Molecular Oncology and Biomarkers Program
Assistant Professor, Biochemistry and Molecular Biology
Assistant Professor, Graduate Studies
Georgia Cancer Center
1410 Laney Walker Blvd., CN-2136
Women with metastatic disease have limited treatment options and shorter lifespans compared to those with indolent tumors. Dissemination via epithelial-mesenchymal-transition (EMT) conversion is a limiting necessary step in the metastatic process. Current understanding suggests that successful metastatic colonization in distant organs requires disseminated tumor cells to revert back to the epithelial phenotype via mesenchymal-epithelial-transition (MET). Our research focuses on the understanding of the early molecular events during the metastatic cascade.
Cancer Stem Cells (CSC)
It is now widely believed that cancers are driven by a subset of cells called cancer stem cells (CSCs) or tumor-initiating cells (TICs) that mediate metastasis, recurrence and treatment resistance. Moreover, it has been well established that epithelial-mesenchymal-transition (EMT) induces the CSC phenotype. Consistent with this, our laboratory and others have provided evidence that activation of inflammatory cytokines in tumors is associated with an aggressive EMT/CSC phenotype. In addition, we have provided a better understanding of the role of CSCs in trastuzumab resistance in HER2+ breast cancer. Our team recently demonstrated that activation of the inflammatory cytokines in basal/triple-negative tumors due to loss of the suppressor of cytokine signaling 3 (SOCS3) results in induction of the EMT/CSC phenotype.
The link between inflammation and metastasis
Although there is a wealth of current information describing the genetic and epigenetic differences between metastatic versus non-metastatic tumors, a knowledge gap exists in the understanding of early events between the tumor and the immune system. Our long-term goal is to dissect the early molecular crosstalk between malignant cells and the immune system in the metastatic process and identify therapeutic targets. Our studies provide evidence that the basal/triple-negative breast cancer (TNBC) cells with an activated inflammatory feedback loop may convert anti-tumor immune responses into cancer-promoting inflammation. Cytokines control immune responses by controlling the Jak/Stat3/NF-kB pathway that is negatively regulated by the suppressor of cytokine signaling 3 (SOCS3). These ongoing studies identify that SOCS3 plays a critical role by negatively regulating the inflammatory cytokines in tumors as well as mediating anti-tumor immune responses. Our team is currently investigating the molecular mechanism of inflammatory cytokines and exploring the therapeutic utility of SOCS3 in patients with aggressive/metastatic disease.
Regulation of tumor plasticity between EMT and MET
Our ongoing studies are aimed at understanding early cross-communication between tumor cells and the immune system. Thus, we performed extensive analyses of the early events in tumor progression using syngeneic mouse models with metastatic versus non-invasive murine breast tumors. We demonstrated that early infiltration of monocytic myeloid-derived suppressor cells (MDSCs) in primary tumors induced an EMT phenotype at the invasive edge and facilitated dissemination while infiltration of granulocytic MDSCs in lungs reverted the EMT phenotype and promoted metastatic growth in secondary organs.
Maria Ouzounova*, Eunmi Lee*, Raziye Piranlioglu, Abduljabar El Andaloussi, Ravindra Kolhe, Mehmet F. Demirci, Daniela Marasco, Iskander Asm, Ahmed Chadli, Khaled A. Hassan, Muthusamy Thangaraju, Ganga Zhou, Ali S. Arbab, John K. Cowell, Hasan Korkaya. Monocytic and granulocytic myeloid derived suppressor cells differentially regulate spatiotemporal tumor plasticity during metastatic cascade. Nature Communication 2017 Apr 6;8:14979
Satish K. Noonepalle, Franklin Gu, Eun-Joon Lee, Jeong-Hyeon Choi, Qimei Han, Jaejik Kim, Maria Ouzounova, Austin Y. Shull, Lirong Pei, Pei-Yin Hsu, Ravindra Kolhe, Fang Shi, Jiseok Choi, Katie Chiou, Tim H.M. Huang, Hasan Korkaya, Libin Deng, Hong-Bo Xin, Shuang Huang, Muthushamy Thangaraju, Arun Sreekumar, Stefan Ambs, Shou-Ching Tang, David H. Munn and Huidong Shi. Promoter methylation modulates indolamine 2,3-Dioxygenase 1 induction by activated T cells in human breast cancers. Cancer Immunology Research 2017 Apr ;5(4):330-344
Anup S. Pathania, Santosh K. guru, Suresh Kumar, Ashok Kumar, Masroor Ahmad, Shashi Bhushan, Parduman R. Sharma, Priya Mahajan, Bhahwal A. Shah, Simmi Sharma, Amit Nargotra, Ram Vishwakarma, Hasan Korkaya and Fayaz Malik. Interplay between cell cycle and autophagy induced by boswellic acid analog. Nature Scientific Reports 2016 Sep 29;6:33146
Erik S. Linklater, Elizabeth A. Tovar, Curt J. Essenburg, Lisa turner, Zachary Madaj, Mary E. Winn, Marianne K. Meinik, Hasan Korkaya, Christiane R. Maroun, James G. Christiensen, Matthew R. Steensma, Julie L. Boerner, Carrie R. Graveel. Targeting MET and EGFR crosstalk signaling in triple-negative breast cancer. 2016 7(43):69903-69915
Hayley J. Paholak, Nicholas O. Stevers, Hongwei Chen, Joseph P. Burnett, Miao He, Hasan Korkaya, Sean P. McDermott, Yadwinder Deol, Shawn G. Clouthier, Tahra Luther, Qiao Li, Max S. Wicha and Duxin Sun. Elimination of epithelial-like and mesenchymal-like breast cancer stem cells to inhibit metastasis following nanoparticle-mediated photothermal therapy. Biomaterials 2016 Jun 23;104:145-157
D’Angelo RC, Ouzounova M, Davis A, Choi D, Tchuenkam SM, Kim G, Luther T, Quraishi AA, Senbabaoglu Y, Conley S, Clouthier S, Hassan K, Wicha MS, Korkaya H. (2015) Notch reporter activity in breast cancer cell lines identifies a subset of cells with stem cell activity. Mol Cancer Therapeutics,14:779-87.
Pathania AS, Wani ZA, Guru SK, Kumar S, Bhushan S, Korkaya H, Seals DF, Mahajan AK, Mondhe DM, Ahmed Z, Chandan BK, Malik F. (2015) The anti-angiogenic and cytotoxic effects of the boswellic acid analog BA145 are potentiated by autophagy inhibitors. Molecular Cancer. 14(1):6.
Kim G, Ouzounova M, Quraishi AA, Davis A, Tawakkol N, Clouthier SG, Malik F, Paulson AK, D’Angelo RC, Korkaya S, Baker TL, Esen ES, Prat A, Liu S, Kleer CG, Thomas DG, Wicha MS, Korkaya H. (2014)SOCS3-mediated regulation of inflammatory cytokines in PTEN and p53 inactivated triple negative breast cancer model. Oncogene.34(6):671-80.
Lin L, Hutzen B, Lee HF, Peng Z, Wang W, Zhao C, Lin HJ, Sun D, Li PK, Li C, Korkaya H, Wicha M, Lin J. (2014) Evaluation of Stat3 signaling in ALDH+ and ALDH+/CD44+/CD24- subpopulations of breast cancer cells. PLOS One.8(12):E82821.
Hassan KA, Wang L, Korkaya H, Chen G, Maillard I, Beer DG, Kalemkerian GP, Wicha MS. (2013) Notch Pathway activity identifies cells with cancer stem cell-like properties and correlates with worse survival in lung adenocarcinoma. Clinical Cancer Research.19(8):1972-80.
Korkaya H, Wicha MS. (2013) HER2 and breast cancer stem cells: more than meets the eye. Cancer Research.73(12):3489-93.
Korkaya H, Wicha MS. (2013) Breast Cancer Stem Cells: we’ve got them surrounded. Clinical Cancer Research. 19(3):511-13.
Ithimakin S, Day KC, Malik F, Zen Q, Dawsey SJ, Bersano-Begey TF, Quraishi AA, Ignatoski KW, Daignault S, Davis A, Hall CL, Palanisamy N, Heath AN, Tawakkol N, Luther TK, Clouthier SG, Chadwick WA, Day ML, Kleer C, Thomas DG, Hayes DF, Korkaya H*, Wicha MS*. (2013) HER2 drives luminal breast cancer stem cells in the absence of HER2 amplification: Implications for efficacy of adjuvant trastuzumab. Cancer Research.73(5):1635-46. * Co-corresponding author
Petrillo LA, Wolf DM, Kapoun AM, Wang NJ, Barczak A, Xiao Y, Korkaya H, Baehner F, Lewicki J, Wicha M, Park JW, Spellman PT, Gray JW, van’t Veer L, Esserman LJ. (2012) Xenografts faithfully recapitulate breast cancer-specific gene expression patterns of parent primary breast tumors. Breast Cancer Res Treat. 135:913–22.
Korkaya H, Kim GI, Davis A, Malik F, Henry NL, Ithimakin S, Quraishi AA, Tawakkol N, D’Angelo R, Paulson AK, Chung S, Luther T, Paholak HJ, Liu S, Hassan KA, Zen Q, Clouthier SG, Wicha MS. (2012) Activation of an IL-6 Inflammatory Loop Mediates Trastuzumab Resistance in HER2+ Breast Cancers by Expanding the Cancer Stem Cell Population.Molecular Cell.47(4):570-84.
Conley SJ, Gheordunescu E, Kakarala P, Newman B, Korkaya H, Heath AN, Clouthier SG, Wicha MS. (2012) Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia. Proc Natl Acad Sci. 109(8):2784-9.
Korkaya H, Liu S, Wicha MS. (2011) Regulation of Cancer Stem Cells by Cytokine Networks: Attacking Cancers Inflammatory Roots. Clinical Cancer Research. 17:6125-9.
Korkaya H, Liu S, Wicha MS. (2011) Breast Cancer Stem Cells, Cytokine Networks and the Tumor Microenvironment. Journal of Clinical Investigation. 121(10):3804-9.
Liu S, Ginestier C, Ou SJ, Clouthier SG, Patel S, Monville F, Korkaya H, Heath A, Dutcher J, Kleer CG, Jung Y, Dontu G, Taichman R, Wicha MS. (2011) Breast Cancer Stem Cells are Regulated by Mesenchymal Stem Cells Through Cytokine Networks. Cancer Research.71(2):614-24.
Li Y, Zhang T, Korkaya H, Liu S, Lee HF, Newman B, Yu Y, Clouthier SG, Schwartz SJ, Wicha MS, Sun D. (2010) Sulforaphane, a Dietary Component of Broccoli/Broccoli Sprouts, Inhibits Breast Cancer Stem Cells. Clinical Cancer Research.16(9):2580-90.