Homeobox A10: Regulator of Pancreatic Cancer Progression and Survival

Author

Sophia G. Kisling, University of Nebraska Medical CenterFollow

ORCID ID

0000-0003-3287-1495

Graduation Date

Spring 5-4-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Biochemistry & Molecular Biology

First Advisor

Surinder K. Batra, Ph.D.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has one of the lowest incidence rates among all major cancers, yet it is disproportionally responsible for 8% of all cancer deaths. This high death rate is primarily attributed to the immunosuppressive tumor microenvironment and a lack of clinically relevant molecular targets. However, the underlying biology responsible for these poor outcomes remains obscure. To facilitate improved management of PDAC, an in-depth understanding of the molecular player(s) involved in PDAC aggressiveness is needed. Therefore, we analyzed the transcriptomic profiles of PDAC patients with long- and short-term survival and performed gene set enrichment analysis (GSEA), identifying a novel short-surviving prognostic subtype driven by master regulator HOXA10. Pathway analyses highlighted the involvement of the HOXA10 signature in immune suppression, cell cycle regulation, and enhanced tumorigenesis. CIBERSORT immune profiling of the HOXA10-associated prognostic genes further demonstrated a significant correlation with immunosuppressive T cells and macrophages, suggesting that they may play a role in the telltale picture of immunosuppression in the PDAC microenvironment. Notably, differential expression of HOXA10 and its associated signature was observed in clinical tissues of long- and short-surviving PDAC patients. We have also demonstrated a positive relationship between HOXA10 expression and disease progression, with a trend of enhanced expression in high-grade compared to low-grade PanIN lesions, and in 20- and 25-week LSL-Kras^G12D/+;LSL-Trp53^R172H/+;Pdx-1-Cre (KPC) tumors compared to 5 weeks. Further, live-cell analysis of Hoxa10 knockdown cells suggested a decrease in their proliferation with concurrent enhancement of apoptosis as compared to the control. Interestingly, our bioluminescence measurements using IVIS imaging demonstrated a substantial delay in orthotopic tumor growth in doxycycline-treated Hoxa10 knockdown tumor-bearing mice compared to the control group. A considerable reduction in the tumor weight was also observed. Additionally, mice harboring Hoxa10 knockdown tumors survived longer. They demonstrated decreased levels of immunosuppressive cell types compared to mice bearing the control tumors, corroborating our findings and indicating an association between the HOXA10 signature and poor patient survival. These findings altogether point towards a potential role of HOXA10 in PDAC tumorigenesis and lethality. Specifically, HOXA10 may contribute to tumor burden through the enrichment of immunosuppressive phenotypes, resulting in the poor survival of PDAC patients.

Comments

2024 Copyright, the authors

Recommended Citation

Kisling, Sophia G., "Homeobox A10: Regulator of Pancreatic Cancer Progression and Survival" (2024). Theses & Dissertations. 831.
https://digitalcommons.unmc.edu/etd/831