue

Research

HERC5 downregulation in non-small cell lung cancer is associated with altered energy metabolism and metastasis

Research

SF3B3-regulated mTOR alternative splicing promotes colorectal cancer progression and metastasis

Research

Pan-cancer analysis implicates novel insights of lactate metabolism into immunotherapy response prediction and survival prognostication

Correction

Correction: Tumor immune microenvironment-based therapies in pancreatic ductal adenocarcinoma: time to update the concept

Research

EMID2 is a novel biotherapeutic for aggressive cancers identified by in vivo screening

Research

GPR65 sensing tumor-derived lactate induces HMGB1 release from TAM via the cAMP/PKA/CREB pathway to promote glioma progression
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits