Biophysical Society Thematic Meeting| Aussois 2019

Biology and Physics Confront Cell-Cell Adhesion

Poster Abstracts

7-POS Board 7 ALDOLASE TRIGGERS METABOLIC REPROGRAMING IN COLORECTAL CANCER IN HYPOXIA AND STIFF DESMOPLASTIC MICROENVIRONMENTS Wey-Ran Lin 2,3,4 ; Hou-Chun Huang 1 ; Chi-Shuo Chen 1 ; 1 National Tsing Hua University, Department of Biomedical Engineering and Environmental Science, Hsinchu, Taiwan 2 Linkou Chang Gung Memorial Hospital, Department of Gastroenterology and Hepatology, Taoyuan, Taiwan 3 Chang Gung University, College of Medicine, Taoyuan, Taiwan 4 Linkou Chang Gung Memorial Hospital, Liver Research Center, Taoyuan, Taiwan Colorectal cancer (CRC) progression is highly associated with desmoplasia. Aerobic glycolysis is another distinct feature that appears during the CRC phase of the adenoma-carcinoma sequence. However, the interconnections between the desmoplastic microenvironment and metabolic reprogramming remain largely unexplored. In our in vitro model, we investigated the compounding influences of hypoxia and substrate stiffness, 2 critical physical features of desmoplasia, on CRC metabolic shift by using engineered polyacrylamide gels. Unexpectedly, we found that, compared to cells on a soft gel (approximately 1.5 kPa, normal tissue), cells on a stiff gel (approximately 8.7 kPa, desmoplastic tissue) exhibited reduced glucose uptake and glycolysis under both normoxia and hypoxia. In addition, the increasing substrate stiffness activated focal adhesion kinase (FAK)/phosphoinositide 3-kinase signaling, but not mitochondrial respiratory inhibitor HIF1α. However, the presence of aldolase B (ALDOB) reverted the CRC metabolic response to mechanosignaling; enhanced glucose uptake (approximately 2- to 3-fold) and obvious aerobatic glycolysis (approximately 1.7-fold) with decreased mitochondrial oxidative phosphorylation was observed. The cytoskeleton assembly and FAK/RhoA pathways were associated with this ALDOB activity. ALDOB also changed the response of CRC traction force, which is related to tumor metastasis, to hypoxia/normoxia. In summary, our data implied a counter influence between hypoxia and substrate stiffness on glucose uptake, and ALDOB upregulation can flip the balance, which drives aerobatic glycolysis synergistically. Our results not only highlight the potential of metabolic reprogramming led by physical alterations in the microenvironment, but also extend our understanding of the essential role of ALDOB in CRC progression from a biophysical perspective.

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