Human tumors instigate granulin-expressing hematopoietic cells that promote malignancy by activating stromal fibroblasts in mice
Open accessAbstract
Systemic instigation is a process by which endocrine signals sent from certain tumors (instigators) stimulate BM cells (BMCs), which are mobilized into the circulation and subsequently foster the growth of otherwise indolent carcinoma cells (responders) residing at distant anatomical sites. The identity of the BMCs and their specific contribution or contributions to responder tumor growth have been elusive. Here, we have demonstrated that Sca1+ cKit- hematopoietic BMCs of mouse hosts bearing instigating tumors promote the growth of responding tumors that form with a myofibroblast-rich, desmoplastic stroma. Such stroma is almost always observed in malignant human adenocarcinomas and is an indicator of poor prognosis. We then identified granulin (GRN) as the most upregulated gene in instigating Sca1+ cKit- BMCs relative to counterpart control cells. The GRN+ BMCs that were recruited to the responding tumors induced resident tissue fibroblasts to express genes that promoted malignant tumor progression; indeed, treatment with recombinant GRN alone was sufficient to promote desmoplastic responding tumor growth. Further, analysis of tumor tissues from a cohort of breast cancer patients revealed that high GRN expression correlated with the most aggressive triple-negative, basal-like tumor subtype and reduced patient survival. Our data suggest that GRN and the unique hematopoietic BMCs that produce it might serve as novel therapeutic targets.
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From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [77]
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- Authors
- Elkabets, M., Gifford, A. M., Scheel, C., Nilsson, B., Reinhardt, F., Bray, M.-A., Carpenter, A. E., Jirström, K., Magnusson, K., Ebert, B. L., Pontén, F., Weinberg, R. A., & McAllister, S. S.
- Affiliations
- Brigham and Women's Hospital (US)
- Whitehead Institute for Biomedical Research (US)
- Broad Institute (US)
- Uppsala University (SE)
- Corresponding author
- McAllister, Sandra S.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2011-02-01
- Volume
- 121
- Issue
- 2
- Pages
- 784-799
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3026724
- OpenAlex
- W2133490025
- Cited by
- 201
- References
- 4
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 2 · 2023: 8 · 2022: 2 · 2021: 10 · 2020: 18 · 2019: 12 · 2018: 25 · 2017: 13 · 2016: 14 · 2015: 16 · 2014: 16 · 2013: 15 · 2012: 28
- FWCI
- 11.98
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion, other-oa)
- Funders
- Breast Cancer Research Foundation
- Alexander and Margaret Stewart Trust
- Broad Institute
- National Institutes of Health (GM089652)
- National Cancer Institute (CA12515, R01CA166284, U54CA126515)
- National Institute of General Medical Sciences (R01GM089652)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- granulin, tumor microenvironment, desmoplastic stroma, stromal fibroblasts, myofibroblasts, bone marrow cells, tumor progression, triple-negative breast cancer, basal-like breast cancer, prognostic factors, therapeutic target
- MeSH terms
- Progranulins, Animals, Bone Marrow Cells, Breast Neoplasms, Cell Line, Female, Fibroblasts, Hematopoietic Stem Cells, Humans, Neoplasm Metastasis, Neoplasm Transplantation, Stromal Cells, Disease Progression, Intercellular Signaling Peptides and Proteins, Mice
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