Promising new target discovered in pancreatic cancer could boost chemotherapy and reduce spread

Good news! Cancer is history (soon)!

"... the study shows that blocking the molecule nidogen-2 enhanced the effectiveness of chemotherapy and reduced the cancer’s spread in mouse models.

The team discovered that nidogen-2 reduces the dense scaffolding tissue within pancreatic tumours, which is a major barrier to treatment and contributes to the cancer’s well known chemotherapy resistance. ...

To identify new therapeutic targets, the ... researchers used an innovative technique called tissue decellularisation, which removes all the cells from a tumour sample, but retains its scaffolding components, otherwise known as the extracellular matrix. By comparing the scaffolds of mouse tumours that metastasise with those that don’t, they discovered that the molecule nidogen-2 was elevated in the matrix of more aggressive tumours as the disease progressed. ..."

From the abstract:

"Pancreatic ductal adenocarcinoma (PDAC) is characterized by increasing fibrosis, which can enhance tumor progression and spread. Here, we undertook an unbiased temporal assessment of the matrisome of the highly metastatic KPC (Pdx1-Cre, LSL-KrasG12D/+, LSL-Trp53R172H/+) and poorly metastatic KPflC (Pdx1-Cre, LSL-KrasG12D/+, Trp53fl/+) genetically engineered mouse models of pancreatic cancer using mass spectrometry proteomics. Our assessment at early-, mid-, and late-stage disease reveals an increased abundance of nidogen-2 (NID2) in the KPC model compared to KPflC, with further validation showing that NID2 is primarily expressed by cancer-associated fibroblasts (CAFs). Using biomechanical assessments, second harmonic generation imaging, and birefringence analysis, we show that NID2 reduction by CRISPR interference (CRISPRi) in CAFs reduces stiffness and matrix remodeling in three-dimensional models, leading to impaired cancer cell invasion. Intravital imaging revealed improved vascular patency in live NID2-depleted tumors, with enhanced response to gemcitabine/Abraxane. In orthotopic models, NID2 CRISPRi tumors had less liver metastasis and increased survival, highlighting NID2 as a potential PDAC cotarget."

Promising new target discovered in pancreatic cancer could boost chemotherapy and reduce spread | Garvan Institute of Medical Research "A molecule called nidogen-2 may be a key driver of pancreatic cancer progression and metastasis, offering a promising new treatment approach for this aggressive cancer, according to a Garvan Institute study"

Temporally resolved proteomics identifies nidogen-2 as a cotarget in pancreatic cancer that modulates fibrosis and therapy response (open access)

Fig. 1. Temporal proteomics of pancreatic cancer GEMMs reveal NID2 as a potential target in aggressive disease.