Research Areas: 

(1) We investigate on the influence of the tumor microenvironment (TME) on cancer resistance and associated mechanisms.  

While cancer was long considered a disease defined and driven by genomic instability, chromosomal alterations, and genetic mutations, the influence of tumor-adjacent stromal cells in the TME is now increasingly appreciated. Tumors are complex tissues comprising not only malignant cells but also genetically stable stromal cells, including fibroblasts, endothelial cells, and immune cells, in addition to the extracellular matrix (ECM) they produce. As in healthy organs, the various cellular compartments of the TME are not mere bystanders, but instead critically regulate tumorigenesis. This extends not only to tumor initiation, malignant progression, and metastasis but importantly also to response to therapy. Moreover, the realization that distinct stromal cell types in different contexts can exhibit tumor-promoting or opposing tumoricidal capacities has further complicated our understanding of cancer biology. We are interested in the role of the TME during tumorigenesis and focus on how the TME regulates therapeutic response, a field that has been rapidly expanding in recent years. As in the context of malignant progression, the TME exhibits a multifaceted ability to influence therapeutic outcome in either a positive or a negative manner. Harnessing this expanding knowledge to improve therapeutic response or even to develop new treatment options through normalization and re-education of the TME is increasingly within reach. The recent clinical success of immune checkpoint inhibitors serves as an illustrative example of this goal. Our recent studies provide essential clues to allow understanding of the different factors contributing to TME-conferred or acquired/adaptive resistance with regard to traditional anticancer therapies, particularly chemotherapy, radiation and molecularly targeted therapies. 

(2) We discover the intracellular signaling network that regulates cellular senescence, senescence-associated secretory phenotype and explore optimal targeting strategies.  

Cellular senescence is an anti-proliferative program that restricts the propagation of cells subjected to different kinds of interior or environmental stresses. Cellular senescence was initially described as a cell-autonomous tumor suppressor mechanism that triggers an irreversible cell cycle arrest that prevents the proliferation of damaged cells at risk of neoplastic transformation. However, discoveries during the last decade have established that senescent cells can also impact the surrounding tissue microenvironment and the neighboring cells in a cell-non-autonomous manner. These cell-non-autonomous activities are, partially, mediated by the selective secretion of extracellular matrix degrading enzymes, cytokines, chemokines and immune modulators, which collectively constitute the senescence-associated secretory phenotype (SASP). One of the key functions of the SASP is to attract immune cells into the local microenvironment, which in turn can orchestrate the elimination of senescent cells in vivo. Interestingly, the clearance of senescent cells seems to be critical to dictate the net effects of cellular senescence. As a general rule, the successful elimination of senescent cells takes place in processes that are considered beneficial, such as tumor suppression, tissue remodeling and embryonic development, while the chronic accumulation of senescent cells leads to more detrimental consequences, namely, cancer and other aging-related pathologies. Nevertheless, exceptions to this rule may exist. Now that cellular senescence is in the spotlight for both anti-cancer and anti-aging therapies, understanding the precise underpinnings of senescent cell removal will be essential to exploit cellular senescence to its full potential. 

Brief Biography:

2000-2005: Dalhousie University (Canada), Ph.D.
1996-1999: Chinese Academy of Sciences, Institute of Genetics and Developmental Biology, M.S.
1992-1996: Yantai University, Biochemistry and Microbiology Department, B.S. 

Selected Publications: (*Corresponding Author)

1. Jiang, B., Zhang, W., Zhang, X. and Sun, Y. 2024. Targeting senescent cells to reshape the tumor microenvironment and improve anticancer efficacy. Semin Cancer Biol. 101: 58-73.

2. Liu H, Xu Q, Wufuer H, Li Z, Sun R, Jiang Z, Dou X, Fu Q*, Campisi J*, Sun Y*. (2024). Rutin is a potent senomorphic agent to target senescent cells and can improve chemotherapeutic efficacy. Aging Cell. 23(1): e13921.

3. Dou X, Fu Q, Long Q, Liu S, Zou Y, Fu D, Xu Q, Jiang Z, Ren X, Zhang G, Wei X, Li Q, Campisi J, Zhao Y*, Sun Y*. (2023). PDK4-dependent Hypercatabolism and Lactate Production of Senescent Cells Promotes Cancer Malignancy. Nat Metab. 5(11):1887-1910.

4. Ren J, Song M, Zhang W, Cai J, Cao F, Cao Z, Chan P, Chen C, Chen G, Chen Z, Chen J, Chen X, Ci W, Ding B, Ding Q, Gao F, Gao S, Han J, He Q, Huang K, Ju Z, Kong Q, Li J, Li J, Li J, Li X, Liu B, Liu F, Liu J, Liu L, Liu Q, Liu Q, Liu X, Liu Y, Luo X, Ma S, Ma X, Mao Z, Nie J, Peng Y, Qu J, Ren R, Song W, Songyang Z, Sun L, Sun Y, Sun Y, Tian M, Tian X, Tian Y, Wang J, Wang S, Wang S, Wang W, Wang X, Wang X, Wang Y, Wang Y, Wong CCL, Xiang A, Xiao Y, Xiao Z, Xie Z, Xiong W, Xu D, Yang Z, Ye J, Yu W, Yue R, Zhang C, Zhang H, Zhang L, Zhang X, Zhang Y, Zhang Y, Zhang Z, Zhao T, Zhao Y, Zhou Z, Zhu D, Zou W, Pei G, Liu G*. (2023). The aging biomarker consortium represents a new era for aging research in china. Nat Med. 29(9): 2162-2165.

5. Zhang C, Wang P, Zhang YN, Lu P, Huang X, Wang Y, Ran L, Xin H, Xu X, Gao W, Sun Y*, Zhang L*, Zhang G*. (2023). Biodegradable nanoplatform upregulates tumor microenvironment acidity for enhanced cancer therapy via synergistic induction of apoptosis, ferroptosis, and anti-angiogenesis. J Nanobiotechnology. 21(1):59.

6. Xie Y, Chen, S, Sheng L, Sun Y*, Liu, S*. (2023). A new landscape of human dental aging: causes, consequences, and intervention avenues. Aging and Disease. 14(4):1123-1144.

7. Duan R, Fu Q, Sun Y*, Li Q*. (2022). Epigenetic clock: A promising biomarker and practical tool in aging. Ageing Res Rev. 81: 101743.

8. Wang C, Long Q, Fu Q, Xu Q, Fu D, Li Y, Gao L, Guo J, Zhang X, Lam EWF, Campisi J, Sun Y*. (2022). Targeting epiregulin in the treatment-damaged tumor microenvironment restrains therapeutic resistance. Oncogene. 41: 4941-4959.

9. Cai Y, Song W, Li J, Jing Y, Liang C, Zhang L, Zhang X, Zhang W, Liu B, An Y, Li J, Tang B, Pei S, Wu X, Liu Y, Zhuang C, Ying Y, Dou X, Chen Y, Xiao F, Li D, Yang R, Zhao Y, Wang Y, Wang L, Li Y, Ma S, Wang S, Song X, Ren J, Zhang L, Wang J, Zhang W, Xie Z, Qu J, Wang J, Xiao Y, Tian Y, Wang G, Hu P, Ye J, Sun Y, Mao Z, Kong Q, Liu Q, Zou W, Tian X, Xiao Z, Liu Y, Liu J, Song M, Han, JJ, Liu G*. (2022). The Landscape of Aging. Sci China Life Sci. 65: 2354-2454.

10. Sun Y*, Li Q*, Kirkland JK*. (2022). Targeting Senescent Cells for a Healthier Longevity: the Roadmap for an Era of Global Aging. Life Med. 1(2):103-119.

11. Fu Q, Duan R, Sun Y*, Li Q*. (2022). Hyperbaric Oxygen Therapy for Healthy Aging: from Mechanisms to Therapeutics. Redox Biology. 53: 102352.

12. Liu H, Zhao H, Sun Y*. (2021). Tumor Microenvironment and Cellular Senescence: Understanding Therapeutic Resistance and Harnessing Strategies. Semin Cancer Biol. 86(Pt 3): 769-781.

13. Xu Q, Fu Q, Li Z, Liu H, Wang Y, Lin X, He R, Zhang X, Ju Z, Campisi J, Kirkland JK, Sun Y*. (2021) The Flavonoid Procyanidin C1 Has Senotherapeutic Activity and Increases Lifespan in Mice. Nat Metab 3(12):1706-1726.

14. Liu H, Zhao H, Sun Y*. (2021) Tumor Microenvironment and Cellular Senescence: Understanding Therapeutic Resistance and Harnessing Strategies. Semin Cancer Biol 77(11):S1044-579X(21)00271-6.

15. Song S, Tchkonia T, Jiang J, Kirkland JL, Sun Y*. (2020) Targeting Senescent Cells for a Healthier Aging: Challenges and Opportunities. Adv Sci 7(23):2002611.

16. Han L, Long Q, Li S, Xu Q, Zhang B, Dou X, Qian M, Jiramongkol Y, Guo J, Cao L, Chin YE, Lam E WF, Jiang J, Sun Y*. (2020) Senescent Stromal Cells Promote Cancer Resistance through SIRT1 Loss-Potentiated Overproduction of Small Extracellular Vesicles. Cancer Res 80(16):3383-3398.

17. Song S, Lam E, Tchkonia T, Kirkland J, Sun Y*. (2020) Senescent Cells: Emerging Targets for Human Aging and Age-Related Diseases. Trends Biochem Sci 45(7):578-592.

18. Xu Q, Long Q, Zhu D, Fu D, Zhang B, Han L, Qian M, Guo J, Xu J, Cao L, Chin YE, Coppé JP, Lam E WF, Campisi J, Sun Y*. (2019) Targeting Amphiregulin (AREG) Derived from Senescent Stromal Cells Diminishes Cancer Resistance and Averts Programmed Cell Death 1 Ligand (PD-L1)-Mediated Immunosuppression. Aging Cell 18(6):e13027.

19. Munoz DP, Yannone SM, Daemen A, Sun Y, Vakar-Lopez F, Kawahara M, Freund AM, Rodier F, Wu JD, Desprez PY, Raulet DH, Nelson PS, van't Veer LJ, Campisi J, Coppé JP. (2019) Targetable Mechanisms Driving Immunoevasion of Persistent Senescent Cells Link Chemotherapy-Resistant Cancer to Aging. JCI Insight 5(14):e124716.

20. Han L, Lam E WF, Sun Y*. (2019) Extracellular Vesicles in the Tumor Microenvironment: Old Stories, But New Tales. Mol Cancer 18(1):59.

21. Zhang B, Lam E WF, Sun Y*. (2019) Senescent Cells: A New Achilles' Heel to Exploit for Cancer Medicine? Aging Cell 18(1):e12875.

22. Chen F, Long Q, Fu D, Zhu D, Ji Y, Han L, Zhang B, Xu Q, Liu B, Li Y, Wu S, Yang C, Qian M, Xu J, Liu S, Cao L, Chin YE, Lam E WF, Coppé JP, Sun Y*. (2018) Targeting SPINK1 in the Damaged Tumour Microenvironment Alleviates Therapeutic Resistance. Nat Commun 9(1):4315.

23. Sun Y*, Coppé JP, Lam E WF. (2018) Cellular Senescence: the Sought or the Unwanted? Trends Mol Med 24(10):871-885.

24. Zhang B, Fu D, Xu Q, Cong X, Wu C, Zhong X, Ma Y, Lv Z, Chen F, Han L, Qian M, Chin YE, Lam E WF, Chiao P, Sun Y*. (2018) The Senescence-Associated Secretory Phenotype Is Potentiated by Feedforward Regulatory Mechanisms Involving Zscan4 and TAK1. Nat Commun 9(1):1723.

25. Zhang B, Chen F, Xu Q, Han L, Xu J, Gao L, Sun X, Li Y, Li Y, Qian M, Sun Y*. (2018) Revisiting Ovarian Cancer Microenvironment: a Friend or a Foe? Protein Cell 9(8):674–692.

26. Han L, Xu J, Xu Q, Zhang B, Lam E WF, Sun Y*. (2017) Extracellular Vesicles in the Tumor Microenvironment: Therapeutic Resistance, Clinical Biomarkers and Targeting Strategies. Med Res Rev 37(6):1318-1349.

27. Gomez-Sarosi L#, Sun Y#, Coleman I, Bianchi-Frias D, Nelson PS. (2017) DNA Damage Induces a Secretory Program in the Quiescent TME that Fosters Adverse Cancer Phenotypes. Mol Cancer Res 15(7):842-851. (co-first author)

28. Sun Y*. (2016) Tumor Microenvironment and Cancer Therapy Resistance. Cancer Lett 380(1):205–215.

29. Xu Q, Chiao P, Sun Y*. (2016) Amphiregulin in Cancer: New Insights for Translational Medicine. Trends Cancer 2(3):111-113.

30. Sun Y*, Zhu D, Chen F, Qian M, Wei H, Chen W, Xu J. (2016) SFRP2 Augments WNT16B Signaling to Promote Therapeutic Resistance in the Damaged Tumor Microenvironment. Oncogene 35(33):4321-4334.

31. Zhang B, Sun Y*. (2015) Landscape and Targeting of the Angpt-Tie System in Current Anticancer Therapy. Transl Med 5(3):157.

32. Laberge RM, Sun Y, Orjalo AV, Patil CK, Freund A, Zhou L, Curran SC, Davalos AR, Wilson-Edell KA, Liu S, Limbad C, Demaria M, Li P, Hubbard GB, Ikeno Y, Javors M, Desprez PY, Benz CC, Kapahi P, Nelson PS, Campisi J. (2015) mTOR Regulates the Pro-Tumorigenic Senescence-Associated Secretory Phenotype by Promoting IL1A Translation. Nat Cell Biol 17(8):1049-1061.

33. Chen F, Zhuang X, Lin L, Yu P, Wang Y, Shi Y, Hu G, Sun Y*. (2015) New Horizons in the Tumor Microenvironment Biology: Challenges and Opportunities. BMC Med 13:45.

(highly accessed and journal-featured article)

34. Sun Y*. (2015) Translational Horizons in the Tumor Microenvironment: Harnessing Breakthroughs and Targeting Cures. Med Res Rev 35(2):408-436.

35. Chen F, Qi X, Qian M, Dai Y, Sun Y*. (2014) Tackling the Tumor Microenvironment: What Challenge Does It Pose to Anticancer Therapies? Protein Cell 5(11):816–826.

36. Sun Y, Campisi J, Higano C, Beer TM, Porter P, Coleman I, True L, Nelson PS. (2012) Treatment-Induced Damage to the Tumor Microenvironment Promotes Prostate Cancer Therapy Resistance through WNT16B. Nat Med 18(9):1359-1368.

37. Sun Y, Nelson PS. (2012) Molecular Pathways: Involving Microenvironment Damage Responses in Cancer Therapy Resistance. Clin Cancer Res 18(15):4019-4025.

38. Bluemn EG, Paulson KG, Higgins EE, Sun Y, Nghiem P, Nelson PS. (2009) Merkel Cell Polyomavirus is not Detected in Prostate Cancers, Surrounding Stroma, or Benign Prostate Controls. J Clin Virol 44()2:164-166.

39. Coppé JP, Patil CK, Rodier F, Sun Y, Munoz DP, Goldstein J, Nelson PS, Desprez P–Y, Campisi J. (2008) Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor. PLoS Biol 6(12):2853-2868.

40. Sun Y, Wong N, Guan Y, Salamanca CM, Cheng JC, Lee JM, Gray JW, Auersperg N. (2008) The Eukaryotic Translation Elongation Factor eEF1A2 Induces Neoplastic Properties and Mediates Tumorigenic Effects of ZNF217 in Precursor Cells of Human Ovarian Carcinomas. Int J Cancer 123(8):1761-1769.

41. Li P, Maines-Bandiera S, Kuo W, Guan Y, Sun Y, Hills M, Huang G, Collins CC, Leung PCK, Gray JW, Auersperg N. (2007) Multiple Roles of the Candidate Oncogene ZNF217 in Ovarian Epithelial Neoplastic Progression. Int J Cancer 120(9):1863-1873.

42. Sun Y, Bojikova-Fournier S, MacRae TH. (2006) Structural and Functional Roles for β-Strand 7 in the α-Crystallin Domain of p26, a Poly-disperse Small Heat Shock Protein from the Extremophile, Artemia franciscana. FEBS J 273(5):1020-1034.

43. Villeneuve TS, Ma X, Sun Y, Oulton MM, Oliver AE, MacRae TH. (2006) Inhibition of Apoptosis by p26: Implications for Small Heat Shock Protein Function during Artemia Development. Cell Stress Chaperones 11(1):71-80.

44. Ma X, Jamil K, MacRae TH, Clegg JS, Russell JM, Villeneuve TS, Euloth M, Sun Y, Crowe JH, Tablin F, Oliver AE. (2005) A Small Stress Protein Acts Synergistically with Trehalose to Confer Desiccation Tolerance on Mammalian Cells. Cryobiology 51(1):15-28.

45. Sun Y, MacRae TH. (2005) Characterization of Novel Sequence Motifs within Amino- and Carboxy-Terminal Extensions of p26, a Small Heat Shock Protein from Artemia franciscana. FEBS J 272(20):5230-5243.

46. Sun Y, MacRae TH. (2005) Small Heat Shock Proteins: Molecular Structure and Chaperone Function. Cell Mol Life Sci 62(21):2460-2476.

47. Sun Y, MacRae TH. (2005) The Small Heat Shock Proteins and their Role in Human Disease. FEBS J 272(11):2613-2627.

48. Sun Y, Mansour M, Crack JA, Gass GL, MacRae TH. (2004) Oligomerization, Chaperone Activity and Nuclear Localization of p26, a Small Heat Shock Protein from Artemia franciscana. J Biol Chem 279(38):39999-40006.

49. Crack J, Mansour M, Sun Y, MacRae TH. (2002) Functional Analysis of a Small Heat Shock/alpha-Crystallin Protein from Artemia franciscana. Eur J Biochem 269(3):933-942.