Abstract SY35-02: Bone marrow remodeling in response to distant tumor starts early in transformation

Abstract

Abstract Bone marrow (BM) stromal cell are sensors of immunological stress signals from peripheral tissue. We showed that chronicity of such signals induces persistent changes in the stromal architecture providing favorable conditions for the establishment and progression of a myeloproliferative spur (Blood 2012, 120: 3541). A key regulator of bone marrow stromal changes is the secreted protein acidic and rich in cysteine (SPARC) a matricellular protein with both structural and regulatory functions on extracellular matrix (ECM) organization. Up- and downregulation of SPARC has been indeed associated with different hematologic neoplasms including myeloid and lymphoid malignancies (Cancer Res. 2017, 77: 3685; Cancer Discovery 2014, 4: 110). We identified SPARC as a common stromal trait of the BM osteoblastic niche and SLO germinal center (GC) microenvironments, where it regulates physiological B lymphopoiesis and B cell development, as well as B cell lymphomagenesis (Oncoimmunology 2014). Like infections and autoimmunity, also the presence of solid tumors involves the establishment of a chronic state of inflammation that can act locally but also be sensed systemically, particularly by the BM. The last responds with an expansion of accessory cells further fostering tumor growth and dissemination.Others and we have indeed demonstrated in tumor mouse models the expansion in the BM of the myeloid compartment that parallels tumor progression. In this context we contributed to identify some of the key molecules involved in the BM-tumor cross talk, such as VEGF, MMP-9 (Cancer Res. 2007, 67:11438). Tumor-expanded myeloid cells are generally endowed with immune suppressive features, which actively contribute to cancer-associated systemic immune suppression.We have recently described two additional mechanisms that contribute to the shaping of the myeloid cell phenotype and suppressive activity in mammary tumors and involve SPARC (Cell Report 2016, 17: 233) and another matricellular protein, i.e. osteopontin (Cancer Res. 2014, 74: 4706). New data indicate that tumor-induced myeloid cell expansion in the BM is associated with profound changes not only in the hematopoietic compartment, but also in the stromal niche organization. In a spontaneous model of mammary carcinogenesis we show significant alterations in the density and localization of Nestin+ mesenchymal stromal elements and in the expression of the prototypical stroma-derived chemotactic factor CXCL12, which were both increased in the hematopoietic interstitium of mammary tumor bearing mice. How early during transformation these hematopoietic and stromal changes are detectable, and the identification of soluble factors involved in these BM modification are the focus of our present research and will be presented in this symposium.Understanding the molecular determinants of cancer-driven hematopoietic adaptation would offer a new prospect on cancer early detection and prognostication, eventually prompting novel strategies to interfere with such detrimental changes besides the specific targeting of functional hematopoietic subsets. Citation Format: Mario P. Colombo. Bone marrow remodeling in response to distant tumor starts early in transformation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY35-02.