Human tumors instigate granulin-expressing hematopoietic cells that promote malignancy by activating stromal fibroblasts in mice
Moshe Elkabets, Ann M. Gifford, Christina Scheel, Bjorn Nilsson, Ferenc Reinhardt, Mark-Anthony Bray, Anne E. Carpenter, Karin Jirström, Kristina Magnusson, Benjamin L. Ebert, Fredrik Pontén, Robert A. Weinberg, Sandra S. McAllister
Moshe Elkabets, Ann M. Gifford, Christina Scheel, Bjorn Nilsson, Ferenc Reinhardt, Mark-Anthony Bray, Anne E. Carpenter, Karin Jirström, Kristina Magnusson, Benjamin L. Ebert, Fredrik Pontén, Robert A. Weinberg, Sandra S. McAllister
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Research Article

Human tumors instigate granulin-expressing hematopoietic cells that promote malignancy by activating stromal fibroblasts in mice

Abstract

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.

Authors

Moshe Elkabets, Ann M. Gifford, Christina Scheel, Bjorn Nilsson, Ferenc Reinhardt, Mark-Anthony Bray, Anne E. Carpenter, Karin Jirström, Kristina Magnusson, Benjamin L. Ebert, Fredrik Pontén, Robert A. Weinberg, Sandra S. McAllister

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Figure 2

BMCs from instigator-bearing animals phenocopy systemic instigation.

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BMCs from instigator-bearing animals phenocopy systemic instigation. (A)...
(A) Experimental scheme to test BMC tumor supportive function: admixtures of BMCs and responding tumor cells are injected subcutaneously into host nude mice. (B) Average mass of resulting tumors 12 weeks after implantation of various indicated mixtures. Tumor incidence is indicated above bars (2 separate experiments, n = 16 per group). Data are expressed as mean ± SEM. (C) Histopathology of resulting responding tumors harvested 12 weeks after implantation of indicated mixtures. Photomicrographs show staining for αSMA (brown) and nuclei counterstained with hematoxylin (blue). Scale bar: 100 μm. (D) Experimental scheme for injecting tumor cells subcutaneously into mice that had previously been engrafted with GFP+ BMCs. (E) Merged immunofluorescent images of responding tumors that had grown for 12 weeks opposite BPLER (top) or MDA-MB-231 (bottom) instigating tumors in GFP+ BMC transplanted mice. Images represent GFP+ BM–derived cells (green); αSMA+ tumor myofibroblasts and pericytes (red); and cell nuclei (DAPI; blue). Yellow signal represents an overlap of 2 different cells, as confirmed by confocal microscopy. Scale bar: 25 μm.