Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

RAB22A triggers intercellular chemoresistance transmission in colorectal cancer by promoting exosome release via the PKM2-pSNAP23 axis

Oncogene volume 44, pages 4205–4217 (2025)Cite this article

Subjects

Abstract

Chemoresistance is not only related to tumor cells themselves, but also regulated by the interaction between cells in the tumor microenvironment (TME). However, the underlying mechanisms are not well understood. RAB22A, a member of the RAB family of small GTPases that was identified by our group previously as an oncogene in colorectal cancer (CRC). In this study, we demonstrated that elevated expression of RAB22A in CRC cells, particularly in chemoresistant CRC cells, is associated with increased exosome secretion and enhanced chemoresistance. Mechanistically, RAB22A augments exosome secretion by inhibiting the ubiquitination and degradation of pyruvate kinase type M2 (PKM2), then promoting the phosphorylation of synaptosome-associated protein 23 (SNAP-23). Furthermore, RAB22A not only directly promotes chemoresistance in CRC cells but also indirectly induces acquired drug resistance of other CRC cells in the TME by promoting the secretion of RAB22A-PKM2-rich exosomes, thereby triggering intercellular chemoresistance transmission. Together, we reveal an essential role of RAB22A-PKM2-SNAP-23 signaling cascade in exosome induction in chemoresistant CRC cells and intercellular chemoresistance transmission, highlighting that targeting the RAB22A/PKM2/pSNAP axis is a potential novel strategy to reverse chemoresistance, and suggest circulating exosomal RAB22A and PKM2 as markers to predict the efficacy of chemotherapy in CRC.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: RAB22A expression is positively correlated with chemoresistance and exosome release in CRC.
Fig. 2: Elevated exosome secretion is closely related to chemoresistance and poor prognosis in CRC.
Fig. 3: RAB22A plays a critical role in the release of exosomes in CRC chemoresistance.
Fig. 4: RAB22A interacts with and stabilizes PKM2 by inhibiting its degradation.
Fig. 5: RAB22A promotes exosome secretion and intercellular chemoresistance transmission by facilitating PKM2-mediated SNAP-23 phosphorylation in CRC cells.
Fig. 6: Chemoresistant CRC cell-derived exosomes induce chemoresistance in vivo.

Similar content being viewed by others

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Ma SC, Zhang JQ, Yan TH, Miao MX, Cao YM, Cao YB, et al. Novel strategies to reverse chemoresistance in colorectal cancer. Cancer Med. 2023;12:11073–96.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Cui K, Wang K, Huang Z. Ferroptosis and the tumor microenvironment. J Exp Clin Cancer Res. 2024;43:315.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Pan W, Miao Q, Yin W, Li X, Ye W, Zhang D, et al. The role and clinical applications of exosomes in cancer drug resistance. Cancer Drug Resist. 2024;7:43.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Wilczynski B, Dabrowska A, Kulbacka J, Baczynska D. Chemoresistance and the tumor microenvironment: the critical role of cell-cell communication. Cell Commun Signal. 2024;22:486.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Yin Y, Yao S, Hu Y, Feng Y, Li M, Bian Z, et al. The Immune-microenvironment confers chemoresistance of colorectal cancer through macrophage-derived IL6. Clin Cancer Res. 2017;23:7375–87.

    Article  CAS  PubMed  Google Scholar 

  6. Shin AE, Giancotti FG, Rustgi AK. Metastatic colorectal cancer: mechanisms and emerging therapeutics. Trends Pharmacol Sci. 2023;44:222–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Thomas LL, Fromme JC. GTPase cross-talk regulates TRAPPII activation of Rab11 homologues during vesicle biogenesis. J Cell Biol. 2016;215:499–513.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ostrowski M, Carmo NB, Krumeich S, Fanget I, Raposo G, Savina A, et al. Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat Cell Biol. 2010;12:19–30.

    Article  CAS  PubMed  Google Scholar 

  9. Cebrian I, Croce C, Guerrero NA, Blanchard N, Mayorga LS. Rab22a controls MHC-I intracellular trafficking and antigen cross-presentation by dendritic cells. EMBO Rep. 2016;17:1753–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wen F, Meng F, Li X, Li Q, Liu J, Zhang R, et al. Characterization of prognostic value and immunological roles of RAB22A in hepatocellular carcinoma. Front Immunol. 2023;14:1086342.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Fan B, Wang L, Wang J. RAB22A as a predictor of exosome secretion in the progression and relapse of multiple myeloma. Aging. 2024;16:4169–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. He M, Shen L, Jiang C, Gao G, Wang K, Jiao Y, et al. Rab22a is a novel prognostic marker for cell progression in breast cancer. Int J Mol Med. 2020;45:1037–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Zeng C, Zhong L, Liu W, Zhang Y, Yu X, Wang X, et al. Targeting the lysosomal degradation of Rab22a-NeoF1 fusion protein for osteosarcoma lung metastasis. Adv Sci. 2023;10:e2205483.

    Article  Google Scholar 

  14. Liao D, Zhong L, Yin J, Zeng C, Wang X, Huang X, et al. Chromosomal translocation-derived aberrant Rab22a drives metastasis of osteosarcoma. Nat Cell Biol. 2020;22:868–81.

    Article  CAS  PubMed  Google Scholar 

  15. Yin Y, Zhang B, Wang W, Fei B, Quan C, Zhang J, et al. miR-204-5p inhibits proliferation and invasion and enhances chemotherapeutic sensitivity of colorectal cancer cells by downregulating RAB22A. Clin Cancer Res. 2014;20:6187–99.

    Article  CAS  PubMed  Google Scholar 

  16. Bian Z, Jin L, Zhang J, Yin Y, Quan C, Hu Y, et al. LncRNA-UCA1 enhances cell proliferation and 5-fluorouracil resistance in colorectal cancer by inhibiting miR-204-5p. Sci Rep. 2016;6:23892.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Fusco C, De Rosa G, Spatocco I, Vitiello E, Procaccini C, Frige C, et al. Extracellular vesicles as human therapeutics: a scoping review of the literature. J Extracell Vesicles. 2024;13:e12433.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Yin Y, Liu B, Cao Y, Yao S, Liu Y, Jin G, et al. Colorectal cancer-derived small extracellular vesicles promote tumor immune evasion by upregulating PD-L1 expression in tumor-associated macrophages. Adv Sci. 2022;9:2102620.

    Article  CAS  Google Scholar 

  19. Hsu C, Morohashi Y, Yoshimura S, Manrique-Hoyos N, Jung S, Lauterbach MA, et al. Regulation of exosome secretion by Rab35 and its GTPase-activating proteins TBC1D10A-C. J Cell Biol. 2010;189:223–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wang T, Gilkes DM, Takano N, Xiang L, Luo W, Bishop CJ, et al. Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis. Proc Natl Acad Sci USA. 2014;111:E3234–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Teng P, Cui K, Yao S, Fei B, Ling F, Li C, et al. SIRT5-mediated ME2 desuccinylation promotes cancer growth by enhancing mitochondrial respiration. Cell Death Differ. 2024;31:65–77.

    Article  CAS  PubMed  Google Scholar 

  22. Bian Z, Yang F, Xu P, Gao G, Yang C, Cao Y, et al. LINC01852 inhibits the tumorigenesis and chemoresistance in colorectal cancer by suppressing SRSF5-mediated alternative splicing of PKM. Mol Cancer. 2024;23:23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lin RC, Scheller RH. Mechanisms of synaptic vesicle exocytosis. Annu Rev Cell Dev Biol. 2000;16:19–49.

    Article  CAS  PubMed  Google Scholar 

  24. Wei Y, Wang D, Jin F, Bian Z, Li L, Liang H, et al. Pyruvate kinase type M2 promotes tumour cell exosome release via phosphorylating synaptosome-associated protein 23. Nat Commun. 2017;8:14041.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Xavier CPR, Belisario DC, Rebelo R, Assaraf YG, Giovannetti E, Kopecka J, et al. The role of extracellular vesicles in the transfer of drug resistance competences to cancer cells. Drug Resist Updat. 2022;62:100833.

    Article  CAS  PubMed  Google Scholar 

  26. Almanza G, Searles S, Zanetti M. Delivery of miR-214 via extracellular vesicles downregulates Xbp1 expression and pro-inflammatory cytokine genes in macrophages. Extracell Vesicles Circ Nucl Acids. 2024;5:249–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. He C, Zheng S, Luo Y, Wang B. Exosome theranostics: biology and translational medicine. Theranostics. 2018;8:237–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zhong L, Liao D, Li J, Liu W, Wang J, Zeng C, et al. Rab22a-NeoF1 fusion protein promotes osteosarcoma lung metastasis through its secretion into exosomes. Signal Transduct Target Ther. 2021;6:59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lin Y, Wei D, He X, Huo L, Wang J, Zhang X, et al. RAB22A sorts epithelial growth factor receptor (EGFR) from early endosomes to recycling endosomes for microvesicles release. J Extracell Vesicles. 2024;13:e12494.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature. 2008;452:230–3.

    Article  CAS  PubMed  Google Scholar 

  31. Wang D, Zhao C, Xu F, Zhang A, Jin M, Zhang K, et al. Cisplatin-resistant NSCLC cells induced by hypoxia transmit resistance to sensitive cells through exosomal PKM2. Theranostics. 2021;11:2860–75.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Li G, Wang D, Zhai Y, Pan C, Zhang J, Wang C, et al. Glycometabolic reprogramming-induced XRCC1 lactylation confers therapeutic resistance in ALDH1A3-overexpressing glioblastoma. Cell Metab. 2024;36:1696–710.e1610.

    Article  CAS  PubMed  Google Scholar 

  33. Bian Z, Zhang J, Li M, Feng Y, Wang X, Zhang J, et al. LncRNA-FEZF1-AS1 promotes tumor proliferation and metastasis in colorectal cancer by regulating PKM2 signaling. Clin Cancer Res. 2018;24:4808–19.

    Article  CAS  PubMed  Google Scholar 

  34. Paumet F, Le Mao J, Martin S, Galli T, David B, Blank U, et al. Soluble NSF attachment protein receptors (SNAREs) in RBL-2H3 mast cells: functional role of syntaxin 4 in exocytosis and identification of a vesicle-associated membrane protein 8-containing secretory compartment. J Immunol. 2000;164:5850–7.

    Article  CAS  PubMed  Google Scholar 

  35. Guo Z, Turner C, Castle D. Relocation of the t-SNARE SNAP-23 from lamellipodia-like cell surface projections regulates compound exocytosis in mast cells. Cell. 1998;94:537–48.

    Article  CAS  PubMed  Google Scholar 

  36. Cosen-Binker LI, Binker MG, Wang CC, Hong W, Gaisano HY. VAMP8 is the v-SNARE that mediates basolateral exocytosis in a mouse model of alcoholic pancreatitis. J Clin Investig. 2008;118:2535–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Madera-Salcedo IK, Cruz SL, Gonzalez-Espinosa C. Morphine prevents lipopolysaccharide-induced TNF secretion in mast cells blocking IkappaB kinase activation and SNAP-23 phosphorylation: correlation with the formation of a beta-arrestin/TRAF6 complex. J Immunol. 2013;191:3400–9.

    Article  CAS  PubMed  Google Scholar 

  38. van Niel G, D’Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol. 2018;19:213–28.

    Article  PubMed  Google Scholar 

  39. Jin G, Liu Y, Zhang J, Bian Z, Yao S, Fei B, et al. A panel of serum exosomal microRNAs as predictive markers for chemoresistance in advanced colorectal cancer. Cancer Chemother Pharmcol. 2019;84:315–25.

    Article  CAS  Google Scholar 

  40. Lin Z, Ji Y, Zhou J, Li G, Wu Y, Liu W, et al. Exosomal circRNAs in cancer: Implications for therapy resistance and biomarkers. Cancer Lett. 2023;566:216245.

    Article  CAS  PubMed  Google Scholar 

  41. Marima R, Basera A, Miya T, Damane BP, Kandhavelu J, Mirza S, et al. Exosomal long non-coding RNAs in cancer: interplay, modulation, and therapeutic avenues. Noncoding RNA Res. 2024;9:887–900.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study was partially supported by grants from the National Natural Science Foundation of China (82472939, 82173193, 82473060, and 82173063), Basic Research Program of Jiangsu Province (BK20241762), Middle-aged People of Wuxi Health Committee (BJ2023060), and Wuxi Medical Key Discipline (ZDXK2021002).

Author information

Author notes

  1. These authors contributed equally: Yuan Yin, Liang Ming.

Authors and Affiliations

  1. Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, China

    Yuan Yin, Liang Ming, Junhui Tang, Bingxin Liu, Yuhang Liu, Guoying Jin, Lingzhen Jiang, Surui Yao & Zhaohui Huang

  2. Laboratory of Cancer Epigenetics, Wuxi School of Medicine, Jiangnan University, Wuxi, China

    Yuan Yin, Liang Ming, Junhui Tang, Bingxin Liu, Yuhang Liu, Guoying Jin, Lingzhen Jiang, Surui Yao & Zhaohui Huang

  3. Department of Pathology, Affiliated Hospital of Jiangnan University, Wuxi, China

    Yan Qin & Xiaowei Qi

Authors
  1. Yuan Yin
    View author publications

    Search author on:PubMed Google Scholar

  2. Liang Ming
    View author publications

    Search author on:PubMed Google Scholar

  3. Yan Qin
    View author publications

    Search author on:PubMed Google Scholar

  4. Junhui Tang
    View author publications

    Search author on:PubMed Google Scholar

  5. Bingxin Liu
    View author publications

    Search author on:PubMed Google Scholar

  6. Yuhang Liu
    View author publications

    Search author on:PubMed Google Scholar

  7. Guoying Jin
    View author publications

    Search author on:PubMed Google Scholar

  8. Lingzhen Jiang
    View author publications

    Search author on:PubMed Google Scholar

  9. Surui Yao
    View author publications

    Search author on:PubMed Google Scholar

  10. Xiaowei Qi
    View author publications

    Search author on:PubMed Google Scholar

  11. Zhaohui Huang
    View author publications

    Search author on:PubMed Google Scholar

Contributions

Zhaohui Huang and Yuan Yin conceived and designed the project. Liang Ming, Yan Qin, Junhui Tang, Bingxin Liu, Yuhang Liu, Guoying Jin, and Lingzhen Jiang performed all the experiments, Junhui Tang. Bingxin Liu and Surui Yao performed the statistical analyses. Yan Qin and Xiaowe Qi were responsible for clinical sample collection and pathological analysis. Zhaohui Huang and Yuan Yin wrote the paper. The author(s) read and approved the final manuscript.

Corresponding authors

Correspondence to Yuan Yin or Zhaohui Huang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yin, Y., Ming, L., Qin, Y. et al. RAB22A triggers intercellular chemoresistance transmission in colorectal cancer by promoting exosome release via the PKM2-pSNAP23 axis. Oncogene 44, 4205–4217 (2025). https://doi.org/10.1038/s41388-025-03566-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41388-025-03566-y

Search

Advanced search

Quick links