Targeting Wnt/β-Catenin-WISP1 Signaling May Improve Glioblastoma Outcomes, Preclinical Study Suggests

A protein known as WISP1 contributes to glioblastoma progression by maintaining glioma stem cells and tumor-supportive macrophages, and blocking an associated signaling pathway helps control glioblastoma in preclinical models.

So reports a Cleveland Clinic-led group of researchers in a study published in Nature Communications (2020 Jun 15;11[1]:3015). The findings raise the prospect of a potential new approach for treating glioblastoma, the most common and lethal type of primary brain tumor.

The researchers showed that administration of carnosic acid (a naturally occurring compound found in plants) to block the Wnt/β-catenin-WISP1 signaling pathway, named for the proteins it involves, markedly reduced tumor growth and extended lifespan in a murine model of glioblastoma.

“Our study suggests that blocking this signaling cascade may help slow disease by disrupting the maintenance of both glioma stem cells and tumor-supportive macrophages, and by interrupting the pro-cancer cross-talk that happens between glioma stem cells and the tumor microenvironment,” says senior author Shideng Bao, PhD, who directs the Center for Cancer Stem Cell Research in Cleveland Clinic’s Lerner Research Institute.

Backdrop to the study

Previous research has shown that Wnt/β-catenin signaling regulates many cell processes, including the progression of several types of cancer. While it has been suggested that this pathway is activated in glioma stem cells and promotes the spread and progression of glioblastoma, how this happens has not been well understood.

“We found that glioma stem cells secrete the protein called WISP1 (Wnt-induced signaling protein 1),” says Dr. Bao. “The increased expression and secretion of WISP1 in glioma stem cells suggested that this protein might play some important roles in driving malignant growth of glioblastoma.”

Findings in brief

To test this hypothesis, the researchers disrupted WISP1 expression to observe the effects on tumor growth and progression. They found that genetically silencing WISP1 in their mouse model inhibited glioma stem cell maintenance and suppressed tumor growth — and, notably, that the number of tumor-associated macrophages was reduced.

Tumor-associated macrophages are recruited into a tumor by factors secreted by cancer cells. It has been well recognized that the majority of tumor-associated macrophages are tumor-supportive, promoting tumor growth and therapeutic resistance. In addition, most tumor-associated macrophages suppress the anti-cancer efforts of other immune cells.

While these analyses suggested that WISP1 and its related signaling pathway promote proliferation and self-renewal of glioma stem cells and survival of tumor-supportive macrophages, Dr. Bao’s team was eager to understand how pharmacologically inhibiting the pathway in a preclinical glioblastoma model would affect the course of disease development (Figure).

“We found that blocking the pathway using carnosic acid effectively inhibited tumor growth and significantly increased lifespan in our preclinical model, which we believe to be very promising,” Dr. Bao observes.

Figure. Schematic showing the autocrine and paracrine roles of the WISP1 protein in glioblastoma. Targeting Wnt/β-catenin-WISP1 signaling with carnosic acid potently inhibits tumor growth and holds therapeutic potential. GSC = glioma stem cell; M2 TAM = tumor-supportive macrophage; M1 TAM = tumor-suppressive macrophage; NSTC = non-stem tumor cell. Reprinted from Nature Communications (2020 Jun 15;11[1]:3015). © Cleveland Clinic Foundation.

Other drug candidates to target the signaling pathway?

While this study made use of carnosic acid, which penetrates the blood-brain barrier, there are likely other small molecules that can target Wnt/β-catenin-WISP1 signaling, Dr. Bao notes. Further preclinical and clinical investigations will be important for identifying useful drug candidates that may be more effective in slowing or eliminating glioblastoma in patients.

The study was supported in part by the National Institute of Neurological Disorders and Stroke.