Medical Molecular Biology Commons^™

Lactate-Mediated Epigenetic Reprogramming Regulates Formation Of Human Pancreatic Cancer-Associated Fibroblasts, Tushar D. Bhagat, Dagny Von Ahrens, Meelad Dawlaty, Yiyu Zou, Joelle Baddour, Abhinav Achreja, Hongyun Zhao, Lifeng Yang, Brijesh Patel, Changsoo Kwak, Gaurav S. Choudhary, Shanisha Gordon-Mitchell, Srinivas Aluri, Sanchari Bhattacharyya, Srabani Sahu, Yiting Yu, Matthias Bartenstein, Orsi Giricz, Masako Suzuki, Davendra Sohal, Sonal Gupta, Paola A. Guerrero, Surinder K. Batra, Michael Goggins, Ulrich Steidl, John Greally, Beamon Agarwal, Kith Pradhan, Debabrata Banerjee, Deepak Nagrath, Anirban Maitra, Amit Verma

Journal Articles: Biochemistry & Molecular Biology

Even though pancreatic ductal adenocarcinoma (PDAC) is associated with fibrotic stroma, the molecular pathways regulating the formation of cancer associated fibroblasts (CAFs) are not well elucidated. An epigenomic analysis of patient-derived and de-novo generated CAFs demonstrated widespread loss of cytosine methylation that was associated with overexpression of various inflammatory transcripts including CXCR4. Co-culture of neoplastic cells with CAFs led to increased invasiveness that was abrogated by inhibition of CXCR4. Metabolite tracing revealed that lactate produced by neoplastic cells leads to increased production of alpha-ketoglutarate (aKG) within mesenchymal stem cells (MSCs). In turn, aKG mediated activation of the …