• Role and mechanisms of cancer cell-secreted factors in the development and progression of esophageal cancer
• Identifying and targeting key molecular pathways for cancer therapy
• Roles of microRNAs in chemoresistance and cancer invasiveness

• The University of Hong Kong Shenzhen Institute of Research and Innovation (HKU-SIRI)

Dr. Cheung received her B.Sc. (with 1st class honours) and PhD degrees from the University of Hong Kong. She joined University of Hong Kong as an academic staff after receiving post-doctoral training at the Royal Postgraduate Medical School, London, and the Wolfson Institute of University of Hull on a Croucher Foundation Fellowship. Dr. Cheung’s research interest is cancer biology.

My research focuses on the molecular mechanisms that promote the development and progression of esophageal squamous cell carcinoma (ESCC). We were the first to report that ectopic expression of a helix-loop-helix protein Id1 in cancer cells leads to activation of the phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway, which is involved in regulating a wide spectrum of cellular functions including proliferation, survival, angiogenesis, invasion and metastasis. We found that this mechanism, which also promotes cancer cell stemness and chemoresistance, is mediated by Id1-induced secretion of insulin-like growth factor 2 (IGF2), which exerts autocrine influence on cancer cells via the insulin-like growth factor 1 receptor (IGF1R). We also found that cancer cell-secreted IGF2 can activate stromal fibroblasts in the tumor microenvironment to secrete vascular endothelial growth factor (VEGF), which in turn instigates VEGF receptor 1 (VEGFR1)-positive bone marrow-derived vascular progenitor cells to promote tumor angiogenesis and metastasis. Taken together, these findings substantiate that the Id1/IGF2/VEGF/VEGFR1 cascade plays a pivotal role in tumor-driven pathological processes during cancer progression. These studies also provide important pre-clinical data to support the use of antibodies against IGF2, VEGF2 and their receptors as a novel approach in esophageal cancer therapy. Our recent focus is serglycin, which is unique among proteoglycans in that it is the only intracellular proteoglycan identified so far.  Other recent projects include identification of microRNAs that can reverse chemoresistance and suppress invasion/metastasis of ESCC cells.

 

1. Yan D, Cui D, Zhu Y, Chan CKW, Choi CHJ, Liu T, Lee NPY, Law S, Tsao SW, Ma S, Cheung ALM*. M6PR- and EphB4-rich exosomes secreted by serglycin-overexpressing esophageal cancer cells promote cancer progression. International Journal of Biological Sciences 2023; 19(2):625-640.
2. Yan D, Cui D, Zhu Y, Chan CKW, Choi CHJ, Liu T, Tsao SW, Ma S, Cheung ALM*. Serglycin-induced interleukin-1β from oesophageal cancer cells upregulate hepatocyte growth factor in fibroblasts to promote tumour angiogenesis and growth. Clinical and Translational Medicine 2022; 12(8):e1031.
3. Zhu Y, Lam AKY, Shum DKY, Cui D, Zhang J, Yan DD, Li B, Xu WW, Lee NPY, Chan KT, Law S, Tsao SW, Cheung ALM*. Significance of serglycin and its binding partners in autocrine promotion of metastasis in esophageal cancer.  Theranostics 2021; 11(6):2722-2741.
4. Cui D, Zhu Y, Yan DD,  Lee NPY, Han L, Law S, Tsao GSW, Cheung ALM*. Dual inhibition of cMET and EGFR by microRNA-338-5p suppresses metastasis of esophageal squamous cell carcinoma. Carcinogenesis 2021; 42(7):995-1007,
5. Han L, Cui D, Li B, Xu WW, Lam AKY4, Chan KT, Zhu Y, Lee NPY, Law SYK, Guan XY, Qin YR, Chan KW8, Ma S, Tsao SW, Cheung ALM*. miR-338-5p reverses chemoresistance and inhibits invasion of esophageal squamous cell carcinoma cells via targeting Id-1. Cancer Science 2019; 110(12):3677-3688.
6. Li B, Hong P, Zheng C-C, Dai W, Chen W-Y, Yang Q-S, Han L, Tsao SW, Chan KT, Lee NPY, Law S, Xu LY, Li EM, Chan KW, Qin YR, Guan XY, Lung ML, He Q-Y, Xu WW*, Cheung ALM*. Identification of miR-29c and its target FBXO31 as key regulatory mechanism in esophageal cancer chemoresistance: functional validation and clinical significance. Theranostics 2019; 9(6):1599-1613.
7. Xu WW, Li B*, Zhao JF, Yang JG, Li JQ, Tsao SW, He QY, Cheung ALM*. IGF2 induces CD133 expression in esophageal cancer cells to promote cancer stemness. Cancer Lett 2018; 425:88-100.
8. Xu WW, Li B, Guan XY, Chung SK, Wang Y, Yip YL, Law SYK, Chan KT, Lee NPY, Chan KW, Xu LY, Li EM, Tsao SW, He Q*, Cheung ALM*. Cancer cell-secreted IGF2 instigates fibroblasts and bone marrow-derived vascular progenitor cells to promote cancer progression. Nat Comm 2017; 8:14399.
9. Li B, Xu WW, Han L, Chan KT, Tsao SW, Lee NPY, Law S, Xu LY, Li EM, Chan KW, Qin YR, Guan XY, He, QY, Cheung ALM*. microRNA-377 suppresses initiation and progression of esophageal cancer by inhibiting CD133 and VEGF. Oncogene 2017; 36(28):3986-4000. 
10. Li B, Xu WW, Guan XY, Qin YR, Law S, Lee NPY, Chan KT, Tam PY, Li YY, Chan, KW, Yuen HF, Tsao SW, He Q, Cheung ALM*. Competitive binding between Id1 and E2F1 to Cdc20 regulates E2F1 degradation and thymidylate synthase expression to promote esophageal cancer chemoresistance. Clin Cancer Res 2016; 22(5):1243-1255.
11. Li B, Tsao SW, Chan KW, Ludwig DL, Novosyadlyy R, Li YY, He QY, Cheung ALM*. Id1-induced IGF-II and its autocrine/endocrine promotion of esophageal cancer progression and chemoresistance – Implications for IGF-II and IGF-IR-targeted therapy. Clin Cancer Res 2014; 20(10): 2651-2662.
12. Liu J, Han L, Li B, Yang J, Huen MSY, Pan X, Tsao SW, Cheung ALM* (2014). F Box only protein 31 (FBXO31) negatively regulates p38 mitogen-activated protein kinase (MAPK) signaling by mediating lysine 48-linked ubiquitination and degradation of mitogen-activated protein kinase kinase 6 (MKK6). J Biol Chem 2014; 289:21508-21518.
13. Deng W, Tsao SW, Mak GWY, Tsang CM, Ching YP, Guan XY, Huen MSY, Cheung ALM*. Impact of G2 checkpoint defect on centromeric instability. Oncogene 2011; 30(11):1281-1289.
14. Li B, Tsao SW, Li YY, Wang X, Ling MT, Wong YC, He QY, Cheung ALM*.  Id-1 promotes tumorigenicity and metastasis of human esophageal cancer cells through activation of PI3K/AKT signaling pathway. Int J Cancer 2009; 125(11):576-2585.

• HK$1,107,909. Role and mechanism of serglycin in the tumor microenvironment of esophageal cancer. Research Grants Council (RGC) General Research Fund (2019/20).
• HK$1,166,553. Significance of miR-338-5p in modulating PAK4 signaling and metastasis of esophageal cancer. Research Grants Council (RGC) Grant General Research Fund (2017/18).
• HK$1,081,941. Role and mechanism of serglycin in promoting esophageal cancer invasion and metastasis. Research Grants Council (RGC) Grant General Research Fund (2016/17).
• RMB740,000. Identification of miR-29c/FBXO31 as a key regulatory mechanism in esophageal cancer chemoresistance - functional validation and implication for therapy. 2014 National Nature Science Foundation of China (NSFC) grant– General Program.
• HK$960,759. Role of miR-338-5p as a novel modulator of chemoresistance in esophageal cancer. Research Grants Council (RGC) General Research Fund (2014/15).
• HK$984,000. Id1-induced IGF2 promotes esophageal cancer progression through instigation of stromal fibroblasts and bone marrow-derived vascular progenitor cells. Research Grants Council (RGC) General Research Fund (2011/12).
• HK$986,000. Role of Id1-induced IGF2 in autocrine/endocrine promotion of esophageal cancer tumorigenesis and metastasis – implications for targeted therapy. Research Grants Council (RGC) General Research Fund (2010/11).
• HK$1,252,500. Centromeric instability in human cells undergoing immortalization: implication for progression of chromosomal instability in carcinogenesis. Research Grants Council (RGC) General Research Fund (2006/07).
• HK$624,000. Telomere erosion and initiation of chromosomal instability in human cells undergoing immortalization. Hong Kong Research Grants Council (RGC) General Research Fund (2003/04).
• HK$845,600. Role of HPV infection in human esophageal squamous cell carcinoma. Hong Kong Research Grants Council (RGC) General Research Fund (1999/00).

• Applied Immunohistochemistry & Molecular Morphology, Lippincott Williams & Wilkins (1999 – )

• Chi Keung CHAN (Senior Technician)
• Dongdong YAN (PhD Student)