The Clark Lab research program focuses on liver metastasis. Cancer mortality predominantly results from distant metastases that are not visible at diagnosis and escape initial chemotherapy to lie as dormant micrometastases for months or years before emerging to form overt fatal metastases. We are interested in determining the operative molecular underpinnings of metastatic dormancy and recurrence within the liver and applying these findings to identify new therapeutic targets to either maintain dormancy and/or prevent recurrence. Our investigations utilize a novel all-human ex vivo 3D hepatic microphysiological system (MPS) to study the dynamic nature of metastatic disease. This MPS has not only enabled the recreation of dormant-emergent metastatic cancer progression but also the identification of mechanisms, biomarkers, and new therapeutic opportunities to target the various stages of metastasis. Current studies are focused on characterizing the cells and cues that support dormancy, provoke emergence and promote therapeutic resistance.
- Dysregualted gut homeostasis drives the emergence of dormant cancer cells in the liver.
- Bi-directional exosome-based crosstalk within the liver metastatic microenvironment promotes dormancy and therapeutic resistance
Link to full publication list NCBI Bibliography
- D. P. Taylor, A. M. Clark, S. E. Wheeler, A. Wells. Hepatic nonparenchymal cells drive metastatic breast cancer outgrowth and partial epithelial to mesenchymal transition. Breast Cancer Res Treat. 2014 Apr;144(3):551-60.
- S. E. Wheeler*, A. M. Clark*, D. P. Taylor, C. L. Young, V. C. Pillai, D. B. Stolz, R. Venkataramanan, D. Lauffenburger, L. Griffith, A. Wells. Spontaneous dormancy of metastatic breast cancer cells in an all human liver microphysiologic system. Br J Cancer. 2014 Dec 30;111(12):2342-50. *Co-first author
- M. Yang, B. Ma, H. Shao, A. M. Clark, A. Wells. Macrophage phenotypic subtypes diametrically regulate epithelial-mesenchymal plasticity in breast cancer cells. BMC Cancer. 2016 Jul 7;16:419.
- B. Ma, S. E. Wheeler, A. M. Clark, D. Whaley, M. Yang, A. Wells. Liver protects metastatic prostate cancer from induced death by activating E-cadherin signaling. Hepatology. 2016 Nov 64(5):1725-1742.
- A. M. Clark, S. E. Wheeler, C. L. Young, L. Stockdale, J. Shepard-Neiman, W. Zhao, D. B. Stolz, R. Venkataramanan, D. Lauffenburger, L. Griffith, A. Wells. A liver microphysiological system of tumor cell dormancy and inflammatory responsiveness is affected by scaffold properties. Lab Chip. 2017 Jan 7;17: 156-168.
- N. Dioufa, A. M. Clark, B. Ma, C. H. Beckwitt, A. Wells. Bi-directional exosome-driven intercommunication between the hepatic niche and cancer cells. Mol Cancer. 2017 Nov 14;16(1):172.
- A. S. Khazali, A. M. Clark, A. Wells. Inflammatory cytokine IL-8/CXCL8 promotes tumor escape from hepatocyte-induced dormancy. Br J Cancer. 2018 Feb 20;118(4):566-576.
- A. M. Clark, M. P. Kumar, S. E. Wheeler, C. L. Young, R. Venkataramanan, D. B. Stolz, L. G. Griffith, D. A. Lauffenburger, A. Wells. A model of dormant-emergent metastatic breast cancer progression enabling exploration of biomarker signatures. Mol Cell Proteomics. 2018 Apr;17(4):619-630.
- C. Beckwitt, A. M. Clark, B. Ma, D. Whaley, Z. Oltvai, A. Wells. Statins attenuate outgrowth of breast cancer metastases. Br J Cancer. 2018 Oct;119(9):1094-1105.
- A. M. Clark, H. L. Heusey, L. G. Griffith, D. A. Lauffenburger, A. Wells. IP-10 (CXCL10) can trigger emergence of dormant breast cancer cells in a metastatic liver microenvironment. Front Oncol. 2021 May;11(1838).
- A. M. Clark, C. Magawa, A. P. Zamora, P. Kelly, M. J. Reynolds, S. J. Ralph. Tea tree oil extract causes mitochondrial superoxide production and apoptosis as an anticancer agent, promoting tumor infiltrating neutrophils cytotoxic for breast cancer to induce tumor regression. Biomed Pharmacother. 2021 Aug;140:111790.
- J. L. Gomez Marti, C. Beckwitt, A. M. Clark, A. Wells. Atorvastatin facilitates chemotherapy effects in metastatic triple negative breast cancer. Br J Cancer. 2021 Aug; online
- A. M. Clark, S.E. Wheeler, D.P. Taylor, V.C. Pillai, C.L. Young, R. Prantil-Baun, T. Nguyen, D.B. Stolz, J.T. Borenstein, D.A. Lauffenburger, R. Venkataramanan, L.G. Griffith, A. Wells. A microphysiological system model of therapy for liver micrometastases. Exp Biol Med. 2014; 239(9):1170-9.
- A. M. Clark, B. Ma, D. L. Taylor, L. Griffith, A. Wells. Liver Metastases: microenvironments and ex-vivo models. Exp Biol Med. 2016 Sep;241(15):1639-52 *Selected as the top biomedical engineering article in EBM for 2016
- C. H. Beckwitt, A. M. Clark, S. E. Wheeler, D. L. Taylor, D. B. Stolz, L. Griffith. Liver 'organ on a chip.' Exp Cell Res. 2018 Feb 1;363(1):15-25.
- B. Ma, A. Wells, A. M. Clark. The pan-therapeutic resistance of disseminated tumor cells: role of phenotypic plasticity and the metastatic microenvironment. Semin Cancer Biol. 2020 Feb;60:138-147.
- D. Korentzelos, A. M. Clark, A. Wells. A perspective on therapeutic pan-resistance in metastatic cancer. Int J Mol Sci. 2020 Oct;21(19):7304.
- A. M. Clark, N. L. Allbritton, A. Wells. Integrative microphysiological tissue systems of cancer metastasis to the liver. Semin. Cancer Bio. 2021 Jun;71:157-169.
- A. M. Clark. Modeling the Complexity of the Metastatic Niche Ex vivo. In: Ebrahimkhani MR, Hislop J, editors. Programmed Morphogenesis: Methods and Protocols. Methods Molecular Biology. 2258: Springer US; 2021.