VDAC1 Silencing in Cancer Cells Leads to Metabolic Reprogramming That Modulates Tumor Microenvironment.

Abstract

Simple SummaryTumors are comprised of proliferating cancer cells, and their microenvironment consists of the extracellular matrix, blood vessels, and a variety of tissue cells. The tumor microenvironment functions in cell growth, proliferation, migration, immunity, malignant transformation, and apoptosis. Understanding the molecular interactions between cancer cells and their microenvironment would facilitate the development of therapeutic strategies to disrupt these interactions and fight cancer. Here, we demonstrate that depleting the mitochondrial gatekeeper VDAC1 in human cancer cells in tumors led to metabolic reprogramming, inhibited tumor growth, and disrupted tumor–host interactions. A next-generation sequencing analysis of human lung cell-derived tumors expressing or depleted of VDAC1 allows distinguishing genes of human or murine origin, thus enabling the separation of the bidirectional cross-talk between malignant cells and the tumor microenvironment. A battery of human cancer cell and mouse genes associated with tumor microenvironment formation and remodeling were altered. The results point to VDAC1 as a novel target for both inhibiting tumor growth and modulating the tumor microenvironment, thus influencing cancer progression, migration, and invasion.The tumor microenvironment (TME) plays an important role in cell growth, proliferation, migration, immunity, malignant transformation, and apoptosis. Thus, better insight into tumor–host interactions is required. Most of these processes involve the metabolic reprogramming of cells. Here, we focused on this reprogramming in cancerous cells and its effect on the TME. A major limitation in the study of tumor–host interactions is the difficulty in separating cancerous from non-cancerous signaling pathways within a tumor. Our strategy involved specifically silencing the expression of VDAC1 in the mitochondria of human-derived A549 lung cancer xenografts in mice, but not in the mouse-derived cells of the TME. Next-generation sequencing (NGS) analysis allows distinguishing the human or mouse origin of genes, thus enabling the separation of the bidirectional cross-talk between the TME and malignant cells. We demonstrate that depleting VDAC1 in cancer cells led to metabolic reprogramming, tumor regression, and the disruption of tumor–host interactions. This was reflected in the altered expression of a battery of genes associated with TME, including those involved in extracellular matrix organization and structure, matrix-related peptidases, angiogenesis, intercellular interacting proteins, integrins, and growth factors associated with stromal activities. We show that metabolic rewiring upon mitochondrial VDAC1 silencing in cancer cells affected several components of the TME, such as structural protein matrix metalloproteinases and Lox, and elicited a stromal response resembling the reaction to a foreign body in wound healing. As tumor progression requires a cooperative interplay between the host and cancer cells, and the ECM is intensively remodeled during cancer progression, VDAC1 depletion induced metabolic reprogramming that targeted both tumor cells and resulted in the alteration of the whole spectrum of TME-related genes, affecting the reciprocal feedback between ECM molecules, host cells, and cancer cells. Thus, VDAC1 depletion using si-VDAC1 represents therapeutic potential, inhibiting cancer cell proliferation and also inducing the modulation of TME components, which influences cancer progression, migration, and invasion.