Cross-Talk Between the Tumor Microenvironment, Extracellular Matrix, and Cell Metabolism in Cancer

Abstract

The extracellular matrix (ECM) is a complex network of secreted proteins which provides support for tissues and organs. Additionally, the ECM controls a plethora of cell functions, including cell polarity, migration, proliferation, and oncogenic transformation. One of the hallmarks of cancer is altered cell metabolism, which is currently being exploited to develop anti-cancer therapies. Several pieces of evidence indicate that the tumor microenvironment and the ECM impinge on tumor cell metabolism. Therefore, it is essential to understand the contribution of the complex 3D microenvironment in controlling metabolic plasticity and responsiveness to therapies targeting cell metabolism. In this mini-review, we will describe how the tumor microenvironment and cancer-associated fibroblasts dictate cancer cell metabolism, resulting in increased tumor progression. Moreover, we will define the cross-talk between nutrient signaling and the trafficking of the ECM receptors of the integrin family. Finally, we will present recent data highlighting the contribution of nutrient scavenging from the microenvironment to support cancer cells growth under nutrient starvation conditions.

Keywords: cancer associated fibroblasts; cell metabolism; extracellular matrix; nutrient scavenging; nutrient signaling.

Figure 1

Schematic representation of different mechanisms through which cancer-associated fibroblasts (CAFs) can modify cancer cell (CC) metabolism. OXPHOS, oxidative phosphorylation; TCA, tricarboxylic acid cycle; Glu, glutamate; Asp, aspartate; ECM, extracellular matrix. (A) Lactate secreted by CAFs promotes OXPHOS in pancreatic CCs. (B) CAF-derived pyruvate promotes TCA activation in lymphoma CCs. (C) Cytokines and TGF beta promote CAF-ovarian CC cross-talk. (D) Asp secreted by CAFs drives nucleotide synthesis in squamous cell carcinoma. (E) ECM density promotes Serine synthesis and Gln metabolism in breast cancer.

Figure 2

(A) Schematic representation of the crosstalk between integrins trafficking and cell metabolism. Nutrient starvation induces ligand (fibronectin or Laminin)-bound integrin internalization through mTORC1 deactivation. On the other hand, activation of AMPK during starvation inhibits tensin expression, opposing integrin activation. There is also a link between integrin mechanosensing and sphingolipid production through CD98hc protein, which is an integrin co-receptor sensing mechanical forces. Activation of CD98hc induces sphingolipid production leading to activation of Src and GEF-H1 upstream of RhoA. (B) Schematic representation of the molecular mechanisms through which nutrient starvation controls macropinocytosis. Macromolecules internalization under nutrient starvation is induced through Ras and growth factor dependent mechanisms. Amino acids extracted from protein uptake can be used to feed the TCA cycle to make ATP or they may be used to make other proteins.