Toppling the Genetic Dominoes in Bone Metastasis

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Approximately 80 percent of prostate cancer patients develop bone metastasis.It’s a grim consequence that is incurable in advanced cases and leads to significant disease morbidity and mortality. For years, this intractable problem has plagued researchers. It became the impetus for Paul Fisher, a molecular geneticist from Virginia Commonwealth University, to identify the major genetic contributors to bone metastasis in prostate cancer. 

Paul Fisher and Swadesh Das siting side by side in the laboratory.

Paul Fisher and Swadesh Das, a coauthor of the study, work together at Virginia Commonwealth University to explore tumor-bone cell cross talk.

Daniel Sang Min, Medical College of Virginia Foundation

He and his collaborators previously identified a gene called melanoma differentiation associated gene-9 (mda-9).2 In a recent study, Fisher and his team demonstrated that MDA-9 initiated a cellular chain reaction that causes tumor growth and promotes bone metastasis.3 Based on these findings, published in the Proceedings of the National Academy of Sciences, MDA-9 could serve as a potential target when developing therapies against prostate cancer and other solid tumors.

mda-9 is a prometastatic gene found in both tumor cells and normal healthy cells. It is expressed in multiple tissues, including bone marrow derived mesenchymal stromal cells (BM-MSC). “Based on genomic literature, mda-9 was a viable target for trying to understand its role in the metastatic process,” said Fisher. MDA-9 protein expression positively correlates with cancer progression and associates with angiogenesis, invasion, and metastasis in various cancer types, including prostate cancer.4

His work and others’ illuminate very interesting therapeutic points of attack, which affect multiple cancer hallmarks.
– Ronald DePinho, MD Anderson Cancer Center

Fisher and his group previously developed mda-9 knockout models to study melanoma and lung metastasis but did not yet study its influence on prostate bone metastasis. “We had a lot of hurdles to overcome because there are not many metastatic prostate cancer transgenic models,” explained Fisher. Since MDA-9 is widely expressed in all tissues and organs, the researchers worried that a global knockout mouse model would not be viable. To Fisher’s surprise, the knocking out of mda-9 was not lethal for the mice.

With this mda-9 mice model, Fisher and his team observed how MDA-9 affected the surrounding tumor microenvironment. The team developed a cell line with a propensity to form bone metastases. The researchers injected these cells into wild type mice and mice that lacked  mda-9. The results differed significantly. 

Tumor cells injected into mice with mda-9 led to bone metastasis, while those injected into mice without mda-9 did not. They found that mda-9 expression regulated bone metastasis progression, altering the differentiation state of bone cells that either deteriorated or reshaped bone. Intrigued by this observation, Fisher decided to identify the downstream signaling molecules linked to disease progression.

When Fisher assessed the serum from these animals, a chemokine, CXCL5, caught his attention. The expression of MDA-9 in mice greatly upregulated CXCL5 levels, positively correlating with tumor and bone metastasis progression. In the absence of CXCL5, tumor growth stopped in its tracks. Then researchers looked into the downstream molecular domino effects initiated by MDA-9, which stimulated a favorable tumor microenvironment between tumor cells and BM-MSC. 

The researchers used human BM-MSC to analyze the signaling pathways and the secreted proteins that upregulate tumor progression. The first pathway that MDA-9 activated was nuclear factor kappa B (NF-κB), an important regulator in cancer cell survival and proliferation. The NF-κB dependent pathway appeared to stimulate the secretion of tumor cell-derived platelet-derived growth factor-AA (PDGF-AA), a main component of this domino effect, into the bone environment. Fisher and his team tested other growth factors, but PDGF-AA was the only one that significantly stimulated CXCL5 production. 

PDGF-AA acted as agents of chaos, binding directly to PDGF receptors on the surface of BM-MSC. This subsequently activated the Hippo signaling pathway, which is responsible for cell regeneration, to promote CXCL5 production. 

The final domino in this chain was the release of CXCL5, which attracted cancer cells into the bone tissue and spurred the tumor cells to subsequently produce more CXCL5 in a vicious cycle, leading to tumor growth, bone fractures, and cell migration. The researchers noted that blunted mda-9 expression decreased the expression of these pathway proteins. The findings strongly suggest that MDA-9/CXCL5 signaling through PDGF-AA facilitates metastasis progression.

“His work and others’ illuminate very interesting therapeutic points of attack, which affect multiple cancer hallmarks,” remarked Ronald DePinho, a cancer geneticist and biologist from MD Anderson Cancer Center who was not involved in the study. “Either monotherapy of any of those agents or combinations of those agents could lead to more durable responses in prostate cancer.”

These findings underscored the importance of ubiquitously expressed MDA-9 and the corresponding molecular dominoes within the tumor-bone cell crosstalk. In future studies, Fisher is optimistic about his plans to investigate the use of an MDA-9 inhibitor. “Because this gene is involved in all the different steps [of metastasis], theoretically, an inhibitor wouldn’t just block a cell that’s invading. It would block a cell that has to attach. It would block angiogenesis and work in tandem with the standard of care,” he said.

References

  1. Rigaud J, et al. Prognostic value of bone scan in patients with metastatic prostate cancer treated initially with androgen deprivation therapy. J Urol. 2002;168(4 Pt 1):1423-1426.
  2. Boukerche H, et al. mda-9/Syntenin: a positive regulator of melanoma metastasis. Cancer Res. 2005;65(23):10901-10911.
  3. Das SK, et al. The MDA-9/Syntenin/IGF1R/STAT3 Axis Directs Prostate Cancer Invasion. Cancer Res. 2018;78(11):2852-2863.
  4. Maji S, et al. MDA-9/Syntenin in the tumor and microenvironment defines prostate cancer bone metastasis. Proc Natl Acad Sci. 2023;120(45):e2307094120.
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