# MUC1 in Therapy Resistance

> **NIH NIH U54** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2024 · $247,902

## Abstract

Abstract. Pancreatic cancer arises as an innately therapy-resistant cancer that is capable of rapidly acquiring
additional resistance to therapy upon treatment. We and others have demonstrated that high levels of expression
of MUC1 contribute to both inherent and acquired resistance of pancreatic cancer (and other lethal cancers) to
therapies. Evidence that MUC1 plays a critical role in resistance to therapy comes from unbiased analysis of
gene expression profiles in different tumors, and results of many experimental knockdown studies, which have
revealed that high levels of MUC1 are associated with resistance to radiation, cisplatin, estrogen receptor targets,
lenalidomide, paclitaxel, tamoxifen, trastuzumab, gemcitabine, FOLFIRINOX, etoposide, and other experimental
drugs in numerous cancers including pancreatic, breast, colorectal, gastric, head and neck, hepatocellular, non-
small cell lung cancer, renal cell and multiple types of cancer stem cells. MUC1 is known to affect oncogenic
signaling and transcriptional programs through interactions and effects with signaling effectors and transcription
factors. Our collaboration with Pankaj Singh's group has shown that MUC1 stabilizes and activates HIF-1a and
increases glucose uptake and metabolism, and that upregulation of MUC1 in Gemcitabine resistant cells and
concomitant stabilization of HIF induces anabolic glucose metabolism to impart Gemcitabine resistance to
pancreatic cancer cells. Recent results from our laboratory, presented below, have provided provocative data
showing that: MUC1 is expressed on tumor cell derived exosomes; that MUC1 expressing exosomes from
tumors contain cargoes distinct from exosomes that do not express MUC1; that MUC1 derived exosomes are
selectively taken up by cancer associated fibroblasts, immune cells, other tumor cells and cells that comprise
the premetastatic niche of pancreatic cancer. Additional data show that MUC1 containing exosomes alter the
biological properties of cells that take them up in ways that enhance tumor growth at primary and metastatic
sites, and increase drug resistance of tumors growing at those sites. This leads us to the Overarching
Hypothesis for the studies in this application: Exosomes from pancreatic cancer cells induce resistance
to chemotherapy and immunotherapy by reprogramming metabolic and functional features of tumor
cells, cancer associated fibroblasts and immune cells in the primary tumor and at distant metastatic
sites. To investigate this hypothesis, we propose two aims: Specific Aim 1. Elucidate the molecular features of
MUC1 positive exosomes that cause therapy resistance through reprogramming of tumor cells, cancer
associated fibroblasts, and immune cells at local or metastatic sites.; Specific Aim 2. Evaluate expression
signatures and pathways of therapy resistance in matched sets of primary tumors and metastatic lesions from
untreated and treated patients (from our tissue core) by utilizing spatial transcriptomics (singl...

## Key facts

- **NIH application ID:** 10926947
- **Project number:** 5U54CA274329-03
- **Recipient organization:** UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
- **Principal Investigator:** Michael A. Hollingsworth
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $247,902
- **Award type:** 5
- **Project period:** 2022-09-20 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10926947

## Citation

> US National Institutes of Health, RePORTER application 10926947, MUC1 in Therapy Resistance (5U54CA274329-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10926947. Licensed CC0.

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