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BRAF Inhibitors Stimulate CAFs to Drive Drug Resistance in Melanoma

Liu, Tianyi
http://orcid.org/0000-0002-2624-7146
http://rave.ohiolink.edu/etdc/view?acc_num=ucin162324201258474

Abstract Details

2021, PhD, University of Cincinnati, Pharmacy: Pharmaceutical Sciences.
Although the groundbreaking discovery of RAF and MEK inhibitors has revolutionized targeted therapy for the treatment of advanced melanoma, a high percentage of patients still die from metastasis despite the initial positive responses to targeted therapy drugs. Both tumor progression and the development of therapeutic resistance are strongly modulated by stromal cells that reside in the tumor microenvironment (TME). The TME is composed of noncancer stromal cells, including endothelial cells, immune cells, and cancer-associated fibroblasts (CAFs), and the noncellular extracellular matrix (ECM). During the past decade, there is a great expansion in research on CAFs, which is one of the most abundant and active stromal cell types to aid the creation of a desmoplastic tumor niche. CAFs have multifaceted roles in regulating tumor progression, including synthesis and remodeling of the ECM and production of growth factors, modulating anti-tumor immune response, and influencing angiogenesis, tumor mechanics, drug access and therapy responses. Although TME-mediated drug resistance mechanism has been extensively studied in the past, it is still not clear how therapy-induced pressure would act on the genetically stable stromal cells and how these cells could add in the occurrence of drug resistance. Here, we show that the number of intratumoral CAFs increases in BRAF inhibitors (BRAFi)/MEK inhibitors (MEKi)-treated melanoma stroma. CAFs also exhibit increased amounts of nuclear ß-catenin under BRAFi/MEKi therapy. ß-catenin has critical roles in both the Wnt/ ß-catenin signaling pathway and cell-cell adhesion. Wnt/ß-catenin signaling is one of the key signaling pathways that are deregulated not only in a variety of human cancer cells, and also in fibroblasts. Aberrant activation of ß-catenin signaling in fibroblasts has been demonstrated to lead to diseases, such as skin fibrosis. Our results suggest that CAFs, which possess the wild-type BRAF gene, could be paradoxically activated via BRAF and CRAF dimerization, which triggers the MEK/ERK signaling pathway and finally leads to increased nuclear ß-catenin expression in CAFs. Further studies show that BRAFi not only leads to increased ß-catenin nuclear accumulation in CAFs and stimulates their biological properties, suggesting BRAFi induces a new resistant phenotype in CAFs. In both in vitro and in vivo models, depleting ß-catenin in CAFs abolishes their ability to elicit melanoma cell growth and drug resistance. RNA-Seq data reveals that ß-catenin is a major regulator of CAF phenotype. We identify matricellular protein periostin (POSTN) as a downstream effector of ß-catenin. In melanoma, periostin is uniquely expressed in CAFs, and BRAFi can specifically upregulate periostin production in CAFs but not in melanoma cells. Recombinant periostin contributes to melanoma cell resistance to BRAFi/MEKi and can compensate for the loss of ß-catenin in CAFs. Additionally, our study reveals that periostin activates PI3K/AKT signaling in melanoma cells, which reactivates the ERK signaling pathway blocked by BRAFi and MEKi. In summary, our data provide a mechanistic insight into the functional reprogramming of CAFs by BRAFi, which is mediated by Wnt-independent nuclear ß-catenin transcriptional activity and periostin as an important downstream effector in conferring BRAFi/MEKi resistance in melanoma.
Yuhang Zhang, Ph.D. (Committee Chair)
Zalfa Abdel-Malek, Ph.D. (Committee Member)
Joan Garrett, Ph.D. (Committee Member)
Ana Luisa Kadekaro, Ph.D. (Committee Member)
Georg Weber, M.D. (Committee Member)
163 p.
Pharmaceuticals
cancer-associated fibroblast; melanoma; BRAF inhibitor; drug resistance; beta-catenin; periostin

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Citations

  • Liu, T. (2021). BRAF Inhibitors Stimulate CAFs to Drive Drug Resistance in Melanoma [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin162324201258474

    APA Style (7th edition)

  • Liu, Tianyi. BRAF Inhibitors Stimulate CAFs to Drive Drug Resistance in Melanoma. 2021. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin162324201258474.

    MLA Style (8th edition)

  • Liu, Tianyi. "BRAF Inhibitors Stimulate CAFs to Drive Drug Resistance in Melanoma." Doctoral dissertation, University of Cincinnati, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=ucin162324201258474

    Chicago Manual of Style (17th edition)

ucin162324201258474
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© 2021, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.