Abstract IA024: Tumor exosome and exomere biomarkers for early cancer detection

Abstract

Abstract In 1889, Stephen Paget first proposed that organ distribution of metastases is a non-random event, yet metastatic organotropism remains one of the greatest mysteries in cancer biology. A growing number of studies demonstrate that tumor-derived microvesicles, referred to as exosomes, may alter the tumor microenvironment at future sites of metastasis promoting pre-metastatic niche formation, and thus creating a favorable “soil” for incoming metastatic “seeds.” However, by what mechanism, and whether their role is significant in tumor progression remains unknown. We have recently demonstrated that exosomes released by lung-, liver- and brain-tropic tumor cells preferentially fuse with resident cells at their future metastatic sites, such as fibroblasts and epithelial cells in the lung, Kupffer cells in the liver, and endothelial cells in the brain. We found that tumor-derived exosome homing to organ-specific cell types prepares the pre-metastatic niche. Moreover, treatment with exosomes derived from lung-tropic models can redirect to the lung the metastatic distribution of cells that normally lack the capacity to form lung metastasis. Proteomic profiling of exosomes revealed distinct integrin expression patterns associated with each organ-specific metastatic site. Whereas exosomal α6β4 integrins were associated with lung metastasis, exosomal integrin αvβ5 was linked to liver metastasis and αvβ3 to brain metastasis. Targeting α6β4 and αvβ5 integrins decreased exosome uptake and metastasis in the lung and liver, respectively. Moreover, our clinical data indicate that integrin expression profiles in circulating plasma exosomes from cancer patients could be used to predict organ-specific metastasis. To gain a more comprehensive understanding of the relationship between exosomal protein cargo and tumor progression, we have built one of the largest exosome proteomics databases, including human and murine normal, pre-cancer and cancer exosomes from a variety sources, from cell lines to plasma and other bodily fluids. This dataset has allowed us to extend the list of markers that can be used to identify and isolate exosomes from human samples. When comparing the protein cargo of blood plasma exosomes isolated from normal subjects versus cancer patients with early stage pancreatic, colorectal, breast and lung cancer, we were able to define a cancer-specific proteomic signature that distinguishes cancer exosomes. Using paired samples from tumor tissue and plasma of the same cancer patients with breast, lung or pancreatic cancer, we were able to derive cancer type-specific exosomal signatures, which can be used as biomarkers to identify and classify tumors of unknown origin. Therefore, proteomic profiling of exosomes has great clinical potential as a non-invasive, rapid liquid biopsy that could aid in tumor detection classification. Citation Format: Ayuko Hoshino, Han Sang Kim, Linda Bojmar, Kofi Ennu Gyan, Haiying Zhang, Irina Matei, David Lyden. Tumor exosome and exomere biomarkers for early cancer detection [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr IA024.