Metastatic Niche

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We recently identified collagen-rich airway smooth muscle cells as a metastatic niche for cancer cell colonization in the lung. Ongoing projects will further characterize its interaction with other immune cells in the microenvironment (e.g. neutrophils, NK cells) to facilitate the process. We are building on existing RNAseq data profiling the niche and cancer cells, functionally integrating with microfluidics system in vitro and established in vivo models to study their mechanistic interactions (see training opportunities).

 

Tumor Microenvironment

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Immune checkpoint blockade therapy is emerging as a major treatment modality for cancer patients. However, a large fraction of patients remain non-responders. Ongoing projects is further characterizing the resistance mechanisms, e.g., i) how to turn cold tumors into hot tumors, via modulating dying cancer cell-released DAMP and iDAMP and dendritic cell cross priming of CD8+ T cells, ii) cancer cell modulation of the immunosuppressive immune microenvironment etc (see training opportunities).

 

Programmed Cell Death

Most anti-cancer therapeutics designate cell death as the end goal, we serendipitously discovered drug-induced dying cells play a major role in inducing residual tumor cell repopulation and immunosuppression. And thus, driving therapeutic resistance. Proteomics discovery identified novel protein complexes associated with various forms of programmed cell death mechanisms. Ongoing studies will further dissect these molecular mechanisms (see training opportunities). 

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Representative Publications

Tipping the immunostimulatory and inhibitory DAMP balance to harness immunogenic cell death. K. Hayashi, F. Nikolos, Y. C. Lee, A. Jain, E. Tsouko, H. Gao, A. Kasabyan, H. E. Leung, A. Osipov, S. Y. Jung, A. V. Kurtova & K. S. Chan. Nature Communications 11, 6299 (2020)

Integrative multi-omics analysis of muscle-invasive bladder cancer identifies prognostic biomarkers for frontline chemotherapy and immunotherapy. Mo Q, Li R, Adeegbe DO, Peng G, Chan KS. Commun Biol 3(1):784 (2020).

Collagen-rich airway smooth muscle cells are a metastatic niche for tumor colonization in the lung. Lee YC, Kurtova AV, Xiao J, Nikolos F, Hayashi K, Tramel Z, Jain A, Chen F, Chokshi M, Lee C, Bao G, Zhang X, Shen J, Mo Q, Jung SY, Rowley D, Chan KS. Nature Communications 10, 2131 (2019)

Prognostic Power of a Tumor Differentiation Gene Signature for Bladder Urothelial Carcinomas. Qianxing MoFotis NikolosFengju ChenZoe TramelYu-Cheng LeeKazukuni HayashiJing XiaoJianjun ShenKeith Syson Chan. Journal of the National Cancer Institute, 110, 448–459 (2018) 

Cellular hierarchy as a determinant of tumor sensitivity to chemotherapy. Ignacio Rodriguez-Brenes, Antonina V Kurtova, Christopher Lin, Yu-Cheng Lee, Jing Xiao, Martha P Mims, Keith Syson Chan and Dominik Wodarz. Cancer Res 77(9):2231-2241 (2017). 

Molecular Pathways: Targeting Cancer Stem Cells Awakened by Chemotherapy to Abrogate Tumor Repopulation. Chan, KS. Clin Cancer Res 22(4):802-6 (2016). 

Blocking PGE2-induced tumour repopulation abrogates bladder cancer chemoresistance. Kurtova AV, Xiao J, Mo Q, Pazhanisamy S, Krasnow R, Lerner SP, Chen F, Roh TT, Lay E, Ho PL, Chan KS. Nature 517, 209–213 (2015)

Three differentiation states risk-stratify bladder cancer into distinct subtypes. Volkmer JP, Sahoo D, Chin RK, Ho PL, Tang C, Kurtova AV, Willingham SB, Pazhanisamy SK, Contreras-Trujillo H, Storm TA, Lotan Y, Beck AH, Chung BI, Alizadeh AA, Godoy G, Lerner SP, van de Rijn M, Shortliffe LD, Weissman IL, Chan KS. Proc Natl Acad Sci U S A 109(6):2078-83 (2012).

Normal and neoplastic urothelial stem cells: getting to the root of the problem. Philip Levy Ho, Antonina Kurtova & Keith Syson Chan. Nature Reviews Urology 9, 583–594 (2012)

Stat3 activation in urothelial stem cells leads to direct progression to invasive bladder cancer. Philip Levy Ho, Erica Julianne Lay, Weiguo Jian, Diana Parra and Keith Syson Chan. Cancer Res 72(13):3135-42 (2012).

Identification, molecular characterization, clinical prognosis, and therapeutic targeting of human bladder tumor-initiating cells. Chan KS, Espinosa IChao MWong DAilles L, Diehn MGill HPresti J, Chang HYvan de Rijn MShortliffe LWeissman IL.

Proc Natl Acad Sci U S A. 106(33):14016-21 (2009).