Fibroblasts Can Promote or Prevent Pancreatic Cancer Cell Growth

Researchers in Texas have identified distinct classes of fibroblasts that either promote or restrain pancreatic cancer growth, potentially explaining why clinical interventions targeting such cells have had inconsistent results. The findings also shed new light on the tumor microenvironment and could lead to new therapeutic strategies for the particularly deadly cancer.

Fibroblasts are found in connective tissue and are involved in biological processes such as wound repair. Cancer-associated fibroblasts (CAFs) accumulate in tumors, and can be found in large numbers in pancreatic cancers.

The precise role of CAFs in cancer development has, however, remained unclear. “Cancer-associated fibroblasts are known to regulate cancer progression, but targeting these cells in pancreatic cancer has largely failed to improve patient outcomes and has, in some cases, worsened response,” says lead author Kathleen McAndrews, Ph.D., postdoctoral fellow in Cancer Biology at University of Texas (UT) MD Anderson Cancer Center. “Our findings provide the first evidence of the functional heterogeneity of CAFs in pancreatic cancer that may explain the variations in patient outcomes.”

Using single-cell RNA sequencing to analyze CAF gene expression,  the team found two distinct versions in the pancreatic tumor microenvironment marked by either expression of fibroblast activation protein (FAP) or alpha-smooth muscle actin (αSMA).

Increased expression of αSMA in treatment-naïve human tumor samples was associated with significantly improved overall survival (OS), whereas elevated FAP levels were associated with significantly decreased OS. These findings suggest that appropriately targeting these unique CAF populations may offer strategies to improve the use of other treatments, such as chemotherapy and immunotherapy.

Using novel mouse models, the researchers also demonstrated that FAP+ and αSMA+ CAFs play distinct and opposing roles in the tumor microenvironment. Loss of FAP+ cells suppressed tumor progression and improved OS, suggesting these cells act to promote tumor development. Conversely, loss of αSMA+ fibroblasts resulted in more aggressive tumors and shorter OS, indicating that these cells work to block pancreatic cancer progression.

“This is a new discovery that helps move the field forward, with a new appreciation of the biology of pancreatic cancer and possible strategies for therapeutic interventions,” says senior author Raghu Kalluri, M.D., Ph.D., professor and chair of Cancer Biology. “Our next steps are to identify therapies that can target the tumor promoting fibroblasts while sparing the sum beneficial responses of our body in its effort to fight cancer.”

The results were published in Cancer Discovery.