Cancer-induced immune responses affect tumor progression and therapeutic response. In multiple murine models and clinical datasets, we identified large variations of neutrophils and macrophages, which define “immune subtypes” of triple negative breast cancer (TNBC) including neutrophil-enriched (NES) and macrophage-enriched subtypes (MES). Different tumor-intrinsic pathways and mutual regulation between macrophages/monocytes and neutrophils contribute to the development of dichotomous myeloid compartment. MES contains predominantly macrophages that are CCR2-dependent and exhibit variable responses to immune checkpoint blockade (ICB). NES exhibits systemic and local accumulation of immunosuppressive neutrophils (or granulocytic myeloid-derived suppressor cells (gMDSCs), is resistant to ICB, and contains a minority of macrophages that appear to be unaffected by CCR2 knockout. A MES-to-NES conversion mediated acquired ICB resistance of initially sensitive MES models. Our results demonstrate diverse myeloid cell frequencies, functionality, and potential roles in immunotherapies, and highlight the need to better understand the inter-patient heterogeneity of the myeloid compartment.
Metastasis is the most devastating stage of cancer progression and causes the majority of cancer-related deaths. Clinical observations suggest that most cancers metastasize to specific organs, a process known as ''organotropism.'' Elucidating the underlying mechanisms may help identify targets and treatment strategies to benefit patients. This review summarizes recent findings on tumor-intrinsic properties and their interaction with unique features of host organs, which together determine organ-specific metastatic behaviors. Emerging insights related to the roles of metabolic changes, the immune landscapes of target organs, and variation in epithelial-mesenchymal transitions open avenues for future studies of metastasis organotropism.
Mechanisms Underlying Organ-Tropism of Metastasis Classic ''Seed and Soil'' MechanismsStephen Paget stipulated that both cancer cell-intrinsic properties (''seed'') and the congenial ME (''soil'') are essential for metastasis formation (Paget, 1889). Research in the past few decades has greatly enhanced our understanding of the molecular and cellular nature of both ''seed'' and ''soil''. In this section, we will review some mechanisms of organ-specific metastasis focusing on the organ-specific ME.
Bone TropismCancers disseminate to bone with different frequencies (Table 1). Breast and prostate cancers are the principal cancers that metastasize to bone (Budczies et al., 2015; DiSibio and French, 2008). Bone and bone marrow comprise unique cell types including osteoblasts, osteocytes, and osteoclasts. Osteoclasts
SUMMARY
The fate of disseminated tumor cells is largely determined by
microenvironment (ME) niche. The osteogenic niche promotes cancer cell
proliferation and bone metastasis progression. We investigated the underlying
mechanisms using pre-clinical models and analyses of clinical data. We
discovered that the osteogenic niche serves as a calcium (Ca) reservoir for
cancer cells through gap junction (GJs). Cancer cells cannot efficiently absorb
Ca from ME, but depend on osteogenic cells to increase intracellular Ca
concentration. The Ca signaling, together with previously identified mTOR
signaling, promotes bone metastasis progression. Interestingly, effective
inhibition of these pathways can be achieved by danusertib, or combination of
everolimus and arsenic trioxide, which provide possibilities of eliminating bone
micrometastases (BMM) using clinically established drugs.
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