title: Microenvironment mediated alterations to metabolic pathways confer increased chemo-resistance in CD133+ tumor initiating cells.
abstract: Chemoresistance in pancreatic cancer has been attributed to tumor-initiating cells (TICs), a minor sub-population of tumor cells. However, the mechanism of chemo-resistance in these cells is still unclear.In the current study, immunohistochemical analysis of LSL-KrasG12D; LSL-Trp53R172H;PdxCre (KPC) murine tumors indicated that hypoxic regions developed through tumor progression. This hypoxic "niche" correlated with increased CD133+ population that had an increased HIF1A activity. Consistent with this observation, CD133+ cells had increased glucose uptake and activity of glycolytic pathway enzymes compared to CD133- cells. Mass spectrometric analysis (UPLC-TQD) following metabolic labeling of CD133+ cells with [13C]-U6 glucose confirmed this observation. Furthermore, although both populations had functionally active mitochondria, CD133+ cells had low mitochondrial complex I and complex IV activity and lesser accumulation of ROS in response to standard chemotherapeutic compounds like paclitaxel, 5FU and gemcitabine. CD133+ cells also showed increased resistance to all three chemotherapeutic compounds and treatment with Glut1 inhibitor (STF31) reversed this resistance, promoting apoptotic death in these cells similar to CD133- cells.Our study indicates that the altered metabolic profile of CD133+ pancreatic TIC protects them against apoptosis, by reducing accumulation of ROS induced by standard chemotherapeutic agents, thereby confering chemoresistance. Since resistance to existing chemotherapy contributes to the poor prognosis in pancreatic cancer, our study paves the way for identifying novel therapeutic targets for managing chemoresistance and tumor recurrence in pancreatic cancer.
authors.affiliation: Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, MN, USA.|Division of Surgical Oncology, Department of Surgery, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.
authors.forename: Alice
authors.initials: A
authors.lastname: Nomura
authors.affiliation: Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, MN, USA.|Division of Surgical Oncology, Department of Surgery, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Dauer
authors.affiliation: Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, MN, USA.|Division of Surgical Oncology, Department of Surgery, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.
authors.forename: Vineet
authors.initials: V
authors.lastname: Gupta
authors.affiliation: Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Olivia
authors.initials: O
authors.lastname: McGinn
authors.affiliation: Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Nivedita
authors.initials: N
authors.lastname: Arora
authors.affiliation: Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Kaustav
authors.initials: K
authors.lastname: Majumdar
authors.affiliation: Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Uhlrich
authors.affiliation: Department of Chemistry, Mass Spectrometry Laboratory, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Dalluge
authors.affiliation: Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, MN, USA.|Division of Surgical Oncology, Department of Surgery, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.
authors.forename: Vikas
authors.initials: V
authors.lastname: Dudeja
authors.affiliation: Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, MN, USA.|Division of Surgical Oncology, Department of Surgery, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.
authors.forename: Ashok
authors.initials: A
authors.lastname: Saluja
authors.affiliation: Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, MN, USA.|Division of Surgical Oncology, Department of Surgery, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.
authors.forename: Sulagna
authors.initials: S
authors.lastname: Banerjee
mesh_terms: D000071916:AC133 Antigen / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002469:Cell Separation / Q000379:methods; D002851:Chromatography, High Pressure Liquid; D019008:Drug Resistance, Neoplasm; D042967:Electron Transport Complex I / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007150:Immunohistochemistry; D053858:Metabolic Networks and Pathways; D055442:Metabolome; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009364:Neoplasm Recurrence, Local / Q000473:pathology*; D009374:Neoplasms, Experimental / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000473:pathology*; D053719:Tandem Mass Spectrometry; D059016:Tumor Microenvironment
chemical_list: D000071916:AC133 Antigen; D000970:Antineoplastic Agents; D051272:Glucose Transporter Type 1; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C000606023:PROM1 protein, human; C000606024:Prom1 protein, mouse; C495678:Slc2a1 protein, mouse; D003576:Electron Transport Complex IV; D042967:Electron Transport Complex I; D005947:Glucose
keywords: CD133; ROS; hypoxia; metabolism; tumor initiating cells