# Role of Cancer-Associated Fibroblasts in Cholangiocarcinoma

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $621,461

## Abstract

Intrahepatic cholangiocarcinoma (ICC) is an aggressive liver tumor with limited therapeutic options and 5-­year 
survival rates of less than 10%. ICC is characterized by its highly desmoplastic nature, with abundance of cancer-­
associated  fibroblasts  (CAF)  and  extracellular  matrix  (ECM).  The  role  of  CAF  and  ECM  in  ICC  remain 
controversial due to the paucity of functional in vivo studies. While the majority of ICC in vitro studies support a 
cancer-­promoting role of CAF, recent studies in endogenously arising pancreatic cancer, a highly desmoplastic 
tumor with many similarities to ICC, have shown that CAF restrain cancer growth. Here, we seek to answer the 
question  whether  CAF  promote  or  restrain  ICC,  using  a  number  of  novel  and  cell-­specific  tools  to  manipulate 
CAF and tumor cells and their crosstalk in endogenously arising ICC in vivo. We hypothesize that CAF and ECM 
provide a niche that promotes ICC growth and survival, and that detailed characterization of ICC-­CAF crosstalk 
will  identify  novel  therapeutic  targets  within  the  tumor  microenvironment.  In  Aim  1,  we  will  determine  the  role 
CAF using novel tools to determine how genetic CAF inhibition or early and late CAF ablation affect ICC growth, 
proliferative and anti-­apoptotic signaling pathways, and mouse survival. In Aim 2, we will investigate pathways 
that  mediate  the  recruitment,  proliferation  and  activation  of  CAF  in  ICC  focusing  on  the  hypothesis  that  tumor 
cells hijack normal fibrogenic mechanism in the liver via tumor-­derived TGFb and PDGF isoforms and TGFb-­
activating integrins, resulting in accumulation and activation of CAF. In addition to detailed mechanistic studies 
in knockout mice and in vitro co-­cultures, we will determine whether pharmacologic inhibition of CAF activation 
by FDA-­approved drug Nintedanib or integrin-­blocking antibodies inhibit ICC growth and prolong mouse survival. 
In Aim 3, we will determine pathways through which CAF modulate ICC growth, focusing on the hypothesis that
CAF-derived ECM activates tumor-promoting signals in the tumor cell compartment. To test this hypothesis, we
will investigate ICC development in mice with CAF-specific knockout of Col1a1, or tumor-selective knockout of
collagen-sensing receptor discoidin domain receptor 1 (DDR1). In addition, we will determine whether ECM-
mediated stiffness and subsequent activation of mechanosensitive signaling in tumor cells promote ICC
development. We will measure tumor stiffness, activation of mechanosensitive signaling pathways and DDR1
expression in human CCA samples and correlate these to clinical outcomes. The role of stiffness and DDR1 in
ICC growth and CAF-ICC crosstalk will be investigated in more detail in vitro through modulation of stiffness and
by co-culturing CAF and ICC cells that lack Col1a1 or DDR1, respectively. In summary, the proposed studies 
will employ novel tools to answer a long-­standing question ...

## Key facts

- **NIH application ID:** 9929562
- **Project number:** 5R01CA228483-03
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Xin Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $621,461
- **Award type:** 5
- **Project period:** 2018-06-19 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9929562

## Citation

> US National Institutes of Health, RePORTER application 9929562, Role of Cancer-Associated Fibroblasts in Cholangiocarcinoma (5R01CA228483-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9929562. Licensed CC0.

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