Targeting an autocrine IL-6–SPINK1 signaling axis to suppress metastatic spread in ovarian clear cell carcinoma

Abstract

A major clinical challenge of ovarian cancer is the development of malignant ascites accompanied by widespread peritoneal metastasis. In ovarian clear cell carcinoma (OCCC), a challenging subtype of ovarian cancer, this problem is compounded by near-universal primary chemoresistance; patients with advanced stage OCCC thus lack effective therapies and face extremely poor survival rates. Here we show that tumor cell expressed serine protease inhibitor Kazal type 1 (SPINK1) is a key driver of OCCC progression and metastasis. Using cell culture models of human OCCC, we find that shRNA silencing of SPINK1 sensitizes tumor cells to anoikis and inhibits proliferation. Knockdown of SPINK1 in OCCC cells also profoundly suppresses peritoneal metastasis in mouse implantation models of human OCCC. We next identify a novel autocrine signaling axis in OCCC cells whereby tumor cell-produced interleukin-6 (IL-6) regulates SPINK1 expression to stimulate a common protumorigenic gene expression pattern leading to anoikis resistance and proliferation of OCCC cells. We further demonstrate that this signaling pathway can be successfully interrupted with the IL-6Rα inhibitor tocilizumab, sensitizing cells to anoikis in vitro and reducing metastasis in vivo . These results suggest that clinical trials of IL-6 pathway inhibitors in OCCC may be warranted, and that SPINK1 might offer a candidate predictive biomarker in this population.

High SPINK4 Expression Predicts Poor Outcomes among Rectal Cancer Patients Receiving CCRT

“…SPINK1 is expressed largely in the pancreas, gastrointestinal tract, and urinary system and has been suggested to promote pancreatic cancer [ 15 ], colorectal cancer [ 16 ], and prostate cancer [ 17 ] progression. Moreover, SPINK1 is involved in tumor metastasis, acts as a prognostic biomarker for lung cancer [ 18 ], and acts as a predictive biomarker for ovarian cancer [ 19 ]. Additionally, SPINK1 is reported to repress granzyme A- and serine protease-induced cell apoptosis and confer resistance to chemotherapy [ 20 , 21 ].…”

The Role of the IL-6 Cytokine Family in Epithelial–Mesenchymal Plasticity in Cancer Progression

“…Resistance to anoikis has been linked to EMP, stemness and metastasis [ 1 ]. IL-6 has been shown to confer anoikis resistance in melanoma, ovarian, pancreatic and cervical cancer cells [ 139 , 140 , 141 , 142 ].…”

SPINKs in Tumors: Potential Therapeutic Targets

“…The expression of the SPINK1 gene depends on the existence of two regulatory regions, including the IL-6 response element and AP-I binding site (36,37). IL-6 produced in ovarian clear cell carcinoma (OCCC) cells stimulates the common tumorigenic gene expression pattern by regulating the expression of SPINK1 to promote tumor peritoneal metastasis, anoikis resistance and proliferation (38). IL-6 activates SPINK1 by activating the typical STAT3 pathway.…”