Using Organotypic Tissue Slices to Investigate the Microenvironment of Pancreatic Cancer: Pharmacotyping and Beyond

Abstract

Organotypic tissue slices prepared from patient tumors are a semi-intact ex vivo preparation that recapitulates many aspects of the tumor microenvironment (TME). While connections to the vasculature and nervous system are severed, the integral functional elements of the tumor remain intact for many days during the slice culture. During this window of time, the slice platforms offer a suite of molecular, biomechanical and functional tools to investigate PDAC biology. In this review, we first briefly discuss the development of pancreatic tissue slices as a model system. Next, we touch upon using slices as an orthogonal approach to study the TME as compared to other established 3D models, such as organoids. Distinct from most other models, the pancreatic slices contain autologous immune and other stromal cells. Taking advantage of the existing immune cells within the slices, we will discuss the breakthrough studies which investigate the immune compartment in the pancreas slices. These studies will provide an important framework for future investigations seeking to exploit or reprogram the TME for cancer therapy.

Keywords: 3D culture; PDAC; microenvironment; organotypic; pancreatic cancer; slices.

Figure 1

Using organotypic slices to examine paracrine signaling in the tumor microenvironment. (A) Processing of tissue slices from donor biopsies while performing autologous cell isolation and co-cultures. Slices are analyzed downstream using functional assays. (B) Live cell calcium imaging using an ex vivo tissue slice from a human pancreatic donor. In situ cytolabeling was performed using the calcium indicator dye fluo4 (green), epithelial cell marker epcam (purple), immune cell marker CD11b (red), and the tissue backscatter (gray).

Figure 2

Personalized medicine approach using ex vivo preparations of living pancreatic tissue slices. (A) The tumor microenvironment of living slices from PDAC tissues is comprised of both cellular and a-cellular (extracellular matrix) compartments. (B) Tumor slices from different donors have distinct features that contribute to tumor killing efficacy of therapeutics. These features, such as tumors with highly enriched tumor-associated macrophages (left panel) or dense collagen deposition (right panel) will guide therapeutic testing of unique microenvironmental signatures.