Loss of Myeloid BMPR1a Alters Differentiation and Reduces Mouse Prostate Cancer Growth

Abstract

The Bone Morphogenetic Protein (BMP) pathway is a member of the TGFβ signaling family and has complex roles in cancer. BMP signaling is rarely mutated and can be frequently overexpressed in many human cancers. The dichotomous role of BMPs as both tumor promoters and suppressors appears to be largely context based in both the cancer cell and the surrounding microenvironment. Myeloid cells including macrophages and neutrophils have been shown to be tumor promoting when stimulated from BMPs. We found that conditional deletion of BMPR1a in myeloid cells (LysMCre) restricts tumor progression in a syngeneic mouse prostate cancer model. Specific changes occurred in myeloid cells both in tumor bearing mice and tumor naïve mice throughout multiple tissues. We profiled myeloid subsets in the bone marrow, spleen and primary tumor and found myeloid BMPR1a loss altered the differentiation and lineage capability of distinct populations by histologic, flow cytometry and high dimensional mass cytometry analysis. We further confirmed the requirement for BMP signaling with pharmacologic inhibition of THP-1 and Raw264.7 activated into M2 macrophages with the BMP inhibitor DMH1. M2 polarized primary bone marrow derived cells from LysMCre BMPR1a knockout mice indicated a distinct requirement for BMP signaling in myeloid cells during M2 activation. These results indicate a unique necessity for BMP signaling in myeloid cells during tumor progression.

Bone Morphogenetic Protein Signaling in Cancer; Some Topics in the Recent 10 Years

“…Ihle et al utilized a LysMCre-mediated myeloid-specific Bmpr1a conditional knockout mouse model along with a syngeneic prostate cancer model and demonstrated the pro-tumorigenic role of ALK3 in myeloid cells. They also confirmed that macrophage polarization is altered by ALK3 inhibition in this setting ( Ihle et al, 2020 ). BMP-7 is upregulated in tumors in a mouse model that does not respond to treatment with immune checkpoint inhibitors ( Cortez et al, 2020 ).…”

Targeting the BMP Pathway in Prostate Cancer Induced Bone Disease

“…We currently demonstrate this phenomenon by examining pharmacologic inhibition of BMP signaling in distinct models of experimental bone metastasis with unique immune repertoires. Our previous findings that BMPR1a deletion in the myeloid LysMCre mouse model restricted primary prostate growth furthers the tumor promoting capacity that BMPs provide (31). However, in this current study the pharmacologic benefit to BMP inhibition was during engraftment of human cells lacking full immune functions (Figure 3).…”

Bone morphogenetic protein receptor 1α promotes osteolytic lesion of oral squamous cell carcinoma by SHH‐dependent osteoclastogenesis

“…A study focusing on prostate cancer found that loss of myeloid BMPR1α restricted tumor progression in a syngeneic mouse prostate cancer model. 43 It was also shown that deletion of BMPR1α in colon cancer could sensitize cells to chemotherapy and that high BMPR1α gene expression was correlated with decreased survival regardless of molecular breast cancer subtype. 44 , 45 Using transcriptomic profiling of isolated bone lining cell subtypes from a murine myeloma model, Gooding et al found that solubilized BMPR1α‐FC receptor‐ligand trap could prevent trabecular and cortical bone volume loss caused by myeloma.…”