Hsp90-stabilized MIF supports tumor progression via macrophage recruitment and angiogenesis in colorectal cancer

Abstract

Macrophage migration inhibitory factor (MIF) is an upstream regulator of innate immunity, but its expression is increased in some cancers via stabilization with HSP90-associated chaperones. Here, we show that MIF stabilization is tumor-specific in an acute colitis-associated colorectal cancer (CRC) mouse model, leading to tumor-specific functions and selective therapeutic vulnerabilities. Therefore, we demonstrate that a Mif deletion reduced CRC tumor growth. Further, we define a dual role for MIF in CRC tumor progression. Mif deletion protects mice from inflammation-associated tumor initiation, confirming the action of MIF on host inflammatory pathways; however, macrophage recruitment, neoangiogenesis, and proliferative responses are reduced in Mif-deficient tumors once the tumors are established. Thus, during neoplastic transformation, the function of MIF switches from a proinflammatory cytokine to an angiogenesis promoting factor within our experimental model. Mechanistically, Mif-containing tumor cells regulate angiogenic gene expression via a MIF/CD74/MAPK axis in vitro. Clinical correlation studies of CRC patients show the shortest overall survival for patients with high MIF levels in combination with CD74 expression. Pharmacological inhibition of HSP90 to reduce MIF levels decreased tumor growth in vivo, and selectively reduced the growth of organoids derived from murine and human tumors without affecting organoids derived from healthy epithelial cells. Therefore, novel, clinically relevant Hsp90 inhibitors provide therapeutic selectivity by interfering with tumorigenic MIF in tumor epithelial cells but not in normal cells. Furthermore, Mif-depleted colonic tumor organoids showed growth defects compared to wild-type organoids and were less susceptible toward HSP90 inhibitor treatment. Our data support that tumor-specific stabilization of MIF promotes CRC progression and allows MIF to become a potential and selective therapeutic target in CRC.

The Gain-of-Function p53 R248W Mutant Promotes Migration by STAT3 Deregulation in Human Pancreatic Cancer Cells

“…A key prerequisite for the gain-of-function (GOF) of some missense p53 mutants is protein stabilization through the Hsp90 chaperone machinery. Importantly, the clinically relevant Hsp90 inhibitors Ganetespib or Onalespib provide therapeutic selectivity toward tumor epithelial cells but not normal cells, making them attractive for anti-cancer therapies (44). Furthermore, in other cellular contexts such as lymphoma ( 23), treatment with the Hsp90 inhibitor Ganetespib downregulated mutp53 protein levels.…”

Deciphering the Intercellular Communication Between Immune Cells and Altered Vascular Smooth Muscle Cell Phenotypes in Aortic Aneurysm From Single-Cell Transcriptome Data

“…We found that MIF-(CD44-CD74) pairs mediated signaling from CD4 + T cells and CD8 + T cells to macrophage-like VSMCs. On the other hand, MIF-(CD74 + CXCR4) mediated signal transmission from contractile VSMCs, T-cell-like VSMCs, and macrophage-like VSMCs to B cells Numerous studies have shown that MIF possesses the function of recruiting and activating macrophages through combining with CD74 and CXCR2 (24)(25)(26) and promote normal cells to acquire an inflammatory phenotype by interacting with the receptor CD74 (27). MIF binds to CD74 + CXCR4, which promotes B-cell migration (28).…”

HSP90 Inhibition Synergizes with Cisplatin to Eliminate Basal-like Pancreatic Ductal Adenocarcinoma Cells

“…In tumor cells, we anticipate that, on top of interfering with the Fanconi anemia pathway, HSP90 inhibition compromises PDAC cell proliferation and survival by additional mechanisms. For instance, HSP90 inhibition negatively regulates the levels of mutant [ 40 , 41 , 42 ] p53 as well as macrophage migration inhibitory factor (MIF) [ 43 , 44 ]. Such mechanisms might further enhance the efficacy of HSP90 inhibitors, in addition to their cooperation with cisplatin.…”