Paper

Primary tumor associated macrophages activate programs of invasion and dormancy in disseminating tumor cells

Entenberg, David, Ye, Xianjun, Coste, Anouchka, Oktay, Maja, Lin, Yu, Karagiannis, George, Condeelis, John, Chen, Xiaoming, Wang, Yarong, Dalla, Erica, Duran, Camille, Borriello, Lucia, Singh, Deepak, Sharma, Ved

2021

Overview

Metastases are initiated by disseminated tumor cells (DTCs) that depart from the primary tumor and colonize target organs. Growing evidence suggests that the microenvironment of the primary tumor lesion primes DTCs to display dormant or proliferative fates in target organs. However, the manner in which events taking place in the primary tumor influence DTC fate, sometimes long after dissemination, remains poorly understood. With the advent of a novel intravital imaging technique called the Window for High-Resolution Intravital Imaging of the Lung (WHRIL), we have, for the first time, been able to study the live lung longitudinally and follow the fate of individual DTCs that spontaneously disseminate from orthotopic breast tumors. We find, across several models, a high rate of success for tumor cells to complete the initial steps of the metastatic cascade in the secondary site, including retention of DTCs in the lung vasculature, speed of extravasation, and survival after extravasation. Importantly, initiation of metastatic growth was controlled primarily by a rate-limiting step that occurred post-extravasation and at the stage of the conversion of single DTCs from a dormant to a proliferative state. Detailed analysis of these events revealed that, even before dissemination, a subset of macrophages within the primary tumor induces, in tumor cells that are about to disseminate, the expression of proteins that regulate a pro-dissemination (MenaINV) and pro-dormancy (NR2F1) phenotype. Surprisingly, if cancer cells are intravenously injected, the rate limiting stages of MenaINV-associated extravasation, dormancy, and other parameters, are lost or altered in a way that impacts how DTCs progress through the metastatic cascade. Our work provides novel insight into how specific primary tumor microenvironments prime a subpopulation of cells for dissemination and dormancy. We also propose that dissecting mechanisms of metastasis, or testing anti-metastatic therapies, may yield results of limited application if derived from models that do not follow spontaneous dissemination. Competing Interest Statement Dr. Julio Aguirre-Ghiso (a Co-author in this article) is a scientific Co-Founder of, Scientific Advisory Board Member, and equity owner in the private company, HiberCell LLC. In addition, Dr. Aguirre-Ghiso receives financial compensation as a consultant for HiberCell LLC. HiberCell LLC. is a Mount Sinai spin-out company focused on the research and development of therapeutics that prevent or delay the recurrence of cancer. Footnotes * https://www.dropbox.com/s/10jksjx2ijjy1hg/Movie%201%20Intravascular%20Tumor%20Cell.avi?dl=0 * https://www.dropbox.com/s/w66acc0mxv5ysqu/Movie%202%20Extravascular%20Tumor%20Cell.avi?dl=0

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: Breast cancer / Cancer / Cancer Biology / Colonization / Dormancy / Drug development / Extravasation / Macrophages / Metastases / Metastasis / Microenvironments / Phenotypes / Tumor cells / Tumors