Abstract A020: Gene expression programs of cancer spread are targets for anti-metastasis treatments

Abstract

Abstract The lack of specific anti-metastasis drugs is due to an incomplete understanding of the molecular mechanisms underlying this process, and hence a lack of potential drug targets. In the past, we have defined the genetic basis of cancer metastasis as aberrant expression or splicing by a unique set of developmentally non-essential stress response genes that physiologically mediate the homing of immune system cells. Thus, the genetic underpinning of metastasis is distinguishable from the genetic underpinnings for uncontrolled growth or immortalization (in contrast to oncogenes or tumor suppressor genes, metastasis genes are not mutated; when mutations do arise, they are typically located in the regulatory elements). More recently, we have expanded our research to gene expression programs with the goal to identify drug targets for combination therapies. Utilizing the gene expression profiles from 653 GEO datasets, we investigated the signatures by diverse cancers in various metastatic sites for common features and for site-specific characteristics. We corroborated the meta-analysis in a murine model. Metastases are generally characterized by a core program of gene expression that induces the oxidative metabolism, activates vascularization/tissue remodeling, silences extracellular matrix interactions, and alters ion homeostasis. This program distinguishes metastases from their originating primary tumors as well as from their target host tissues. For site specificity, the release from the primary tumor is associated with a suppression of functions that are important for the identity of the organ of origin, such as a down-regulation of steroid hormone responsiveness in the disseminated foci derived from prostate cancer. Metastases adjust to their target microenvironment by upregulating—even overexpressing—genes and genetic programs that are characteristic of that organ. Further, alterations in RNA and protein processing as well as immune deviation are common. Although the drug treatment of malignant tumors has made impressive progress in recent years, the successes have been achieved mostly against the primary tumors. Once a cancer has disseminated, the prognosis worsens dramatically. There is a paucity of suitable anti-metastasis drugs. Conceivably, chemotherapy of disseminated cancer might be more efficacious if selected to match the genetic makeup of the metastases rather than the organ of origin by the primary tumor. In this regard, new potential has opened up by our finding that the gene expression of metastases is characterized by a four-pronged core program, which is common to all metastases and distinguishes them from the primary tumor as well as from the target site. Drug combinations that suppress the genetic core program of metastasis may fill an important void in cancer chemotherapy. Our ongoing research has identified lead compounds that may lay the foundation for anti-metastasis combination chemotherapies. Citation Format: Gulimerouzi F. Fnu, Franz Hartung, Georg F. Weber. Gene expression programs of cancer spread are targets for anti-metastasis treatments [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A020.