Distinct classes of fibroblasts in tumors play opposing roles, promoting
or restraining pancreatic cancer growth
Study provides new understanding of tumor microenvironment, identifies possible therapeutic strategies
Date:
March 29, 2022
Source:
University of Texas M. D. Anderson Cancer Center
Summary:
Researchers discovered that two distinct classes of fibroblast cells
accumulate in pancreatic tumors and play opposing roles to promote
and restrain pancreatic cancer growth. Appropriately targeting
these cells may offer options to improve treatment outcomes.
FULL STORY ========================================================================== Researchers at The University of Texas MD Anderson Cancer Center have discovered that two distinct classes of cancer-associated fibroblasts
(CAFs) accumulate in the pancreatic tumor microenvironment and play
opposing roles to promote and restrain pancreatic cancer development.
==========================================================================
The preclinical findings suggest that appropriately targeting these
unique CAF populations may offer strategies to improve the use of other treatments, such as chemotherapy and immunotherapy. The results were
published today in Cancer Discovery, a journal of the American Association
for Cancer Research.
"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," said
lead author Kathleen McAndrews, Ph.D., postdoctoral fellow in Cancer
Biology. "Our findings provide the first evidence of the functional heterogeneity of CAFs in pancreatic cancer that may explain the variations
in patient outcomes." Fibroblasts, a type of cell found in connective
tissue, are involved in important biological processes, such as wound
repair. Cancer-associated fibroblasts are those that accumulate in
tumors. These cells can be found in large numbers in pancreatic cancers,
but their precise role in cancer development had remained unclear.
The researchers performed single-cell RNA sequencing to analyze
gene expression and clarify the types of CAFs present in pancreatic
tumors. They identified two distinct subsets of CAFs marked by expression
of fibroblast activation protein (FAP) and alpha-smooth muscle actin
(aSMA).
Interestingly, the researchers found that expression of these proteins
in treatment-nai"ve human tumor samples correlated with eventual outcomes.
Increased expression of aSMA was associated with significantly improved
overall survival (OS), whereas elevated FAP levels were associated with significantly decreased OS.
========================================================================== Using novel mouse models, the researchers demonstrated that FAP+ and aSMA+
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 aSMA+ fibroblasts resulted in more aggressive tumors
and shorter OS, indicating that these cells work to block pancreatic
cancer progression.
Loss of FAP+ vs. aSMA+ cells resulted in distinct gene expression
changes in the tumor, resulting in altered regulation of various cancer-associated pathways and different accumulation of immune cells
in the tumor microenvironment.
To clarify the distinct roles of FAP+ and aSMA+ cells, the research team
also analyzed secreted proteins that may affect the tumor and surrounding cells. The immune signaling protein interleukin 6 (IL-6) is produced by
both classes of CAFs. Loss of IL-6 in aSMA+ cells, but not FAP+ cells,
improved responses to chemotherapy and immunotherapy with significantly improved OS.
These results are indicative of the complex and heterogeneous roles of
these different classes of CAFs, explained senior author Raghu Kalluri,
M.D., Ph.D., professor and chair of Cancer Biology.
"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," Kalluri said. "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." This research was supported primarily by the Cancer Prevention and Research Institute of Texas (CPRIT) (RP150231) with
additional funding from the National Institutes of Health/National Cancer Institute (UL1TR000371, P01CA117969, P30CA016672), the Sid W. Richardson Foundation, the American Legion Auxiliary Fellowship and Ergon Foundation Postdoctoral Fellowships.
========================================================================== Story Source: Materials provided by University_of_Texas_M._D._Anderson_Cancer_Center. Note: Content may be
edited for style and length.
========================================================================== Journal Reference:
1. Kathleen M. McAndrews et al. Identification of Functional
Heterogeneity
of Carcinoma-Associated Fibroblasts with Distinct IL-6 Mediated
Therapy Resistance in Pancreatic Cancer. Cancer Discovery, 2022 DOI:
10.1158/ 2159-8290.CD-20-1484 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/03/220329114707.htm
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