# Project 2: Biological Effects of Patient-derived Mutations in MUC16 on PC Metastasis

> **NIH NIH P01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2020 · $316,438

## Abstract

Abstract
Pancreatic adenocarcinoma (PDAC) is a lethal disease, the fourth-leading cause of cancer-related death in the
United States. Metastasis is responsible for 90% of the cancer-related deaths. Expression of MUC16 (50-60%)
is highly associated with metastatic pancreatic cancer. We recently discovered that cancer associated isoforms
of CA125/MUC16 have biological activity: cancer associated forms of the MUC16 glycoprotein contain
multivalent ligands with high avidity for epidermal growth factor receptor (EGFR1, 2 and 3) and integrin (α4/β1)
complexes, which results in constitutive activation of signaling cascades that include Akt and FAK and
concomitant increases in the oncogenic potential of pancreatic cancer cells. Interestingly, these activities were
enhanced by aberrant (truncated) O-glycosylation of MUC16. This finding together with our recent
documentation of the widespread expression of MUC16 in metastatic pancreatic cancer, suggest that in
addition to serving as a biomarker for adenocarcinoma, MUC16 can function as an oncogenic cytokine or
growth factor. Further, whole genome analyses of clinical samples of PDAC have revealed that MUC16 is
among the most highly mutated genes in pancreatic cancer. Hence, in addition to serving as a biomarker for
adenocarcinomas, we hypothesize that tumor associated and mutated forms of circulating CA125/MUC16
have biological roles as a growth factor or cytokines that may contribute to paracrine oncogenic signaling
interactions in the distant organ sites that may contribute to tumor progression and secondary effects of tumor
growth. Our long term goal is to determine the molecular and biological mechanisms by which MUC16
mediates tumor aggressiveness, progression, early metastasis and systemic effects of cancer progression. To
achieve this, we propose to investigate the hypothesis that site specific mutation contributes to activation of
biologically active isoforms and/or proteolytic cleavage of MUC16, and evaluate the biological activity in cell
based models of pancreatic cancer (Aim 1). We will investigate contribution of mutated MUC16 to tumor
progression in an in vivo orthotopic pancreas tumor model system (Aim 2). We will determine the sites of
mutation on MUC16, and investigate its biological functions in clinical specimens of pancreatic cancer (Aim 3).
These studies will lead to a new understanding of the function and effects of secreted tumor products that are
biomarkers on tumor growth, metastasis to distant organ sites, configuration of the tumor microenvironment
and other aspects of tumor progression.

## Key facts

- **NIH application ID:** 9940728
- **Project number:** 5P01CA217798-03
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Michael A. Hollingsworth
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $316,438
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9940728

## Citation

> US National Institutes of Health, RePORTER application 9940728, Project 2: Biological Effects of Patient-derived Mutations in MUC16 on PC Metastasis (5P01CA217798-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9940728. Licensed CC0.

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