Serine proteases have been implicated as key drivers and facilitators of lung cancer malignancy, and while these proteins represent straightforward targets for therapeutic inhibitors, identification of optimal points for intervention has been complicated by the complex networks in which these enzymes function. Here we implicate a signaling pathway consisting of PRSS3/mesotrypsin and kallikrein-related peptidase 5 (KLK5) in lung adenocarcinoma malignancy. We show that elevated PRSS3/mesotrypsin expression is prognostic for poor outcome for patients with lung adenocarcinoma, and that genetic or pharmacologic targeting of PRSS3/mesotrypsin reduces lung adenocarcinoma cell invasiveness and proliferation. We further show that genetic targeting of KLK5, a known target of PRSS3/mesotrypsin, phenocopies the effect of PRSS3/mesotrypsin knockdown, and also that elevated expression of KLK5 is similarly prognostic for outcome in lung adenocarcinoma. Finally, we use transcriptional profiling experiments to show that PRSS3/mesotrypsin and KLK5 control a common malignancy-promoting pathway. These experiments implicate a potential PRSS3/mesotrypsin-KLK5 signaling module in lung adenocarcinoma and reveal the potential therapeutic benefit of selectively targeting these pathways.
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.
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