Tumor progression depends on both tumor-intrinsic processes and interactions with different cell types within tumor microenvironment. Identifying targets that have dual effects on both tumor cells and their interacting surrounding cells, such as tumor-infiltrating immune cells, represent a novel therapeutic approach to treat cancer patients CD44 is a ubiquitously expressed protein that plays an important role in cell adhesion and migration, and is an established cancer stem cell marker. Alternative splicing of CD44 gives rise to CD44 standard isoform (CD44s) and CD44 variant isoforms (CD44v) with distinct functions. In this context, we previously demonstrated that CD44s, not CD44v, is required for epithelial to mesenchymal transition (EMT) to occur and breast cancer metastasis. In the first part of my dissertation, I continued to investigate the cell-autonomous role of CD44s in driving cancer cell survival. Here, we identified Hyaluronan synthase 2 (HAS2) as a downstream target of CD44s. HAS2 and its product, hyaluronan (HA), are required for CD44s-mediated Akt activation, which in turn stimulate HAS2 transcription. Further, we found Akt downstream target, FOXO1, is a bona fide transcriptional repressor of HAS2. HAS2 is de-repressed as a result of FOXO1 phosphorylation by Akt activation. Consequently, HAS2 is able to continuously produce HA that binds to CD44s for Akt activation. Together, our data suggest that Akt signaling is sustained through a feed-forward regulatory loop, involving CD44s, HAS2 and HA, in breast cancer cells. Continuing our endeavor to better understand the role of CD44 in cancer progression, the second part of my dissertation focuses on the effect of host CD44 on tumor progression. Here, we found that host CD44 expression promotes cancer progression in both breast cancer and melanoma mouse models. Mechanistically, CD44s expression on dendritic cell (DC) suppresses its maturation and ability to stimulate CD8+ T cell proliferation, thereby hindering host immune response to tumor growth and progression. Furthermore, we found that CD44s expression in DCs is required for IL-6-mediated STAT3 activation, which is a critical negative regulator of DC maturation and function. Treatment of tumor-bearing WT mice with anti-CD44 antibody significantly boosted anti-tumor immune response and reduced tumor growth and burden. Collectively, these data reveal critical roles for CD44s in modulating both tumor cell survival and anti-tumor immunity. Targeting CD44s may have addictive effect on inhibiting tumor progression.

Last modified

• 02/22/2019

Creator

• Sali Liu

DOI

• https://doi.org/10.21985/N2744K

Subject

• Driskill Graduate Training Program in Life Sciences

Keyword

• Dendritic cells
• CD44s
• Splice isoform
• Breast Cancer
• Akt

Date created

• 2017-01-01

Resource type

• Dissertation

Rights statement

• In Copyright