Project Details
Description
ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies. Full transcriptome defines
clinically relevant “subtypes” of disease and the basal-like subtype of PDAC is associated with advanced
stage, metastasis, resistance to treatment, and poor patient survival. The mechanism by which the tumor
microenvironment drives PDAC subtype differentiation remains uncharacterized. Understanding the cancer-
extrinsic factors in the tumor microenvironment that promotes the basal-like state could uncover cancer
vulnerabilities and lead to the development of new therapeutic approaches. We found that inactivation of the
histone demethylase gene Kdm8 reprograms PDAC cells into a highly metastatic state. Morphologically, Kdm8
inactivation reduces the expression of genes defining the classical PDAC subtype and drives a profound loss
of differentiation in a genetically engineered PDAC mouse model. Importantly, the enzymatic function of Kdm8
requires molecular oxygen and hypoxia diminished the phenotypic changes induced by Kdm8 inactivation. We
noted a global upregulation of histone 3 lysine 27 (H3K27) trimethylation upon the inactivation of Kdm8,
supporting the involvement of its demethylase function in regulating the chromatin and cell state. In human
PDAC, KDM8-regulated gene signatures are an exceptionally good predictor of the disease subtype. Our
preliminary results suggest that hypoxia within the tumor microenvironment restricts the demethylase function
of Kdm8, thereby suppressing the classical PDAC subtype while promoting a basal-like state and metastasis
through epigenetic reprogramming. We hypothesize that a hypoxia-KDM8-chromatin axis plays a critical role in
PDAC subtype determination and metastatic ability.
In the proposed study, we aim to determine the mechanism by which Kdm8 controls PDAC subtypes and
metastatic progression and the mechanism by which hypoxia suppresses Kdm8 function to promote chromatin
reprogramming and PDAC metastasis. Overall, our study will fill the major gap in our understanding of how
hypoxia within the PDAC tumor microenvironment promotes the basal-like molecular subtype and metastasis.
Our mechanistic study will uncover fundamental insights into the role of KDM8 in subtype determination and
may discover novel vulnerabilities of the basal-like PDAC state. The long-term objective is to gain a better
understanding of the key cell-extrinsic factors in the tumor microenvironment that promote the aggressive or
basal-like PDAC subtypes.
Status | Finished |
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Effective start/end date | 1/1/24 → 12/31/24 |
Funding
- National Cancer Institute: $480,423.00
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