Transcriptomic profiling of the myeloma bone-lining niche reveals BMP signalling inhibition to improve bone disease

Gooding, Sarah; Olechnowicz, Sam W. Z.; Morris, Emma V.; Armitage, Andrew E.; Arezes, João; Frost, J. E. F.; Repapi, Emmanouela; Edwards, James; Ashley, Neil; Waugh, Craig; Gray, Nicola E.; Martı́nez-Hackert, Erik; Lim, Pei Jin; Pasricha, Sant‐Rayn; Knowles, Helen J.; Mead, Adam J.; Ramasamy, Karthik; Drakesmith, Hal; Edwards, Claire M.

doi:10.1038/s41467-019-12296-1

Cited by 46 publications

(39 citation statements)

References 64 publications

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“…Prostate cancer cells as well as the stroma of the bone marrow are supported by BMP signaling to drive bone metastases (65). A recent study showed that inhibition of BMP signaling improved bone health without increasing tumor growth in the bones of a multiple myeloma mouse model (66). Our findings support further investigation into how myeloid BMP drives tumor progression, and how to target BMP signaling in the metastatic tumor microenvironment.…”

Section: Discussionsupporting

confidence: 73%

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

et al. 2020

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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.

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Section: Discussionsupporting

confidence: 73%

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

et al. 2020

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“…To further demonstrate that RIP1 promoted the expression of BMP7, the concentration of BMP7 in the cultural supernatant of chondrocytes was determined before and after RIP1 overexpression, the result showed that RIP1 increased secreted BMP7 level in a dose-dependent manner (Figure 8B). As BMPs play pivotal roles in the regulation of bone induction, maintenance and repair, we also performed Alizarin red staining to reveal the formation of calcium deposits in chondrocytes, which are indicative of ossification (Lowery and Rosen, 2018;Gooding et al, 2019;Wei et al, 2020). As expected, RIP1-overexpressing chondrocytes showed positive reaction with Alizarin red while control cells were negative, indicating that RIP1 indeed induces endochondral ossification, a crucial process during OA progression (Figure 8C).…”

Section: Identification Of Bmp7 As the Target Of Rip1 In Chondrocytesmentioning

confidence: 62%

RIP1 Perturbation Induces Chondrocyte Necroptosis and Promotes Osteoarthritis Pathogenesis via Targeting BMP7

Cheng

Duan

et al. 2021

Front. Cell Dev. Biol.

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Osteoarthritis (OA) is a highly prevalent and debilitating joint disorder that characterized by progressive destruction of articular cartilage. There is no effective disease-modifying therapy for the condition due to limited understanding of the molecular mechanisms on cartilage maintenance and destruction. Receptor-interacting protein kinase 1 (RIP1)-mediated necroptosis plays a vital role in various diseases, but the involvement of RIP1 in OA pathogenesis remains largely unknown. Here we show that typical necrotic cell morphology is observed within human OA cartilage samples in situ, and that RIP1 is significantly upregulated in cartilage from both OA patients and experimental OA rat models. Intra-articular RIP1 overexpression is sufficient to induce structural and functional defects of cartilage in rats, highlighting the crucial role of RIP1 during OA onset and progression by mediating chondrocyte necroptosis and disrupting extracellular matrix (ECM) metabolism homeostasis. Inhibition of RIP1 activity by its inhibitor necrostatin-1 protects the rats from trauma-induced cartilage degradation as well as limb pain. More importantly, we identify bone morphogenetic protein 7 (BMP7) as a novel downstream target that mediates RIP1-induced chondrocyte necroptosis and OA manifestations, thereby representing a non-canonical regulation mode of necroptosis. Our study supports a model whereby the activation of RIP1-BMP7 functional axis promotes chondrocyte necroptosis and subsequent OA pathogenesis, thus providing a new therapeutic target for OA.

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“…However, the wealth of molecular information obtained from a bone biopsy outweighs the procedural and technical risks. In a multiple myeloma mouse model, transcriptomic profiling of the bone microenvironment identified bone morphogenetic protein signaling as a targetable approach for treatment of myeloma TIBD 75 . Based on the cellular and molecular composition of an individual patient's TIBD, appropriate therapeutics can be selected to improve patient outcomes.…”

Section: New Horizons For Metastatic Bonementioning

confidence: 99%

Integrating the immune microenvironment of prostate cancer induced bone disease

Ihle

Owens

2020

Molecular Carcinogenesis

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Prostate cancer (PCa) is the most frequently diagnosed cancer for men in the U.S. but does not impede patient survival until the disease is metastatic. Metastatic lesions most frequently occur in the bone, which exhibits a distinct microenvironment of immune and bone cell populations. Advances in the diagnosis and treatment of primary PCa allow for the use of tailored therapeutic approaches based on biomarkers, protein expression, and histopathology. Understanding the molecular and cellular characteristics of primary tumors has advanced therapeutic development and survival for patients with PCa.Personalized medicine has only recently emerged for the treatment of metastatic bone lesions. Tumor induced bone disease (TIBD) in patients with PCa can be classified into lytic, blastic, or mixed pathologies, with most patients exhibiting the blastic phenotype.Progress has been made in treating TIBD, but metastatic PCa has yet to be cured. Immune checkpoint inhibitors have exhibited limited responses in immunosuppressivePCa tumors, but have yet to be assessed in metastatic sites which may be susceptible to an increased inflammatory response. Recent discoveries have uncovered distinct tumor microenvironments (TMEs) of blastic and lytic bone metastases from patients with PCa, identifying actionable targets for therapeutic applications, including immune checkpoint inhibitors and targeted therapeutics. Enrichment for macrophages and T cells in patient samples suggests metastatic sites may be reappraised as immunologically targetable, despite their immunologically "cold" primary tumors. The practice of performing bone biopsies will help identify unique cellular and protein targets in the bone TME that can guide therapy decisions. K E Y W O R D S bone metastasis, immmunotherapy, prostate cancer, tumor microenvironment 1 | PROSTATE CANCER 1.1 | Scope of prostate cancer Prostate cancer (PCa) is the most commonly diagnosed cancer for men in the U.S., accounting for more than one in five new cancer diagnoses. 1 Thanks to early diagnosis and effective treatment options, survival is extremely high at >99% for localized and regional tumors. 2 Of the 191 930 estimated new cases of PCa in the U.S. for 2020, only 33 330 patients are expected to succumb to the disease. 1 However, once distant metastases are present patient with PCa survival drops to 30%, as patients face fewer therapeutic

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Transcriptomic profiling of the myeloma bone-lining niche reveals BMP signalling inhibition to improve bone disease

Cited by 46 publications

References 64 publications

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

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

RIP1 Perturbation Induces Chondrocyte Necroptosis and Promotes Osteoarthritis Pathogenesis via Targeting BMP7

Integrating the immune microenvironment of prostate cancer induced bone disease

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