Tumors can force nearby cells to support cancer growth by releasing lactate into their local environment, according to researchers at Weill Cornell Medicine. The findings pave the way for future drug therapies that thwart the defense mechanism to help cancer patients.
In the study, published May 10 in Cell Reports, the researchers determined how tumors, as they develop, recruit nearby cells called fibroblasts to act as their enablers. Fibroblasts are part of the ‘stroma’ or connective tissue of organs, and they usually have important repair and maintenance functions. But cancer-associated fibroblasts (CAFs) are gaining properties that allow them to help tumors in ways that make tumors more malignant and harder to kill.
The researchers also discovered that widely used cancer drugs called PARP-1 inhibitors mimic one of the key steps in CAF recruitment, and thus may often impair its efficacy by converting local fibroblasts to this cancer-enabling mode.
Future therapies that prevent the state of fibroblasts associated with cancer may be useful on their own or as a way to improve the efficacy of PARP-1 inhibitors.”
Dr. Maria Diaz Mico, study co-lead author, Professor of Pathology Oncology Homer T. Hearst III and a member of the Sandra and Edward Mayer Cancer Center at Weill Cornell Medicine
Dr. Diaz Miko collaborated on the study with the lab of senior co-author Dr. George Muscat, who is also the Homer T. Hirst III Professor of Pathology Oncology and a member of the Mayer Cancer Center at Weill Cornell Medicine. Co-authors are Dr. Joan Linares, Instructor of Pathology and Laboratory Medicine, and Dr. Tania Syed Diaz, Postdoctoral Associate in Pathology and Laboratory Medicine.
Scientists have known for decades that the development of tumors often modifies their local environments in ways that promote their survival and growth. Cancer-associated fibroblasts are a central component of the tumor microenvironment in prostate, lung, colon, and many other cancers. Therefore targeting these cells is seen as a promising complementary approach to standard cancer therapy – and it can work very broadly against cancers of different cellular and genetic origins.
“Cancer-associated fibroblasts support tumor growth by providing essential tumor growth factors and metabolites, by fending off anti-tumor immune cells, and in many other ways,” said Dr. Muscat. “The result is a more malignant tumor that is resistant to treatment.”
The Moscat and Diaz-Meco labs discovered several years ago that a protein called p62, which is produced in fibroblasts, usually suppresses CAF, although many tumors find a way to restore this state by decreasing p62 fibroblast production. In the new study, they show that tumors achieve this by secreting high levels of an organic compound called lactate, also known as lactic acid.
Lactate is a natural by-product of certain energy-producing processes in cells – processes that are often overactive in tumors. In experiments with prostate cancer cells, researchers detailed the molecular cascade of events by which tumor-secreted lactate disrupts normal fibroblast metabolism, leading to decreased p62 gene activity and activation of a tumor-enabled CAF state.
The discovery is significant in itself because it demonstrates a major cancer-promoting pathway, which could in principle be targeted with future drugs as a stand-alone or add-on therapeutic strategy.
But there was a second surprising discovery. The major step leading from tumor lactate secretion to p62 inhibition of fibroblasts has been shown to be inhibition of a DNA repair enzyme called PARP1. A class of cancer drugs called PARP1 inhibitors have a similar effect — suggesting that these drugs may work in part against themselves by creating a more favorable microenvironment for tumors.
Researchers in cancer cells and mouse models confirmed that the PARP1 inhibitor olaparib reduces p62 in fibroblasts, driving them into a CAF state, making tumors more resistant to the effect of the main cancer-killing drug.
Thus, the researchers emphasized that future therapies that reprogram CAF cells to a non-cancerous state or inhibit their growth may significantly enhance the anti-tumor efficacy of PARP1 inhibitors.
“We are now studying several potential treatments to block CAF in our labs,” said Dr. Muscat.
Linaris, J.F., et al. (2022) activates the lactate-NAD+ axis in cancer-associated fibroblasts by downregulating p62. Cell reports. doi.org/10.1016/j.celrep.2022.110792.