Regulation of hematopoiesis during tumor progression

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Project Summary/Abstract The immune system plays an important role during tumor progression, having the ability to recognize and kill tumor cells (T cells and NK cells) [1]. Unfortunately, these immune responses can be bypassed through a variety of mechanisms, including creating an immune suppressive environment that alters the ability of T cells and NK cells to inhibit tumor growth [2]. Major players in suppressing anti-tumor immune responses are immature myeloid populations originating in the bone marrow. Several lines of evidence indicate a correlation between increased numbers of immature myeloid populations in bone marrow, circulation and at tumor site, with disease progression and reduced survival [3, 4]. Altered bone marrow hematopoiesis, with skewing towards myelopoiesis, is indeed observed in cancer patients, regardless of the tumor type and/or dissemination to bone. However, the impact of a primary tumor on bone marrow hematopoietic stem cells (HSC) and the factors involved in changing their frequency and/or functionality remain to be elucidated. Dkk1, a Wnt/β-catenin inhibitor, exerts immune suppressive effects in various cancer types, by either supporting myeloid suppressor populations or inhibiting anti-tumor immune responses [5-7]. However, the mechanisms by which Dkk1 induces the changes in immune populations during tumor progression are not fully understood and evidence of direct effects of Dkk1 on mature immune cells are sparse. Interestingly, Dkk1 is required for hematopoietic stem cell (HSC) regeneration [8], and over expression can promote long-term HSC exhaustion in transplantation models [9]. Currently, the role of Dkk1 on hematopoietic stem and progenitor cells (HSPCs) during cancer progression has not been investigated. My preliminary studies show Dkk1-dependent increases in HSPC frequencies following orthotopic injection of EO771 breast cancer cells, demonstrating systemic effects of a primary tumor on bone marrow hematopoiesis. Based on these observations, this training opportunity will allow me to test the hypothesis that bone derived Dkk1 alters HSPCs frequency and function to increase myelopoiesis and transform the immune landscape during tumor progression. Thus, I propose the following aims: Aim 1: To uncover alterations to HSPCs during breast cancer progression; and Aim 2: To investigate the role of bone derived Dkk1 on HSPCs. These aims will reveal the impact of tumor progression on hematopoiesis and the role of the bone in orchestrating a tumor-conducive, immune suppressive environment. The training received through this proposal will allow me to pursue my interests in bone biology and hematology, strengthen my research skills, and allow me to develop the skill set necessary for an Academic career at the intersection of bone biology, hematology, and immunology.