U01CA274295
Cooperative Agreement
Overview
Grant Description
Regulation of PDAC metabolism and immunity by collagen and its cleavage products - 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.
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.
Funding Goals
TO PROVIDE FUNDAMENTAL INFORMATION ON THE CAUSE AND NATURE OF CANCER IN PEOPLE, WITH THE EXPECTATION THAT THIS WILL RESULT IN BETTER METHODS OF PREVENTION, DETECTION AND DIAGNOSIS, AND TREATMENT OF NEOPLASTIC DISEASES. CANCER BIOLOGY RESEARCH INCLUDES THE FOLLOWING RESEARCH PROGRAMS: CANCER CELL BIOLOGY, CANCER IMMUNOLOGY, HEMATOLOGY AND ETIOLOGY, DNA AND CHROMOSOMAL ABERRATIONS, TUMOR BIOLOGY AND METASTASIS, AND STRUCTURAL BIOLOGY AND MOLECULAR APPLICATIONS.
Grant Program (CFDA)
Awarding / Funding Agency
Place of Performance
La Jolla,
California
92093
United States
Geographic Scope
Single Zip Code
Related Opportunity
Analysis Notes
Amendment Since initial award the total obligations have increased 208% from $971,140 to $2,987,434.
San Diego University Of California was awarded
Regulation of PDAC metabolism and immunity by collagen and its cleavage products
Cooperative Agreement U01CA274295
worth $2,987,434
from National Cancer Institute in September 2022 with work to be completed primarily in La Jolla California United States.
The grant
has a duration of 5 years and
was awarded through assistance program 93.396 Cancer Biology Research.
The Cooperative Agreement was awarded through grant opportunity Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional).
Status
(Ongoing)
Last Modified 6/20/25
Period of Performance
9/21/22
Start Date
8/31/27
End Date
Funding Split
$3.0M
Federal Obligation
$0.0
Non-Federal Obligation
$3.0M
Total Obligated
Activity Timeline
Subgrant Awards
Disclosed subgrants for U01CA274295
Transaction History
Modifications to U01CA274295
Additional Detail
Award ID FAIN
U01CA274295
SAI Number
U01CA274295-942181970
Award ID URI
SAI UNAVAILABLE
Awardee Classifications
Public/State Controlled Institution Of Higher Education
Awarding Office
75NC00 NIH National Cancer Institute
Funding Office
75NC00 NIH National Cancer Institute
Awardee UEI
UYTTZT6G9DT1
Awardee CAGE
50854
Performance District
CA-50
Senators
Dianne Feinstein
Alejandro Padilla
Alejandro Padilla
Budget Funding
| Federal Account | Budget Subfunction | Object Class | Total | Percentage |
|---|---|---|---|---|
| National Cancer Institute, National Institutes of Health, Health and Human Services (075-0849) | Health research and training | Grants, subsidies, and contributions (41.0) | $2,100,655 | 100% |
Modified: 6/20/25