Professor Sun Beicheng et al.'s latest "Nature": collagen lysis-dependent DDR1 signaling determines the prognosis of pancreatic cancer

▎Editor of WuXi AppTec content team

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor with a short average survival of five years and no effective treatment
。 This week, Professor Sun Beicheng of the Affiliated Drum Tower Hospital of Nanjing University School of Medicine and Professor Michael Karin of the University of California, San Diego (UCSD) revealed for the first time in a paper published in Nature that the degradation status of type I collagen (Col I) in the extracellular matrix determines the development of PDAC and the survival of patients, so tumor treatment with tumor cells and extracellular matrix as targets has good application prospects
。 This discovery is another important achievement after Professor Sun Beicheng and Professor Michael Karin first proposed a strategy for the treatment of PDAC by combining inhibition of autophagy and MP in Nature Cancer in 2021, providing new ideas
for the treatment of PDAC.

PDAC's tumor cells are encased in large amounts of connective tissue, creating a microenvironment
of hypoxia, nutrient deficiencies, and immunosuppression.
The microenvironment of PDAC includes the extracellular matrix, tumor-associated fibroblasts, and a small number of blood vessels
.
Previous studies have found that the matrix status of PDAC is correlated with patient prognosis: an inert matrix with low expression of metalloproteinases (MMP) tends to correspond to a better clinical prognosis
.
How do different stromal states determine the development and prognosis of patients with PDAC?

Col I is the most abundant protein in the extracellular matrix and contains two different states: the full full-length form Col I (iCol I), and the cut form Col I (cCol I), which is cleaved by MMP to form 3/4 Col I and 1/4 Col I
.
The research team conducted histological analysis of a large number of PDAC patient samples and correlated analysis with their survival, and found that patients with high expression of cCol I had shorter survival and patients with high expression of iCol I had longer
survival.

The cutting of Col I controls the growth of PDAC (Image source: Reference [1])

In order to study how the presence of Col regulates tumor cell growth, the authors used the matrices of wild mice and Col I mice that cannot be cut by MMP to simulate lytic matrix and inert matrix, respectively, and found that iCol I can significantly inhibit the development and liver metastasis of pancreatic implant tumors in mice, and inhibit PDAC liver metastases
simulated by intrasplenic transplant tumors.

Subsequent experiments found that Col I's non-cleavage fibroblasts (RR) significantly inhibited tumor cell growth, while knockout Col I could reverse this effect, but did not affect the role of wild-type fibroblasts (WT) in promoting tumor growth
, and these results showed that iCol I's inhibition of tumor cell growth was specific.

Subsequently, combined with RNA sequencing and metabolic analysis of PDAC cells on the WT and RR matrices, the authors found that cCol I promoted while iCol I inhibited MP activity, MP-related protein expression, mitochondrial number, and mitochondrial-related protein expression in
PDAC cells.
These results suggest that the Col I state controls tumor cell metabolism
.

The next question is, how does the Col I state control tumor cell metabolism, which in turn affects tumor cell growth? By knocking out the receptor of Col I in PDAC cells, the authors found that only knockout of the discoidal domain receptor DDR1 significantly inhibits MP activity and mitochondrial occurrence
of PDAC cells growing on the extracellular matrix of WT.
Through a series of biochemical, molecular biology and cell biology methods, the authors found that cCol I is activated and iCol I inhibits the activity of tyrosine kinase DDR1, thereby promoting/inhibiting the NF-kB-p62-NRF2 pathway
.

Histological analysis of 106 PDAC clinical samples showed that the protein levels of cColI were significantly and positively correlated
with the protein levels of DDR1, NF-kB (p65), p62, NRF2, MP-related proteins and mitochondrial proteins (SDHB).
More importantly, patients with high-expression PDACs had shorter
survival compared to PDAC patients with low expression of cCol I, DDR1, and NRF2.
These results are consistent with the preclinical model of PDAC constructed by the authors, indicating that the lysis-type matrix drives recurrence
in patients with PDAC after surgery by NRF2-regulated MP activity and mitochondrial development.

Finally, the authors found through intervention in Col-mediated DDR1-NF-kB-p62-NRF2 pathway, MP activity, and in vivo and in vivo study that blocking the above targets can significantly inhibit tumor cell metabolism, in situ and liver metastasis PDAC development
.
The above results show that the presence of Col is an important factor in controlling the development of PDAC and patient prognosis, laying a foundation
for the treatment of tumor cell-matrix interaction.

▲Professor Sun Beicheng (Source: Professor Sun Beicheng photo)