Tissue-resident macrophages in omentum promote metastatic spread of ovarian cancer

Abstract

Experimental and clinical evidence suggests that tumor-associated macrophages (TAMs) play important roles in cancer progression. Here, we have characterized the ontogeny and function of TAM subsets in a mouse model of metastatic ovarian cancer that is representative for visceral peritoneal metastasis. We show that the omentum is a critical premetastatic niche for development of invasive disease in this model and define a unique subset of CD163+ Tim4+ resident omental macrophages responsible for metastatic spread of ovarian cancer cells. Transcriptomic analysis showed that resident CD163+ Tim4+ omental macrophages were phenotypically distinct and maintained their resident identity during tumor growth. Selective depletion of CD163+ Tim4+ macrophages in omentum using genetic and pharmacological tools prevented tumor progression and metastatic spread of disease. These studies describe a specific role for tissue-resident macrophages in the invasive progression of metastatic ovarian cancer. The molecular pathways of cross-talk between tissue-resident macrophages and disseminated cancer cells may represent new targets to prevent metastasis and disease recurrence.

The omentum, a niche for premetastatic ovarian cancer

“…Journal of Experimental Medicine 2 of 3 The omentum, a niche for premetastatic ovarian cancer https://doi.org/10.1084/jem.20192312 antibody can target CD163 and CSF1R, which was avidly shown, using genetic tools, to be highly efficient in abrogating the TRMs and preventing disease progression ( Fig. 6 in Etzerodt et al, 2020). Last but not least, since CSF1 is a critical survivor factor for the TRMs, targeted delivery of CSF1-antagonists can also be explored.…”

“…It is in this backdrop that Etzerodt et al (2020) demonstrate here in a murine model of metastatic ovarian cancer (ID8) that there are four prominent groups of CD11b + , CD64 + , F4/80 + , CD169 hi , Lyve + macrophages in omentum, designated P1-P4, characterized by their expression level of CD163 and Tim4, i.e., CD163 + Tim4 + (P1), CD163 + Tim4 − (P2), CD163 − Tim4 − (P3), and CD163 − Tim4 + (P4). Using genetic fate-mapping and shielded chimera experiments, the researchers show that CD163 + Tim4 + omental resident macrophages are derived from embryonic progenitors and maintained in the omentum independently of bone marrow-derived monocytes, whereas the other three populations are most likely bone marrow derived and replenished from circulating monocytes.…”

“…Ascites-associated OCCs occur as single cells or multicellular spheroids and are likely to be responsible for peritoneal dissemination and to contribute to relapse of the disease (Liao et al, 2014). Further analyses by Etzerodt et al (2020) showed that the acquisition of epithelial to mesenchymal transition (EMT) and CSC characteristics by ID8 cells, and the development of invasive disease, were dependent on the presence of CD163 + Tim4 + TRMs in the omentum. Not only did the specific depletion of the TRMs in Cd163-Csf1r DTR mice decrease the formation of malignant ascites, it also reduced the frequency of CSCs among the few ascitic tumor cells that did accumulate.…”

“…It is somewhat perplexing that ID8 tumor progression had a severe effect on the number of the tumor-promoting TRMs in omentum ( Fig. 5 A in Etzerodt et al, 2020). This was unexpected, since Zhu et al (2017) showed in a genetically engineered orthotopic pancreatic ductal carcinoma (PDAC) model that pancreas-resident macrophages that originated from embryonic development expanded through in situ proliferation and promoted tumor progression (Zhu et al, 2017).…”

“…The work by Etzerodt et al (2020) instinctively invites an immediate sequel: What is the molecular basis of the dialog between TRMs and OCCs leading to the upregulation of JAK-STAT signaling, EMT, and CSC? RNA sequencing-based clustering analysis by the investigators revealed that the CD163 + Tim4 + omentum TRMs were enriched for genes associated with positive regulation of the JAK-STAT pathway.…”