Display options
Cite
Cheng W, Li HL, Xi SY, et al. Growth differentiation factor 1-induced tumour plasticity provides a therapeutic window for immunotherapy in hepatocellular carcinoma. Nat Commun. 2021;12(1):7142doi: 10.1038/s41467-021-27525-9.
Cheng, W., Li, H. L., Xi, S. Y., Zhang, X. F., Zhu, Y., Le Xing, Mo, Y. X., Li, M. M., Kong, F. E., Zhu, W. J., Chen, X. G., Cui, H. Q., Cao, Z. M., Gong, Y. F., Tang, Y. Q., Zhang, Y., Guan, X. Y., Ma, N. F., & Liu, M. (2021). Growth differentiation factor 1-induced tumour plasticity provides a therapeutic window for immunotherapy in hepatocellular carcinoma. Nature communications, 12(1), 7142. https://doi.org/10.1038/s41467-021-27525-9
Cheng, Wei, et al. "Growth differentiation factor 1-induced tumour plasticity provides a therapeutic window for immunotherapy in hepatocellular carcinoma." Nature communications vol. 12,1 (2021): 7142. doi: https://doi.org/10.1038/s41467-021-27525-9
Cheng W, Li HL, Xi SY, Zhang XF, Zhu Y, Le Xing, Mo YX, Li MM, Kong FE, Zhu WJ, Chen XG, Cui HQ, Cao ZM, Gong YF, Tang YQ, Zhang Y, Guan XY, Ma NF, Liu M. Growth differentiation factor 1-induced tumour plasticity provides a therapeutic window for immunotherapy in hepatocellular carcinoma. Nat Commun. 2021 Dec 08;12(1):7142. doi: 10.1038/s41467-021-27525-9. PMID: 34880251.
Copy Download .nbib Format: NLM
Share it on

Nat Commun. 2021 Dec 08;12(1):7142. doi: 10.1038/s41467-021-27525-9.

Growth differentiation factor 1-induced tumour plasticity provides a therapeutic window for immunotherapy in hepatocellular carcinoma.

Nature communications

Wei Cheng, Hao-Long Li, Shao-Yan Xi, Xiao-Feng Zhang, Yun Zhu, Le Xing, Yan-Xuan Mo, Mei-Mei Li, Fan-En Kong, Wen-Jie Zhu, Xiao-Gang Chen, Hui-Qing Cui, Zhi-Ming Cao, Yuan-Feng Gong, Yun-Qiang Tang, Yan Zhang, Xin-Yuan Guan, Ning-Fang Ma, Ming Liu

Affiliations

  1. Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, 510095, China.
  2. Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Science, Guangzhou Medical University, Guangzhou, 511436, China.
  3. State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
  4. Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
  5. Department of Clinical Oncology, State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China.
  6. Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, 510095, China. [email protected].
  7. Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Science, Guangzhou Medical University, Guangzhou, 511436, China. [email protected].

PMID: 34880251 DOI: 10.1038/s41467-021-27525-9

Abstract

Tumour lineage plasticity is an emerging hallmark of aggressive tumours. Tumour cells usually hijack developmental signalling pathways to gain cellular plasticity and evade therapeutic targeting. In the present study, the secreted protein growth and differentiation factor 1 (GDF1) is found to be closely associated with poor tumour differentiation. Overexpression of GDF1 suppresses cell proliferation but strongly enhances tumour dissemination and metastasis. Ectopic expression of GDF1 can induce the dedifferentiation of hepatocellular carcinoma (HCC) cells into their ancestral lineages and reactivate a broad panel of cancer testis antigens (CTAs), which further stimulate the immunogenicity of HCC cells to immune-based therapies. Mechanistic studies reveal that GDF1 functions through the Activin receptor-like kinase 7 (ALK7)-Mothers against decapentaplegic homolog 2/3 (SMAD2/3) signalling cascade and suppresses the epigenetic regulator Lysine specific demethylase 1 (LSD1) to boost CTA expression. GDF1-induced tumour lineage plasticity might be an Achilles heel for HCC immunotherapy. Inhibition of LSD1 based on GDF1 biomarker prescreening might widen the therapeutic window for immune checkpoint inhibitors in the clinic.

© 2021. The Author(s).

References

  1. El-Serag, H. B. Hepatocellular carcinoma. N. Engl. J. Med. 365, 1118–1127 (2011). - PubMed
  2. Llovet, J. M. et al. SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 359, 378–390 (2008). - PubMed
  3. Bruix, J. et al. RESORCE investigators. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 389, 56–66 (2017). - PubMed
  4. Kudo, M. et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet 391, 1163–1173 (2018). - PubMed
  5. El-Khoueiry, A. B. et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 389, 2492–2502 (2017). - PubMed
  6. Garraway, L. A. & Sellers, W. R. Lineage dependency and lineage survival oncogenes in human cancer. Nat. Rev. Cancer 6, 593–602 (2006). - PubMed
  7. Lan, X. et al. Fate mapping of human glioblastoma reveals an invariant stem cell hierarchy. Nature 549, 227–232 (2017). - PubMed
  8. Tirosh, I. et al. Single-cell RNA-seq supports a developmental hierarchy in human oligodendroglioma. Nature 539, 309–313 (2016). - PubMed
  9. Boumahdi, S. & de Sauvage, F. J. The great escape: tumour cell plasticity in resistance to targeted therapy. Nat. Rev. Drug Disco. 19, 39–56 (2020). - PubMed
  10. Yuan, S., Norgard, R. J. & Stanger, B. Z. Cellular plasticity in cancer. Cancer Disco. 9, 837–851 (2019). - PubMed
  11. Marquardt, J. U., Andersen, J. B. & Thorgeirsson, S. S. Functional and genetic deconstruction of the cellular origin in liver cancer. Nat. Rev. Cancer 15, 653–667 (2015). - PubMed
  12. Tarlow, B. D. et al. Bipotential adult liver progenitors are derived from chronically injured mature hepatocytes. Cell Stem Cell 15, 605–618 (2014). - PubMed
  13. Yimlamai, D. et al. Hippo pathway activity influences liver cell fate. Cell 157, 1324–1338 (2014). - PubMed
  14. Llovet, J. M. & Bruix, J. Molecular targeted therapies in hepatocellular carcinoma. Hepatology 48, 1312–1327 (2008). - PubMed
  15. Liu, M. et al. A hepatocyte differentiation model reveals two subtypes of liver cancer with different oncofetal properties and therapeutic targets. Proc. Natl Acad. Sci. USA 117, 6103–6113 (2020). - PubMed
  16. Havel, J. J., Chowell, D. & Chan, T. A. The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nat. Rev. Cancer 19, 133–150 (2019). - PubMed
  17. Miranda, A. et al. Cancer stemness, intratumoral heterogeneity, and immune response across cancers. Proc. Natl Acad. Sci. USA 116, 9020–9029 (2019). - PubMed
  18. Malta, T. M. Cancer Genome Atlas Research Network. et al. Machine learning identifies stemness features associated with oncogenic dedifferentiation. Cell 173, 338–354 (2018). - PubMed
  19. Vasaikar, S. V., Straub, P., Wang, J. & Zhang, B. LinkedOmics: analyzing multi-omics data within and across 32 cancer types. Nucleic Acids Res. 46, D956–D963 (2018). - PubMed
  20. Wakefield, L. M. & Hill, C. S. Beyond TGFβ roles of other TGFβ superfamily members in cancer. Nat. Rev. Cancer 13, 328–341 (2013). - PubMed
  21. Jones, P. A., Ohtani, H., Chakravarthy, A. & De Carvalho, D. D. Epigenetic therapy in immune-oncology. Nat. Rev. Cancer 19, 151–161 (2019). - PubMed
  22. Simpson, A. J., Caballero, O. L., Jungbluth, A., Chen, Y. T. & Old, L. J. Cancertestis antigens, gametogenesis and cancer. Nat. Rev. Cancer 5, 615–625 (2005). - PubMed
  23. Lee, J. S. & Ruppin, E. Multiomics prediction of response rates to therapies to inhibit programmed cell death 1 and programmed cell death 1 ligand 1. JAMA Oncol. 5, 1614–1618 (2019). - PubMed
  24. Yang, W. et al. Immunogenic neoantigens derived from gene fusions stimulate T cell responses. Nat. Med. 25, 767–775 (2019). - PubMed
  25. Ohue, Y. et al. Serum Antibody Against NY-ESO-1 and XAGE1 Antigens Potentially Predicts Clinical Responses to Anti-Programmed Cell Death-1 Therapy in NSCLC. J. Thorac. Oncol. 14, 2071–2083 (2019). - PubMed
  26. Sia, D. et al. Identification of an Immune-specific Class of Hepatocellular Carcinoma, Based on Molecular Features. Gastroenterology 153, 812–826 (2017). - PubMed
  27. Liau, B. B. et al. Adaptive chromatin remodeling drives glioblastoma stem cell plasticity and drug tolerance. Cell Stem Cell 20, 233–246 (2017). - PubMed
  28. Kim, I. S. et al. Microenvironment-derived factors driving metastatic plasticity in melanoma. Nat. Commun. 8, 14343 (2017). - PubMed
  29. Tata, P. R. et al. Developmental history provides a roadmap for the emergence of tumor plasticity. Dev. Cell 44, 679–693.e5 (2018). - PubMed
  30. Plaks, V., Kong, N. & Werb, Z. The cancer stem cell niche: how essential is the niche in regulating stemness of tumor cells. Cell Stem Cell 16, 225–238 (2015). - PubMed
  31. Pickup, M., Novitskiy, S. & Moses, H. L. The roles of TGFβ in the tumour microenvironment. Nat. Rev. Cancer 13, 788–799 (2013). - PubMed
  32. Majumdar, A. et al. Hepatic stem cells and transforming growth factor β in hepatocellular carcinoma. Nat. Rev. Gastroenterol. Hepatol. 9, 530–538 (2012). - PubMed
  33. Lonardo, E. et al. Nodal/Activin signaling drives self-renewal and tumorigenicity of pancreatic cancer stem cells and provides a target for combined drug therapy. Cell Stem Cell 9, 433–446 (2011). - PubMed
  34. Rankin, C. T., Bunton, T., Lawler, A. M. & Lee, S. J. Regulation of left-right patterning in mice by growth/differentiation factor-1. Nat. Genet. 24, 262–265 (2000). - PubMed
  35. Fuerer, C., Nostro, M. C. & Constam, D. B. Nodal·Gdf1 heterodimers with bound prodomains enable serum-independent nodal signaling and endoderm differentiation. J. Biol. Chem. 289, 17854–17871 (2014). - PubMed
  36. Yang, W. et al. Epigenetic silencing of GDF1 disrupts SMAD signaling to reinforce gastric cancer development. Oncogene 35, 2133–2144 (2016). - PubMed
  37. Craig, A. J., von Felden, J., Garcia-Lezana, T., Sarcognato, S. & Villanueva, A. Tumour evolution in hepatocellular carcinoma. Nat. Rev. Gastroenterol. Hepatol. 17, 139–152 (2020). - PubMed
  38. Mariathasan, S. et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554, 544–548 (2018). - PubMed
  39. Sheng, W. et al. LSD1 ablation stimulates anti-tumor immunity and enables checkpoint blockade. Cell 174, 549–563.e19 (2018). - PubMed
  40. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005). - PubMed
  41. Broutier, L. et al. Culture and establishment of self-renewing human and mouse adult liver and pancreas 3D organoids and their genetic manipulation. Nat. Protoc. 11, 1724–1743 (2016). - PubMed

Publication Types

Grant support