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Background: The role of PPARβ/δ in colorectal cancer has been a hot topic for debate, with both tumor-promoting and anti-tumor roles been reported. Current studies on colorectal cancer have focused on either the whole intestine or on the major tissue type, the intestinal epithelium. In recent years, various studies have emphasized the pro-inflammatory and tumor promoting effects of tumor stroma in various cancers. However, the involvement of tumor stroma in adenocarcinoma development remains a largely unexplored realm of colorectal research. Hence, we hypothesized that PPARB/D expression in colorectal tumor stroma may play an important role in colorectal carcinogenesis. Methods: In this study, we aimed to investigate the role of PPARβ/δ in the colorectal tumor stroma. To study the role of the tumor stroma in vivo, we have adopted a model organism approach involving adult APCmin mice and AOM/DSS-treated wild-type mice models. We collected intestinal adenocarcinomas from these mice and extracted tumor stroma using microscopy-directed laser capture micro-dissection. The collected stroma were recovered for mRNA and analyzed for gene expression levels using real-time PCR. Results and conclusion: We observed contrasting trends in the PPARβ/δ mRNA expression, with elevated levels in stroma of APCmin adenocarcinoma but decreased in AOM/DSS-induced tumors. Our results to date demonstrate the heterogeneity of colorectal tumor stroma and provide an insight to the distinct differences between the two often co-studied murine models of colorectal carcinogenesis. We therefore plan to study if this trend is also observed in human colorectal tumor samples and in murine colorectal cancer models carrying stromal-specific deletion of PPARβ/δ expression. Citation Format: Eddie Han Pin Tan, Ming Keat Sng, Jeremy Soon Kiat Chan, Nguan Soon Tan. Heterogeneity of PPARβ/δ expression in colorectal tumor stroma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3211. doi:10.1158/1538-7445.AM2015-3211

The reprogrammed cancer metabolism is an emerging cancer hallmark pervasive in many cancers and is fundamental to neoplastic progression. Many key cancer-promoting pathways are known to converge on the regulation of cellular metabolism. Besides providing basic sustenance to fuel cancer cells limitless replicative potential, emerging data reveals critical roles for the reprogammed metabolism during maglignant progression. Metastasis is often regarded as the end-stage of malignancy and majority of cancer mortality is attributed to the metastatic dissemination of the malignant cancer cells. The initiation of metastasis has been pinpointed as pivotal event, without which, the malignant cancer cells loses their motility and invasive capabilities for distal dissemination. This initiation event highly resembles epithelial-mesenchymal transition (EMT) process that occurs during embryogenesis and wound healing. Microenvironmental signals such as hypoxia and the inflammatory milleu that initiate EMT, interestingly, are also shown to be critical in rewiring cancer metabolism. Thus, it is conceivable that the manipulation of cancer metabolism can impact EMT. Furthermore, whether such metabolic reprogramming is a functional pre-requisite for the initiation of EMT remains unclear. Using three distinct in vitro EMT models, we show that EMT is an energy-demanding process. Comparative microarray analysis of the EMT models reveals that genes involved in fatty acid, glucose and ROS metabolism are altered. We went further to show that cancer cells undergoing EMT, derives much of the ATP/energy from glucose and lipid metabolism. Importantly, we identified several key molecular drivers that coordinate EMT and cellular bioenergetics, which is validated by our in vivo EMT model. Citation Format: Zi Qiang Teo, Ming Keat Sng, Jeremy CHAN, Nguan Soon Tan. Molecular drivers of metabolic reprogramming during EMT. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-198. doi:10.1158/1538-7445.AM2015-LB-198