Human Tumor–Derived Matrix Improves the Predictability of Head and Neck Cancer Drug Testing

Abstract

In vitro cancer drug testing carries a low predictive value. We developed the human leiomyoma–derived matrix “Myogel” to better mimic the human tumor microenvironment (TME). We hypothesized that Myogel could provide an appropriate microenvironment for cancer cells, thereby allowing more in vivo–relevant drug testing. We screened 19 anticancer compounds, targeting the epidermal growth factor receptor (EGFR), MEK, and PI3K/mTOR on 12 head and neck squamous cell carcinoma (HNSCC) cell lines cultured on plastic, mouse sarcoma–derived Matrigel (MSDM), and Myogel. We applied a high-throughput drug screening assay under five different culturing conditions: cells in two-dimensional (2D) plastic wells and on top or embedded in Matrigel or Myogel. We then compared the efficacy of the anticancer compounds to the response rates of 19 HNSCC monotherapy clinical trials. Cancer cells on top of Myogel responded less to EGFR and MEK inhibitors compared to cells cultured on plastic or Matrigel. However, we found a similar response to the PI3K/mTOR inhibitors under all culturing conditions. Cells grown on Myogel more closely resembled the response rates reported in EGFR-inhibitor monotherapy clinical trials. Our findings suggest that a human tumor matrix improves the predictability of in vitro anticancer drug testing compared to current 2D and MSDM methods.

Comparative Analysis of Vascular Mimicry in Head and Neck Squamous Cell Carcinoma: In Vitro and In Vivo Approaches

“…For instance, the protein composition of Myogel is substantially different from other EHS-based matrices. Further, crucial carcinogenesis-related properties, such as tumour cell invasion and response to HNSCC-targeted therapy, were more efficiently represented in Myogel than in Matrigel [ 18 , 33 ]. A fascinating observation is that a primary cell line (SCC-24A) formed merely a few tubes compared with an extensively interlaced network formed by its metastatic counterpart (SCC-24B), albeit both were established from the same patient.…”

Ex Vivo Drug Screening Informed Targeted Therapy for Metastatic Parotid Squamous Cell Carcinoma

“…In addition to these epithelial cell lineage markers, the EpCAM + cells were also found to express CD47, a potential immune evasion marker ( 30 ), CD54 ( 31 ), CD64, CD73 ( 32 ), CD151, and c-MET ( Figure 6C ), which could explain the cells’ responsiveness to the c-METi crizotinib ( Figure 1B and Supplementary Figure S2B ). Currently, subcultures of the cells devoted a cell line named MISB10, which have undergone an excess of 80 passages; they show continuous growth and can recover from repeated cryopreservation cycles; they show responsiveness to EGFR-TKi targeted therapies and form multicellular organotypic spheroids while grown in human tumor microenvironment mimicking 3D culture conditions ( 33 ) ( Supplementary Figure S6 ).…”

“…While up to 44% of parotid duct carcinomas have been reported to have HER2 amplifications or high protein or mRNA level expression of HER2 ( 20 , 35 ), the number of HER2-positive parotid SCC cases is lower ( 36 ). This suggests that while less frequent in parotid SCC than parotic duct carcinomas, HER2 aberrations represent a significant target, biomarker, and opportunity for targeted treatment also in a subset of patients with parotid SCC tumors ( 17 , 20 , 33 , 37 ). To improve outcomes and efficacy of treatment of primary and/or metastatic parotid SCC, systematic studies involving larger series of HER2 + salivary gland cancers or stratification of patients to HER2-targeted therapies by alternative strategies are needed to determine the contribution of HER2 targeting on tumor response outcomes in parotid SCC and other salivary gland cancers ( 17 ).…”

Development of a Bioassay for Continuous Monitoring of TWIST1 Activity

“…Having demonstrated the advantages and possibilities of the Gaussia luciferase-based system, we decided to investigate possible applications of the mCherry-based system. To this end, we performed a series of transfections of prostate cancer cells (PC3) to induce overexpression of specific factor for the epithelial state (E-cadherin) and for the mesenchymal state (SNAIL) and culture them in conditions as close as possible to human environment using Myogel, a human-tumor derived origin matrix [45,67]. While cells overexpressing E-cadherin showed lower invasiveness and TWIST1 activity, SNAIL-expressing cells migrated out of the spheroid, as thus having a more mesenchymal phenotype, are these cells also expressed the TWIST reporter more actively, which, in line with previous research [68], providing more evidence that TWIST1 is an important player in mesenchymal transformation and migration.…”