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-1?, and iii) MYB-HIF-1? 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-HIF1? 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-1? by studying coordinated regulation of MYB and HIF-1? under hypoxia, and any reciprocity that may exist between them.
In aim 2, we will define the role of interaction between MYB and HIF-1? in their transcriptional reprogramming and hypoxia adaptive-response pathways. Specifically, we will examine if the MYB/HIF-1? 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-1? in pancreatic tumor progression and metastasis by using genetically-engineered, luciferase-tagged MYB- and HIF-1? 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-1? 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-1?. 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-1?) 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 prevention and treatment. Therefore, proposed studies have significant potential to impact pancreatic cancer research at various levels that will ultimately support effective management of this devastating malignancy.
We have compelling data to support a pathobiological role of MYB/HIF-1? cross-talk in pancreatic cancer. Proposed research will generate additional convincing evidence at the functional, mechanistic and clinical levels to establish the significance of this novel molecular cross-talk in pancreatic cancer pathobiology, and thus improve our understanding of molecular pathogenesis of pancreatic cancer. In the longer term, the knowledge gained from the proposed research will enable the development of novel preventive and therapeutic strategies, and lead to better life expectancy and quality of life for pancreatic cancer patients.
|Deshmukh, Sachin Kumar; Singh, Ajay P; Singh, Seema (2018) ETV4: an emerging target in pancreatic cancer. Oncoscience 5:260-261|