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MODELING COLORECTAL CANCER DRUG RESISTANCE USING THREE-DIMENSIONAL TUMOR MODELS

Lamichhane, Astha
http://orcid.org/0000-0003-1968-7298
http://rave.ohiolink.edu/etdc/view?acc_num=akron1684246393440001

Abstract Details

2023, Doctor of Philosophy, University of Akron, Biomedical Engineering.
Cancer is the second most common cause of death in the United States, with an estimated 1,958,310 new cases and 609,820 deaths in 2023. Cancer is a complex disease with different sub-populations of genetically diverse cells forming tumors. Despite advancements in identifying molecular drivers of cancer to develop new therapies, drug resistance remains a major barrier against effective cancer treatments. A key driver of drug resistance is a population of tumor cells known as cancer stem cells (CSCs), which possess the ability to change their state under drug pressure and evade drug toxicity. Identifying approaches to target CSCs is expected to improve treatment outcomes. Preclinical models provide a major tool in cancer research. Three-dimensional (3D) tumor models have gained significant momentum in the past decade due to their ability to recapitulate the biological characteristics of tumors and facilitate mechanistic studies and drug testing applications. Here, we developed and used 3D spheroids and organoids of both cancer cell lines and primary patient-derived tumor cells to study drug resistance of colorectal cancer cells with mutations in KRAS and BRAF kinases. We used tumor spheroid cultures in long-term cyclic treatments with targeted therapies against MAPK/MEK pathway to model adaptive drug resistance of cancer cells. We found that inhibiting MAPK/MEK pathway led to the stemness of cancer cells and activated several oncogenic signaling pathways. A combination treatment using a MEK inhibitor and a CSC inhibitor blocked stemness and oncogenic signaling. We also developed an organotypic model consisting of organoids of primary tumor cells and specific components of the tumor microenvironment such as patient-derived cancer-associated fibroblasts (CAFs) and the extracellular matrix. We used this model to elucidate the role of stemness, Wnt/ß-catenin pathway, and signaling with CAFs in the organoid formation of tumor cells and their responses and resistance to MEK inhibition. Colorectal CAFs predominantly secreted hepatocyte growth factor (HGF) into the local microenvironment to activate MET receptor tyrosine kinase on cancer cells and promote their proliferation and drug resistance. Overall, this study established physiologically relevant 3D tumor models to elucidate the role of cancer stemness and interactions with the tumor microenvironment in drug resistance of colorectal cancer and design and develop treatment strategies to effectively overcome stemness-mediated drug resistance.
Hossein Tavana (Advisor)
Yang H Yun (Committee Member)
Ronaldo J.J Ramirez (Committee Member)
Nic Leipzig (Committee Member)
Ge (Christie) Zhang (Committee Member)
169 p.
Biomedical Engineering; Oncology
Colorectal cancer, Drug resistance, Cancer stem cells, Spheroid, Organoid, Combination treatment, Tumor microenvironment, Organotypic model

Recommended Citations

Citations

  • Lamichhane, A. (2023). MODELING COLORECTAL CANCER DRUG RESISTANCE USING THREE-DIMENSIONAL TUMOR MODELS [Doctoral dissertation, University of Akron]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=akron1684246393440001

    APA Style (7th edition)

  • Lamichhane, Astha. MODELING COLORECTAL CANCER DRUG RESISTANCE USING THREE-DIMENSIONAL TUMOR MODELS. 2023. University of Akron, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=akron1684246393440001.

    MLA Style (8th edition)

  • Lamichhane, Astha. "MODELING COLORECTAL CANCER DRUG RESISTANCE USING THREE-DIMENSIONAL TUMOR MODELS." Doctoral dissertation, University of Akron, 2023. http://rave.ohiolink.edu/etdc/view?acc_num=akron1684246393440001

    Chicago Manual of Style (17th edition)

akron1684246393440001
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© 2023, some rights reserved.Creative Commons License MODELING COLORECTAL CANCER DRUG RESISTANCE USING THREE-DIMENSIONAL TUMOR MODELS by Astha Lamichhane is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by University of Akron and OhioLINK.
Release 3.2.12