Abstract 4725: Hematopoietic stem cell niche activation and progenitor mobilization mediate cancer-associated immunosuppression and metastasis
Authors: Giles Amber J. , Murgai Meera , Vicioso Yorleny , Highfill Steven , Kasai Miki , Vahdat Linda , Wexler Leonard , Mackall Crystal , Lyden David , Kaplan Rosandra 
Published: August 2015

Metastatic tumors have been shown to establish microenvironments in distant tissues that are permissive to disseminated tumor cells. Hematopoietic cells are essential components of this microenvironment, yet the events that initiate the hematopoietic response remain unclear. Further, the functional contribution of hematopoietic stem and progenitor cells (HSPCs) to metastatic progression has not been addressed. Here, we utilized two highly metastatic C57bl/6 murine cell lines capable of spontaneous metastasis following orthotopic injection to study how the hematopoietic response is initiated and can function to promote metastatic progression in immune competent tumor-bearing mice. In both the E0771 breast carcinoma model and M3-9-M rhabdomyosarcoma model we found that a primary tumor drove expansion of HSPCs within the bone marrow prior to establishment of metastatic lesions. To detect changes within the bone marrow microenvironment that accounted for the observed HSPC expansion in tumor-bearing mice, we performed qPCR analysis of whole femur lysate from control or pre-metastatic tumor-bearing mice. We found the bone marrow microenvironment of tumor-bearing mice expressed a transcriptional program of hematopoietic niche activation that promoted expansion as well as mobilization of hematopoietic progenitors, including downregulation of the HSPC homing cytokine CXCR4. Consistent with this, we detected elevated HSPCs in the circulation of newly diagnosed cancer patients as well as pre-metastatic tumor-bearing mice. By using a pharmacological antagonist of CXCR4 to mobilize HSPCs as seen in the tumor bearing setting, we demonstrated that circulating HSPCs were functionally capable of significantly enhancing metastasis in mice. To determine the mechanisms by which circulating HSPCs can promote metastatic progression, we tracked the developmental fate of flow cytometry-sorted HSPCs injected into the circulation of control or tumor-bearing pre-metastatic mice. We found that HSPCs localized within pre-metastatic tissues preferentially differentiated into the myeloid lineage. Further, depletion of these myeloid cells abrogated the metastasis-promoting effects of HSPC mobilization. Together, these data establish bone marrow niche activation as one of the earliest steps of the metastatic process and identify circulating HSPCs as a potential indicator of metastatic niche initiation.

Citation Format: Amber J. Giles, Meera Murgai, Yorleny Vicioso, Steven Highfill, Miki Kasai, Linda Vahdat, Leonard Wexler, Crystal Mackall, David Lyden, Rosandra Kaplan. Hematopoietic stem cell niche activation and progenitor mobilization mediate cancer-associated immunosuppression and metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4725. doi:10.1158/1538-7445.AM2015-4725