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Capase-1 cleaves PPARg for potentitating the pro-tumor action of TAMs

ABSTRACT: Tumor-associated macrophages (TAMs) are increasingly viewed as a target of great relevance in the tumor microenvironment, because of their important role in cancer progression and metastasis. However, the endogenous regulatory mechanisms underlying TAM differentiation remain largely unknown. Here, we report that caspase-1 promotes TAM differentiation by cleaving peroxisome proliferator-activated receptor gamma (PPARγ) at Asp64, thus generating a 41 kDa fragment. This truncated PPARγ translocates to mitochondria, where it directly interacts with medium-chain acyl-CoA dehydrogenase (MCAD). This binding event attenuates MCAD activity and inhibits fatty acid oxidation, thereby leading to the accumulation of lipid droplets and promoting TAM differentiation. Furthermore, the administration of caspase-1 inhibitors or the infusion of bone marrow-derived macrophages (BMDMs) genetically engineered to overexpress murine MCAD markedly suppresses tumor growth. Therefore, targeting the caspase-1/PPARγ/MCAD pathway might be a promising therapeutic approach to prevent tumor progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE99960 | GEO | 2017/06/14

SECONDARY ACCESSION(S): PRJNA390240

REPOSITORIES: GEO

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Project description:Cells undergoing apoptosis are known to modulate their tissue microenvironments. By acting on phagocytes, notably macrophages, apoptotic cells inhibit immunological and inflammatory responses and promote trophic signaling pathways. Paradoxically because of their potential to cause death of tumor cells and thereby militate against malignant disease progression, both apoptosis and tumor-associated macrophages (TAM) are often associated with poor prognosis in cancer. In order to better understand the influence of tumor cell apoptosis and in particular its effect on TAM, we investigated global gene expression signatures of undisturbed TAM engaged in engulfment of apoptotic tumor cells. We studied a xenograft model of an aggressive ‘starry-sky’ non-Hodgkin’s lymphoma, Burkitt’s lymphoma (BL), in which apoptotic tumor cells are common and frequently observed in association with the starry-sky TAM (SS-TAM, so called because they appear histologically as ‘stars’ in a ‘sky’ of tumor cells) that accumulate in these tumors. We used a BL cell line (BL2) whose cells phenotypically resemble the tumor biopsy cells from which the line was derived including the capacity to undergo apoptosis constitutively. BL xenografts in SCID mice closely recapitulated the starry-sky histological picture of the human lymphoma. Due to the high sensitivity of macrophages to their environments, we adopted laser-capture microdissection of individual SS-TAM in BL xenografts in order to obtain unbiased in situ transcriptional profiles of these cells, which we compared specifically with those of similarly-captured macrophages, the tingible-body macrophages from normal germinal centers (GCM). The rationale for this comparison was based upon BL being a germinal center malignancy and tingible-body macrophages being regarded as normal equivalents of SS-TAM. Gene expression profiles of SS-TAM from BL2 xenograft tumors were compared to splenic GCM profiles. Three mice from each group were analysed. RNA was isolated from 1000 captured macrophages from each mouse and global gene expression signatures were obtained using Affymetrix Mouse Gene 1.0 GeneChip arrays.

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Capase-1 cleaves PPARg for potentitating the pro-tumor action of TAMs

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