# Project 3-Cancer cell interaction with oncogenic type 1 collagen in PDAC

> **NIH NIH P01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2021 · $546,750

## Abstract

Project 3 -­ Abstract/Summary 
The desmoplastic  stroma,  consisting of fibroblasts,  extracellular  matrix  (ECM)  and  immune  cells,  is  a defining 
feature  of  human  pancreatic  ductal  adenocarcinoma  (PDAC),  however  its  precise  contribution  to  cancer 
progression is still evolving. Type I collagen (Col1), a dominant component of PDAC desmoplasia, is uniquely 
regulated in PDAC. Our preliminary studies uncovered that cancer cells produce a novel Col1 variant consisting 
of alpha 1 chain (Col1a1) homotrimers. Genetic deletion of the oncogenic Col1 in cancer cells extends the overall 
lifespan of PDAC genetically engineered mice (GEMs). Oncogenic Kras (Kras*), a central driver for PDAC, plays 
a key role in determining the host response, including tumor immunity and metabolic adaptation. We discovered 
that Kras* drives cancer cells’ production of oncogenic Col1 via epigenetic silencing of Col1a2.  In contrast with 
the classical Col1 heterotrimer produced by fibroblasts, oncogenic Col1 uniquely promotes PDAC initiation and 
progression by influencing tumor metabolism and immunity. Col1 homotrimers bind to a3b1 integrin on PDAC 
cancer cells, a collagen receptor distinctly upregulated in mouse and human PDAC.  This induces a sustained 
activation of FAK, Akt and Erk1/2 when compared with Col1 heterotrimers, promoting cancer cells growth and 
survival. Oncogenic Col1 also suppresses intratumoral T cells, and oncogenic Col1 deletion synergizes with anti-­
PD-­1  immune  checkpoint  blockade  to  suppress  tumor  growth  and  increase  overall  survival  of  PDAC  GEMs. 
Cancer  cell-­directed  oncogenic  Col1  homotrimer  signaling  also  enhances  glycolysis  and  mTOR  signaling, 
supporting the metabolic reprogramming driven by Kras*.  In Project 3, in close collaboration with Projects 1 and 
2, we will define the role and regulation of Kras*-­induced oncogenic Col1 signaling in impacting tumor immunity 
and metabolism. The proposed aims investigate Col1 homotrimers-­ a3b1 integrin targeting, immunotherapy, and 
anti-­metabolism  strategies,  as  an  informed  combination  treatment  modality.  Our  preliminary  data  support  the 
feasibility  and  significance  of  this  novel  approach,  and  exploit  a  new  vulnerability  in  PDAC  signaling,  with  a 
translational potential to inform new therapies for PDAC.

## Key facts

- **NIH application ID:** 10170991
- **Project number:** 2P01CA117969-16
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** RAGHU KALLURI
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $546,750
- **Award type:** 2
- **Project period:** 2005-12-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10170991

## Citation

> US National Institutes of Health, RePORTER application 10170991, Project 3-Cancer cell interaction with oncogenic type 1 collagen in PDAC (2P01CA117969-16). Retrieved via AI Analytics 2026-06-08 from https://api.ai-analytics.org/grant/nih/10170991. Licensed CC0.

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