The most common metastatic lesions of prostate cancer are in bone and can be classified into three distinct pathology subtypes: lytic, blastic, and an indeterminate mixture of both. We investigated a cohort of decalcified formalin-fixed and paraffin-embedded (FFPE) patient specimens from the bone that contained metastatic prostate cancer with lytic or blastic features. These tissue sections were utilized for immunohistochemistry (IHC) staining, isolation of RNA for gene expression, and Digital Spatial Profiling (DSP) of changes in both the tumor and microenvironment. A diverse set of unique immune cell populations and signaling pathways to both lytic and blastic types of prostate cancer metastases were present. In blastic lesions immune cells were enriched for pSTAT3 and components of the JAK-STAT pathway. In lytic-type lesions, immune cells were enriched for pAKT activity and components of the PI3K-AKT pathway. Enrichment for immune checkpoints including PD-L1, B7-H4, OX40L, and IDO-1 were identified in blastic prostate cancer, providing new therapeutic targets for patients with bone metastases. Biopsies could guide selection of patients into appropriate therapeutic interventions based on protein levels and RNA expression of desired targets in metastatic disease. Molecular pathology has been an excellent complement to the diagnosis, treatment, and management of primary tumors and could be successfully extended to patients with metastatic lesions.
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.
From the 33,000 men in the U.S. who die from prostate cancer each year, the majority of these patients exhibit metastatic disease with bone being the most common site of metastasis. Prostate cancer bone metastases are commonly blastic, exhibiting new growth of unhealthy sclerotic bone, which can cause painful skeletal related events. Patient’s current care entails androgen deprivation therapy, anti-resorptive agents, radiation, and chemotherapy to help control the spread of the cancer but little intervention is available to treat blastic bone disease. The transforming growth factor beta (TGFβ) and bone morphogenetic protein (BMP) pathways are known to regulate bone growth and resorption of destructive lytic bone lesions, yet the role of TGFβ/BMP signaling in prostate cancer blastic vs lytic bone lesions are not fully understood. We hypothesized that to target the BMP/TGFβ pathway, a useful biomarker of bone lytic or blastic pathology would have superior response. We show distinct BMP vs. TGFβ signaling in clinical samples of human prostate cancer bone metastases with either lytic or blastic pathologies. BMPs exhibit distinct effects on bone homeostasis, so to examine the effect of BMP inhibition on healthy bone, we treated mice with the BMP receptor small molecule antagonist DMH1 and saw a modest temporary improvement in bone health, with increased trabecular bone. We next sought to use the BMP inhibitor DMH1 to treat bone metastasis engraftment seeded by a caudal artery injection of the lytic human prostate cell line PC3 in immunodeficient mice. The colonization by PC3 cells to the bone were restricted with DMH1 treatment and bone health was importantly preserved. We next proceeded to test BMP inhibition in an injury model of established bone metastasis via intratibial injection of the MYC-CaP mouse prostate cell line into FVBN syngeneic mice. DMH1 treated mice had a modest decrease in trabecular bone and reduced lymphocytes in circulation without affecting tumor growth. Taken together we show unique responses to BMP inhibition in metastatic prostate cancer in the bone. These studies suggest that profiling bone lesions in metastatic prostate cancer can help identify therapeutic targets that not only treat the metastatic tumor but also address the need to better treat the distinct tumor induced bone disease.
Background: Prostate cancer is a common cancer in men that annually results in more than 33 000 US deaths. Mortality from prostate cancer is largely from metastatic disease, reflecting on the great strides in the last century of treatments in care for the localized disease. Metastatic castrate resistant prostate cancer (mCRPC) will commonly travel to the bone, creating unique bone pathology that requires nuanced treatments in those sites with surgical, radio and chemotherapeutic interventions.The bone morphogenetic protein (BMP) pathway has been historically studied in the capacity to regulate the osteogenic nature of new bone. New mineralized bone generation is a frequent and common observation in mCRPC and referred to as blastic bone lesions. Less common are bone destructive lesions that are termed lytic.Methods: We queried the cancer genome atlas (TCGA) prostate cancer databases for the expression of the BMP pathway and found that distinct gene expression of the ligands, soluble antagonists, receptors, and intracellular mediators were altered in localized versus metastatic disease. Human prostate cancer cell lines have an innate ability to promote blastic-or lytic-like bone lesions and we hypothesized that inhibiting BMP signaling in these cell lines would result in a distinct change in osteogenesis gene expression with BMP inhibition.Results: We found unique and common changes by comparing these cell lines response and unique BMP pathway alterations. We treated human PCa cell lines with distinct bone pathologic phenotypes with the BMP inhibitor DMH1 and found distinct osteogenesis responses. We analyzed distinct sites of metastatic PCa in the TCGA and found that BMP signaling was selectively altered in commons sites such as lymph node, bone and liver compared to primary tumors.Conclusions: Overall we conclude that BMPs in metastatic prostate cancer are important signals and functional mediators of diverse processes that have potential for individualized precision oncology in mCRPC.
Breast cancer (BC) patient prognosis has improved over the past 2 decades with a 99% 5 year survival rate for localized BC, yet metastatic BC continues to cause high mortality with a 5 year survival rate of 27%. Recent advances have been made in the treatment of primary BC, providing an opportunity to apply this positive momentum towards treating metastatic disease. Approximately 70% of BC metastases occur in the bone, with the majority of patients retaining estrogen receptor positive (ER+) disease. The BC tumor microenvironment (TME) in bone exhibits an osteolytic bone pathology of bone destruction and is composed of primarily four cellular groups including the cancer, immune, vascular and bone cells. These cellular constituents are uniquely responsive to estradiol (E2) and exhibit unique TMEs dependent on menopause status, when circulating E2 is lost. Both menopause and BC endocrine therapies induce an E2-deprived post-menopausal state in patients. However, studying the distinctions of pre- and post-menopausal BC patient TMEs is still necessary to understand how natural menopause status impacts non-treatment naïve ER+ BC that is already in a therapy induced menopausal state. In particular the full extent of the unique phenotypes harbored by pre- versus post-menopausal ER+ BC tumor induced bone disease (TIBD) remains unknown, and elucidation of these difference may identify novel mechanisms of TIBD. We investigated a cohort of demineralized formalin-fixed and paraffin-embedded (FFPE) pre- and post-menopausal lytic bone metastasis biopsies from non-treatment naïve ER+ BC patients. We utilized immunohistochemistry (IHC), NanoString nCounter gene expression panels and GeoMx Digital Spatial Profiling (DSP) to observe distinct TMEs in our archival biopsy cohort. IHC staining of pre- and post-menopausal samples displayed alterations to immune cell infiltration and composition. Differential gene expression analysis revealed enrichment of myeloid function in pre-menopausal patients compared to post-menopausal patients. Alterations to immune signaling pathways and cell profiles were also exhibited in pre-menopausal patients compared to post-menopausal patients. DSP analysis presented changes in both the tumor and microenvironment, and unique immune cell infiltration with checkpoint proteins in both pre-menopausal and post-menopausal ER+ BC bone metastases. The identification of these targetable markers unique to pre- and post-menopausal TIBD could provide new therapeutic strategies for ER+ BC patients with bone lesions. Thus, we propose that bone biopsies could be performed to guide selection for metastatic BC patients into appropriate therapeutic interventions, with pre- and post-menopausal patients receiving tailored treatments based on their distinct protein and RNA expression of available therapies. This personalized approach to treating metastatic disease could enhance patient quality of life and survival. Citation Format: Claire Ihle, Meredith Provera, Desiree Straign, Katy Zolman, Erin Smith, Adrie Van Bokhoven, Scott Lucia, Philip Owens. Distinct tumor microenvironments of breast cancer bone metastases in pre- and post-menopausal patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS14-14.
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