Poster Presentation 32nd Lorne Cancer 2020

Metabolic crosstalk in the tumour microenvironment (#362)

Srimayee Vaidyanathan 1 2 , Kristin Brown 1 2 3
  1. Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  2. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne , VIC, Australia
  3. Department of Biochemistry and Molecular Biology, The University of Melbourne, Melbourne, VIC, Australia

In order to proliferate without control, cancer cells exhibit increased biosynthetic demands relative to normal tissues. These demands are met through reprogramming of cellular metabolism and nutrient utilisation. The metabolic phenotype of a cancer cell is dependent upon a range of cell-intrinsic and cell-extrinsic factors. Cell-intrinsic regulators of cancer cell metabolism, such as oncogenic mutations, have been extensively studied. In contrast, less is known about cell-extrinsic/microenvironmental regulation of cancer cell metabolism. A key component of the tumour microenvironmental niche is the extracellular matrix (ECM), a non-cellular macromolecular network that, in addition to acting as a scaffold to organise cells within a tissue, has a major impact on cell behaviour. Dysregulation of ECM function is a key feature of cancer, with solid tumours frequently exhibiting a fibrotic phenotype characterised by excessive collagen deposition and altered organisation and modification of various ECM proteins. ECM dysfunction is known to actively promote tumour progression in invasive breast cancer by facilitating local invasion of cancer cells and promoting pro-oncogenic signalling. Emerging evidence also suggests that the cancer-associated ECM influences cancer cell metabolism. Moreover, recent studies have provided evidence that ECM remodelling may be directly underpinned by reprogramming of metabolism. The goal of our studies is to characterise metabolic crosstalk between breast cancer cells and the cancer-associated ECM. Our preliminary work has investigated the impact of oncogenes and changes in nutrient utilisation on ECM production by cancer cells and cancer-associated fibroblasts (CAFs), a prominent cell type within the tumour microenvironment. We find that the oncogenic transcriptional co-activator YAP dramatically impacts ECM composition and the expression of ECM-modifying proteins. Moreover, we demonstrate that altering the availability of specific nutrients modulates ECM production. By better understanding the bidirectional relationship between cancer cell metabolism and the ECM, we hope to elucidate novel metabolic vulnerabilities that can be targeted for breast cancer therapy.