Distant Inflammation Drives Emergence from Metastatic Dormancy
Abstract
Metastatic breast cancer remains incurable. Tumor cells escape into the blood early during primary tumor development, and the danger stems from a subset that lie dormant for years to decades before re-emerging into clinically detectable metastases, even after seeming curative removal of the initial tumor. The overarching challenge of this proposal focuses on determining why/how breast cancer cells lie dormant for years and then re-emerge (recurrence); determine how to prevent recurrence. Determining the molecular instigators behind recurrence is key to turning metastatic disease into a clinically irrelevant manageable disease and prolonging the lives of the women who have already survived primary breast cancer. Scientific Rationale: The proposal focuses on helping the many women that unknowingly harbor latent disseminated disease. The body’s inflammatory system has been implicated as driving metastatic recurrence. We propose to study an underappreciated aspect of the body’s inflammation – the involvement of inflammation in distant uninvolved organs, in this instance the gut, in driving emergence of dormant metastases. We hypothesize that inflammatory signals from gut travel to the liver and awaken dormant metastatic cells to proliferate and outgrow. The liver and gut are highly relevant organs to study breast cancer recurrence – the liver is a main site of breast cancer metastases, and the gut is the largest immune compartment of the body. Inflammatory signals from the gut directly impact the liver as it receives most of its blood supply from the gut. Inflammation triggered by disruption of the gut homeostasis has been directly linked to disease development elsewhere in the body, including the initiation, progression, and spread of numerous cancers. The role of the gut in metastatic emergence remains to be elucidated; however, our preliminary data demonstrated that gut-derived signals (e.g., bacterial products and molecules from immune cells) stimulate dormant breast cancer cells in a liver to awaken and outgrow. Recurrence of breast cancer has been a challenging aspect of metastasis to study due to the paucity of relevant model systems. While animal models have provided valuable insights, they are not fully representative of the human situation due to issues of interspecies functions (e.g., immune and metabolic) and such studies also use immune compromised mice. Furthermore, dissection of the proposed investigation requires the ability to study both the metastatic site in isolation and in communication with the “influencer” organ, something now enabled by our innovative all-human ex vivo multi-organ microphysiological system (MPS). The multi-organ MPS links a liver module that reproduces dormant breast cancer metastases in fluidic communication with an immune-active gut module. The liver-based MPS does provide unmatched benefits and advantages, as it is both the main site of drug metabolism and dose-limiting toxicity for most common cancer therapies. Of note, although the studies use a model of liver metastasis, findings are likely translatable to other distant sites as the morphologic shifts and dormancy noted in the liver are also seen in breast cancer metastases to the lung, brain, and bone marrow. To ensure relevance, we will use human patient-derived breast tumor cells and validate findings in preclinical animal models of spontaneous metastasis. Clinical Applicability and Impact: The major goal of this project is to turn metastatic breast cancer into a clinically irrelevant manageable disease by maintaining disseminated cells in a dormant, silent state. The successful completion of the proposed work will advance breast cancer research by elucidating the pro-emergent signal(s) produced by the gut that induce the awakening and outgrowth of dormant metastatic breast cancer cells. Significantly for women living with the threat of recurrence, the translation of our findings into actual benefit may
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910494
Entities
People
- Amanda M Clark
Organizations
- United States Army
- University of Pittsburgh