# A novel molecular cross-talk driving pancreatic cancer progression

> **NIH NIH R01** · UNIVERSITY OF SOUTH ALABAMA · 2022 · $339,625

## Abstract

Tumor cells inevitably face hypoxia during the course of their progression and their adaptation to hypoxic
stress promotes invasive, metastatic and treatment-resistant phenotypes. Therefore, understanding the
molecular basis underlying adaptive responses to hypoxia and identification of involved molecular targets will
greatly facilitate the development of effective strategies for cancer management. We have recently provided
first experimental evidence for a pathobiological role of MYB in pancreatic cancer (PC). Our novel preliminary
findings now demonstrate i) role of MYB in hypoxic cell survival, ii), MYB-mediated regulation of HIF-1α, and iii)
MYB-HIF-1α interaction and co-localization. In other novel findings, we show differential binding of MYB to its
two target gene promoters under hypoxia. In addition, our novel data support the clinical significance of MYB
by showing its wide-spread expression in pancreatic tumor cases, which is also suggestive of its association
with increasing tumor-grade and patient's survival. Based on these compelling findings, we
hypothesize that MYB-HIF1α crosstalk plays an important role in pancreatic cancer progression and metastasis, which will be
tested in four specific aims. In aim 1, we will investigate the regulatory cross-talk between MYB and HIF-1α by
studying coordinated regulation of MYB and HIF-1α under hypoxia, and any reciprocity that may exist between
them. In aim 2,  we will define the role of interaction between MYB and HIF-1α in their transcriptional
reprogramming and hypoxia adaptive-response pathways. Specifically, we will examine if the MYB/HIF-1α
crosstalk alters their genomic occupancy leading to changes in transcriptome, and characterize hypoxia
adaptive-response phenotypes that are jointly or independently regulated by them. In aim 3, we will examine
the cooperative functional significance of MYB and HIF-1α in pancreatic tumor progression and metastasis by
using genetically-engineered, luciferase-tagged MYB- and HIF-1α expressing or knockout PC cells in an
orthotopic mouse model. Histological and immunohistochemical studies will be performed to measure changes
in tumor hypoxia, vasculature, cell proliferation/apoptosis, and metastasis. Finally, in aim 4, we will study the
clinical significance of MYB-HIF-1α cross-talk in PC by performing immunohistochemical analysis in human
pancreatic tumor samples along with adjacent and healthy normal pancreatic tissues to assess incidence,
intensity and co-expression of MYB and HIF-1α. We will also examine their correlation (alone and in
combination) with tumor -grade, -stage, and patient's survival. Together, these studies will deliver novel insight
into the functional and mechanistic significance of a novel molecular cross-talk (MYB/HIF-1α) in PC
pathobiology, and highlight its clinical significance. Resulting data would enhance our understanding of
molecular pathogenesis of PC and, thus, facilitate the development of novel approaches for its preventio...

## Key facts

- **NIH application ID:** 10335167
- **Project number:** 5R01CA224306-05
- **Recipient organization:** UNIVERSITY OF SOUTH ALABAMA
- **Principal Investigator:** Ajay Pratap Singh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $339,625
- **Award type:** 5
- **Project period:** 2018-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10335167

## Citation

> US National Institutes of Health, RePORTER application 10335167, A novel molecular cross-talk driving pancreatic cancer progression (5R01CA224306-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10335167. Licensed CC0.

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