Researchers at Weill Cornell Medicine have discovered that tumors can enlist the support of nearby cells by releasing lactate into their local environment. The new findings may lead to future therapies that dismantle the defense mechanism of lactate.
Their findings are published in the journal Cell Reports in a paper titled, “The lactate-NAD+ axis activates cancer-associated fibroblasts by downregulating p62.”
“Reduced p62 levels are associated with the induction of the cancer-associated fibroblast (CAF) phenotype, which promotes tumorigenesis in vitro and in vivo through inflammation and metabolic reprogramming,” wrote the researchers. “However, how p62 is downregulated in the stroma fibroblasts by tumor cells to drive CAF activation is an unresolved central issue in the field. Here we show that tumor-secreted lactate downregulates p62 transcriptionally through a mechanism involving reduction of the NAD+/NADH ratio, which impairs poly(ADP-ribose)-polymerase 1 (PARP-1) activity.”
The researchers determined that when tumors develop, they recruit fibroblasts to work as their enablers. Fibroblasts are part of the “stroma,” or connective tissue of organs, and normally have important repair and maintenance functions. However, cancer-associated fibroblasts (CAFs) acquire properties that allow them to assist tumors in ways that make the tumors more malignant and resistant.
The researchers also observed that PARP-1 inhibitors mimic one of the key steps in CAF recruitment, and may hinder their own effectiveness by switching the role of local fibroblasts to CAFs.
“Future therapeutics that block this cancer-associated state of fibroblasts might be useful on their own or as a way to improve the effectiveness of PARP-1 inhibitors,” said study co-senior author Maria Diaz-Meco, PhD, a Homer T. Hirst III professor of oncology in pathology and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.
Diaz-Meco collaborated in the study with the laboratory of co-senior author Jorge Moscat, PhD, a Homer T. Hirst III professor of oncology in pathology and a member Meyer Cancer Center at Weill Cornell Medicine.
Scientists have known that developing tumors often modify their local environments in ways that promote their survival.
“Cancer-associated fibroblasts support tumor growth by providing growth factors and essential metabolites to the tumor, by fending-off anti-tumor immune cells, and in many other ways,” Moscat added. “The result is a tumor that is more malignant and treatment-resistant.”
Several years ago, the Moscat and Diaz-Meco laboratories discovered that a protein called p62, produced in fibroblasts, normally suppresses the CAF state.
In the current study, the researchers demonstrated that tumors achieve this by secreting high levels of the organic compound called lactate.
In experiments with prostate cancer cells, the researchers detailed the molecular chain of events by which tumor-secreted lactate disrupts the normal metabolism of fibroblasts, leading to a downshifting of p62 gene activity and the activation of the tumor-enabling CAF state.
The researchers also observed that a key step leading from tumor lactate secretion to fibroblast p62 suppression turned out to be the inhibition of a DNA-repair enzyme called PARP1.
The researchers confirmed in cancer cells and mouse models that the PARP1 inhibitor olaparib does reduce p62 in fibroblasts, and pushes them into the CAF state, which in turn makes tumors more resistant to the drug’s primary cancer-killing effect.
The researchers are now studying several potential CAF-blocking therapeutics in their labs.
“This is a critical finding because CAF activation in the TME by PARP inhibitors might limit or even blunt their therapeutic efficacy,” noted the researchers. “Therefore, a better understanding of the fundamental mechanisms controlling the activation of the stroma has the potential to identify vulnerabilities that can improve cancer therapies.”