# Project 1: The Role and Mechanism(s) of MUC16 and MUC16-Cter in Potentiating PC Metastasis

> **NIH NIH P01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2020 · $315,252

## Abstract

Abstract
Pancreatic cancer (PC) is a highly metastatic and therapy-resistant malignancy with patients presenting with
local and distant metastases at the time of diagnosis. Like other epithelial cancers, PC progression is
characterized with aberrant mucin overexpression. Our previous study indicated that while MUC16 was
undetectable in the normal pancreas, there was a progressive increase in MUC16 expression with the increase
in grade of PanIN lesions, tumor and metastasis. We also demonstrated that MUC16 and MUC16-Cter play
critical roles in metastasis of pancreatic cancer. However, functional and mechanistic involvement of MUC16 in
pancreatic cancer metastasis remains poorly understood. MUC16 is a multi-domain protein that can potentially
play multifaceted role in metastasis of PC. In our preliminary studies, silencing of MUC16 in PC cells resulted in
reduced cell growth and migration along with alterations in EMT markers. We thus hypothesize that MUC16 is
associated with PC metastasis, which, in part, is mediated by MUC16-Cter domain. To test the hypothesis and
achieve the aforementioned objectives, three specific aims are proposed. First aim will evaluate the role of
MUC16 in mediating cell-to-cell interactions during metastatic spread of PC cells. In this aim, we will analyze the
cellular and molecular functions of MUC16 by analyzing cell-cell and cell-extracellular matrix interactions. These
studies will provide insights into the role of MUC16 in facilitating the interaction of tumor cells with the endothelial
cells, platelets and leukocytes during metastasis. Studies in Aim 2 will delineate the molecular mechanism(s) of
MUC16-Cter-mediated PC metastasis and identify MUC16 interacting partners. Since MUC16-Cter is enriched
in the chromatin bound fraction in the nucleus, its effect on global gene expression will be evaluated using ChIP-
Seq analyses. Further, the effect of various point mutations affecting N-glycosylation, ubiquitylation and
phosphorylation will be addressed in the light of its functional consequences. Third aim will investigate the
cooperative action of MUC16 with other defined oncogenic mutations in the metastasis of PC using Muc16–/–and
MUC16Cter transgenic mice. In this context, it is important to determine the role of MUC16, alone and in
combination with oncogenic K-ras and p53, during PC development. To validate our in vitro findings of the role
of MUC16 in PC, we will generate MUC16Cter transgenic with pancreas specific expression. Further, depending
on the phenotypes of MUC16-Cter N-glycosylation, ubiquitylation and/or phosphorylation mutants, we will
generate mutant specific transgenic to understand the in vivo relevance of such mutations. Overall the proposed
studies will allow us to define the molecular mechanisms by which MUC16 and its Cter facilitate metastasis and
contribute to the aggressiveness of PC. These novel insights into the underlying mechanisms of PC metastasis
combined with the new data, reagents and...

## Key facts

- **NIH application ID:** 9940708
- **Project number:** 5P01CA217798-03
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Surinder K. Batra
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $315,252
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9940708

## Citation

> US National Institutes of Health, RePORTER application 9940708, Project 1: The Role and Mechanism(s) of MUC16 and MUC16-Cter in Potentiating PC Metastasis (5P01CA217798-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9940708. Licensed CC0.

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