Microenvironments and Signaling Pathways Regulating Early Dissemination, Dormancy, and Metastasis
Abstract
In the last period before this final report, we devoted effort to both aims, to optimize methods and publish the first phase of efforts. SA1 was to understand the intrinsic mechanisms of dissemination by early-progressed cancer cells and how the microenvironment in these primary sites, named P-TMEM (Primary Tumor Microenvironment of Metastases), contribute to early dissemination. Our data suggested that a signature of early dissemination markers consisting on HER2HI/p-ATF2LO/E-cadhLO could identify motile early-progressed tumor cells and predict for dissemination. We further showed that mammary tissue macrophages and HER2HI/p-ATF2LO/E-cadhLO tumor cells cooperate to disseminate early. This further supports our hypothesis that even in early cancer lesions macrophages and tumor cells assemble with endothelial cells a TMEM structure. We also made progress in generating a standardized triple staining that captures all these cell types in all tissues and we used intravital imaging to document live intravasation in early cancer lesions. Our work revealed that the presence of intraepithelial macrophages in DCIS samples in mouse models or humans could accurately predict dissemination in 70% of the cases of patients with bone marrow DTCs (Disseminated Tumor Cells). SA2 focused on elucidating how S-TMEMs (Secondary Tumor Microenvironment of Metastases) contribute to the dormancy phase of early DTCs. We found that early DTCs appear to undergo a p38-independent but TWIST-dependent dormancy in secondary organs, revealing a new pathway for dormancy induction. Our data also showed that depletion of macrophages during early dissemination steps significantly reduces metastasis that develop in the late stages of progression, providing functional support for macrophages in P- and S-TMEM structures in metastasis development. This work is part of two papers, one published in the journal Nature and the other published in Nature Communications (accepted pending editorial revisions).
Document Details
- Document Type
- Technical Report
- Publication Date
- Nov 01, 2017
- Accession Number
- AD1056235
Entities
People
- John Condeelis
- Julio Aguirre-Ghiso
Organizations
- Albert Einstein College of Medicine