ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic and therapy-resistant cancer. The role of
the desmoplastic stroma in PDAC remains elusive with studies supporting both tumor-promoting or tumor-
restricting functions. The failure of stroma targeting therapies suggests that a deeper understanding of the
complex cancer-stroma interaction is needed. Type I collagen (Col I), the major ECM protein in PDAC, can
physically restrain tumors and limit nutrient availability. Yet, PDAC cells adapt and exploit the surrounding stroma
to acquire more advanced malignant traits. Moreover, the desmoplastic collagen-rich stroma may suppress
immunosurveillance and activate tumor-promoting mechanosensitive signaling. It is likely that tumor-promoting
and tumor-suppressive effects of CAF and ECM occur in parallel and that their balance determines the net effect
on PDAC growth. We seek to better understand these opposing functions by focusing on Col I as a key mediator
of stroma-PDAC crosstalk. Clinical studies show improved progression-free survival (PFS) after resection in
patients with “inert stroma” characterized by extensive ECM deposition and low fibrolytic activity, whereas highly
fibrolytic stroma is associated with much shorter PFS times. Based on this finding we hypothesize that rather
than the sheer quantity of CAF and stroma, collagen fibrolysis and differential effects of receptors that
discriminate between intact and cleaved Col I dictate tumor growth and immunity. Our preliminary data support
this hypothesis, indicating differential regulation of cancer cell metabolism by intact and cleaved collagen through
a specific receptor, DDR1; as well as high expression of the inhibitory Col I receptor LAIR1 on immune cells and
a role for Col I in immune cell infiltration and activation in PDAC spread to the liver, the most common site of
metastasis and a suppressor of systemic anti-tumor immunity. Our long-term goal is to develop therapies that
target collagen receptors and shift the balance from immunosuppression and tumor promotion by cleaved
collagen to tumor starvation, growth inhibition and enhanced anti-tumor immunity, rather than CAF depletion or
modulation, which so far had resulted in untoward effects. Our interdisciplinary team of basic and clinical-
translational investigators will utilize clinical specimens, tumor slice cultures, single cell RNA-sequencing, spatial
transcriptomics, mouse models and PDAC-ECM co-cultures to elucidate the role of collagen receptor signaling
via two closely integrated specific aims: 1. Test the hypothesis that collagen fragments and fibers antagonistically
control PDAC metabolism through the PDAC-intrinsic collagen receptor DDR1, whose inhibition can switch off
tumor metabolism and induce cell death. 2. Test the hypothesis that stimulatory and inhibitory collagen receptors
control anti-PDAC immunity and can be combined with immune checkpoint inhibitors to increase anti-tumor
immunity. The successful completion of these research goals will provide us with novel tools for converting
stroma-mediated tumor growth and immunosuppression to growth inhibition and anti-tumor immunity.