Tumor Engraftment in Nude Mice and Enrichment in Stroma- Related Gene Pathways Predict Poor Survival and Resistance to Gemcitabine in Patients with Pancreatic Cancer

Abstract

Purpose To evaluate prospectively the engraftment rate, factors influencing engraftment, and predictability of clinical outcome of low-passage xenografts from patients with resectable pancreatic ductal adenocarcinoma (PDA) and to establish a bank of PDA xenografts. Experimental Design Patients with resectable PDA scheduled for resection at the Johns Hopkins Hospital were eligible. Representative pieces of tumor were implanted in nude mice. The status of the SMAD4 gene and content of tumor-generating cells were determined by immunohistochemistry (IHC). Gene expression was performed using U133 Plus 2.0 array. Patients were followed for progression and survival. Results 94 patients with PDA were resected, 69 tumors implanted in nude mice, and 42 (61%) engrafted. Engrafted carcinomas were more often SMAD4 mutant, had a metastatic gene expression signature and worse prognosis. Tumors from patients resistant to gemcitabine were enriched in stroma-related gene pathways. Tumors sensitive to gemcitabine were enriched in cell cycle and pyrimidine gene pathways. The time progression for patients who received treatment with gemcitabine for metastatic disease (n=7) was double in patients with xenografts sensitive to gemcitabine. Conclusion A successful xenograft was generated in 61% of patients attempted, generating a pool of 42 PDA xenografts with significant biological information and annotated clinical data. Patients with PDA and SMAD4 inactivation have a better engraftment rate. Engraftment is a poor prognosis factor, and engrafted tumors have a metastatic gene expression signature. Tumors from gemcitabine-resistant patients were enriched in stromal pathways.

Interrogating open issues in cancer precision medicine with patient-derived xenografts

“…Similarly, tumour grafts of pancreatic ductal adenocarcinoma displayed higher expression of metastasis-associated genes compared with samples that failed engraftment, and patient donors of successfully engrafted tumours had shorter survival 154 .…”

Anti-DLL4 Has Broad Spectrum Activity in Pancreatic Cancer Dependent on Targeting DLL4-Notch Signaling in Both Tumor and Vasculature Cells

“…This functional tumorigenicity assay makes no assumptions about the frequency, FACS marker profile, or heterogeneity of the tumor initiating cell population and facilitates the analysis of a diverse panel of tumors. Garrido-Laguna and colleagues have recently described the utility of patient-derived pancreatic cancer tumor models in predicting response to gemcitabine in the clinic (48). It was observed in their study that despite treatment with very high doses of gemcitabine (100 mg/ kg, administered 3 times per week) many of the tumors were not sensitive to gemcitabine.…”

Nupr1-Aurora Kinase A Pathway Provides Protection against Metabolic Stress-Mediated Autophagic-Associated Cell Death

“…Moreover, in the fraction of patients who qualify for surgery, chemotherapy/radiotherapy-resistant metastases often arise after surgical resection of the primary tumor. The resistance to chemo and radiotherapy is thought to be associated both with the intrinsic nature of pancreatic cancer cells (3) and with the abundant fibrotic stroma of the tumors, which favors rapid tumor progression and creates a physical barrier preventing drug delivery and immune cell infiltration (4,5). In addition to the importance of fibrotic stroma, PDAC histolopathology is characterized by poor vascularization indicating that pancreatic cancer cells must cope with an adverse microenvironment with nutrient and oxygen shortage.…”