October 26, 2021

Development of an arteriolar niche and self-renewal of breast cancer stem cells by lysophosphatidic acid/protein kinase D signaling

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featured discovery

Ren photo instagram facebookBin Ren, M.D., Ph.D., FAHA, William D. Jordan, Jr. M.D., Endowed Professor in the Department of Surgery, is the latest winner of the Heersink School of Medicine’s Featured Discovery.

This initiative celebrates important research from Heersink faculty members.

Ren and his team’s study, “Development of an arteriolar niche and self-renewal of breast cancer stem cells by lysophosphatidic acid/protein kinase D signaling,” was recently published in Communications Biology (Nature).

Ren explains that breast cancer stem cells are a sub-population of breast cancer cells, and they contribute to tumor initiation, metastasis, and drug resistance. “The Ren Laboratory of Molecular and Vascular Pathobiology has recently shown that a subset of cancer stem cells appears to accumulate near small arterioles within the breast cancer microenvironment,” said Ren. “Furthermore, lysophosphatidic acid (a lipid signaling mediator) and protein kinase D signaling appear to regulate the development of the tumor arterioles and the stemness features of the breast cancer stem cells.”

First co-authors from the Ren Lab in the Department of Surgery include Yinan Jiang, M.D., Ph.D., a research scholar; Yichen (Hailey) Guo, a Ph.D. student; and Jinjin Hao, M.D., Ph.D., a research scholar.

This study has laid a foundation for biomedical researchers to better understand the role and mechanisms of tumor microenvironment, particularly a unique vascular niche (microenvironment) in the expansion of breast cancer stem cells and the progression of cancers with robust growth of new blood vessels within the tumor microenvironment. Their work provides new and significant insights into testing innovative and effective therapeutic strategies against aggressive breast cancers.

Read more about the study in an article by UAB News.

The School of Medicine communications staff sat down with Dr. Ren to gain insights about the research of this study, UAB, and the science community.

Q: What compelled you to pursue this research?

I studied tumor angiogenesis at Harvard Medical School as a postdoctoral fellow immediately after my Ph.D. degree, working on a National Cancer Institute-sponsored programmed project group titled, “Temporal and Spatial Regulation of Angiogenesis.” The group was led by Dr. Harold F. Dvorak, whose lab discovered vascular endothelial growth factor, or VEGF, which is known as vascular permeability factor, or VPF (Senger et al., Science 1983). During my training in Boston, I was lucky to have a lunch with Dr. Judah Folkman, a surgeon and pioneer in the field of tumor angiogenesis, which is the growth of new blood vessels in tumors. He talked about his exciting studies in tumor angiogenesis and the future of this field. He told me that he usually started his day around 3:00 or 4:00 in the morning. He said his lab was also studying thrombospondin 1, the molecule I was then working on. I was deeply impressed by his passion for scientific research and his work ethic. At that moment, I made up my mind to dedicate myself to the field of angiogenesis. As a trainee, and later with my own lab, I have pursued angiogenesis research, in the context of cancers and ischemic cardiovascular diseases. All my research experiences and related discoveries at different institutions have led to my current studies on the arteriolar niche (microenvironment) in the development of cancer stem-like cells.

Q: What was your most unexpected finding?

I had been intrigued by the role and mechanisms of newly formed blood vessels during adulthood in ischemic cardiovascular diseases and cancers. In the field of tumor angiogenesis, current antiangiogenic treatments that mostly target the VEGF pathway, but failed to significantly inhibit tumor progression and metastasis. I believe this may result from limited targeting at newly formed capillaries within the tumor microenvironment. I wondered how different types of blood vessels contribute to disease progression, and we observed the existence of small arteries, in addition to capillaries, in clinical samples from human patients with estrogen-positive breast cancer. Unexpectedly, we found that cancer stem cells tended to accumulate near those arteriolar blood vessels. In addition, LPA/PKD-1 signaling appeared to regulate not only the stemness features of the breast cancer cells but also arteriolar development within the breast cancer microenvironment.

Q: How do you feel your research will impact the science community?

I think that PKD-1/Notch1 signaling-induced formation of the arteriolar niche (microenvironment) for cancer stem-like cell self-renewal or expansion— via the provision of a high level of perfusion of oxygen and nutrients — represents a significant paradigm shift in tumor angiogenesis studies. Pursuing this innovative study can provide basic and clinical evidence that challenges and/or complements the current mainstream concepts of hypoxia and tumor progression in many types of highly angiogenic cancers, including breast cancer, glioblastoma, lung cancer, malignant melanoma and pancreatic neuroendocrine tumors, to name a few.

Q: How do you feel your research will impact the science community?

Conventional drugs designed to target tumor angiogenesis have shown disappointing results in aggressive and metastatic breast cancers. Tumor arterioles and cancer stem-like cells may be essential contributors to this problem. Our preliminary finding that the arteriolar microenvironment may enhance the self-renewal capacity of breast cancer stem cells via activation of the LPA/PKD-1 signaling pathway may provide a new angle to further understand how different types of newly formed blood vessels within the tumor microenvironment promote tumor progression and metastasis. This finding may attract the interest of biomedical scientists in the field of cancer research to study the role and mechanisms of heterogeneity of tumor-associated endothelial cells and newly formed heterogeneous tumor vessels in the progression of a variety of highly angiogenic cancers, as well as to discover innovative and effective anti-angiogenic strategies against these cancers.

Q: What made you come to UAB?

I had known that UAB is a top-notch research institution from my mentor Dr. Roy Silverstein at Medical College of Wisconsin, colleagues, and some UAB graduates before I joined the Heersink School of Medicine. I was lucky that Dr. Herbert Chen and Dr. Adam Beck, as well as the leadership, appreciate my scientific passion and value. I like the inclusive culture and collaborative scientific environment at UAB.