# Mucin Splice Variants in Pancreatic Cancer Diagnosis and Pathogenesis

> **NIH NIH F31** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2020 · $39,788

## Abstract

PROJECT SUMMARY/ABSTRACT
 Pancreatic cancer (PC) survival rates are dismally on track to make it the second most lethal malignancy
by the end of the decade. Over half of all patients are diagnosed at stage 4 disease limiting the availability and
success of therapeutic intervention. In PC, presentation with advanced disease is theresult of both asymptomatic
disease initiation and early metastasis. While surgical resection currently yields the best outcome, less than one
quarter of patients are eligible at presentation, frequently limited by appreciable metastasis or vascular
involvement. Compounding the issue of late stage diagnosis is the innate therapeutic resistance observed in PC
tumors, either directly or resulting from reduced treatment delivery to tumors. PC tumors demonstrate a range
of aberrant findings, including a high rate of KRAS mutations, CDKN2A deletion, and anomalous early
expression of mucins. Mucins are large glycoproteins that have been demonstrated to significantly contribute to
disease progression, metastasis, and drug resistance. A number of alternatively spliced mucin species have
been reported, but their role in PC pathology remains elusive. Using RNA-seq data from TCGA, I discovered
that select MUC1, MUC4, and MUC16 transcripts are significantly associated with survival outcome in PC
patients. Of these 5 significant transcripts, a single MUC4 isoform (MUC4∆6) contains an in-frame deletion of
exon 6 and has previously been found by our lab in patient tumors. Exon 6 in MUC4 corresponds to the NIDO
domain and may alter interactions between the expressing cell and tumor stroma. Because of the high rate of
expression, I hypothesize that this transcript serves as a prognostic molecule, detectable in patient biofluids, and
contributes to metastatic behavior of PC cells. To facilitate addressing this hypothesis, I propose two independent
specific aims. Aim 1 will employ a custom multiplexed assay for the detection of PC-specific RNA transcripts
using gold nanoparticle-bound fluorescent oligonucleotide probes. We will demonstrate that this assay can detect
the presence MUC4∆6, KRAS mutant, and CDKN2A transcripts in patient plasma with high sensitivity. Detection
and quantification of target RNA transcripts using our nanoprobe-based approach requires perfect hybridization
of both probe and RNA followed by subsequent enzymatic cleavage. The ultility in this novel assay technology
is that it can detect down to single nucleotide mutations, permits quantification, and requires a minimal amount
of blood for testing. This will be validated in orthotopic animals and PC cell lines. Aim 2 involves the generation
of MUC4∆6-sparing knockdown of MUC4 using constitutively expression of shRNA in PC cell lines. These cell
lines will be used for in vitro functional studies of MUC4∆6 to elucidate its role in tumor cell mobility, stromal
interactions, drug resistance, and proliferative effects. Subsequently, these features will be tested in vivo usi...

## Key facts

- **NIH application ID:** 9993110
- **Project number:** 5F31CA243469-02
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Christopher Michael Thompson
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $39,788
- **Award type:** 5
- **Project period:** 2019-07-01 → 2021-04-23

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9993110

## Citation

> US National Institutes of Health, RePORTER application 9993110, Mucin Splice Variants in Pancreatic Cancer Diagnosis and Pathogenesis (5F31CA243469-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9993110. Licensed CC0.

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