Understanding how tumour cells signal in a heterogeneous environment.
“Context is everything”, is a quote frequently used to highlight how information can be interpreted, or misinterpreted, depending on a particular situation. Similarly, the cellular and environmental context is critical when considering how cells communicate where co-occurring signals are integrated to direct cellular behavior. Importantly, solid tumours are complex ‘organs’, which contain a number of non-mutated host cells such as immune cells, fibroblasts and endothelial cells in addition to the mutated cancer cells (Figure 1). As such, not only have the tumour cells acquired mutations that alter their behavior, the context of the environment is also pathologically altered. This is particularly prominent in pancreatic ductal adenocarcinoma (PDA) – where on average 80% of the tumour volume is made up by the tumour stroma (host cells and fibrosis). Specifically, in PDA the microenvironment influence how tumour cells progress and respond to therapeutic intervention, however the mechanisms for this is not well described.
Figure 1: Pancreatic Ductal Adenocarcinoma (PDAC) is characterized by extensive stromal reaction and desmoplasia. Immunohistochemistry for epithelia (pan-cytokeratine), activated fibroblasts (alpha Smooth muscle actin, SMA) and collagen (Massons Trichrome) shown on pancreatic tissue isolated from Genetic Engineered Mouse model of Pancreatic Cancer. Shown is normal wild type (WT), KRas expressing early stages pancreatic ductal neoplasia (KC) or KRas/P53R172H expressing PDAC. Noteworthy, the epithelia lose its structure progressively as disease develops alongside an extensive fibroblast activation and Collagen deposition.
The central aim of the systems oncology laboratory is to determine how tumour cells exchange information with host cells to support tumour growth and resistance to therapies. Specifically, we aim to describe the key mechanisms whereby tumour cells co-opt stromal cells and conversely how the contextual impact of the microenvironment steer specific cancer cell phenotypes. Understanding these rules will enable development of synergistic combination therapies to co-target tumour cell intrinsic dependencies together with tumour cell extrinsic dependencies on stromal reciprocal signals.
We have developed methods to differentially label tumour and host cells, such that we can co-culture these in vitro and determine how information is exchanged using proteomics. Recently, we applied these technologies to study how expression of the most frequently mutated oncogene (KRAS) in tumour cells initiates a signal (SHH), which co-opt resident fibroblasts. Co-opted fibroblasts in turn secrete a number of signals following response to SHH, some of which (IGF1 and GAS6) initiate reciprocal signalling in the KRAS-expressing tumour cells. Importantly, while mutated KRAS can activate signaling through specific pathways (such as the MAPK pathway) in a cell autonomous manner, signaling through other pathways (such as AKT pathway) is strictly dependent on reciprocal signals from co-opted fibroblasts (Figure 2). This is important because tumour cells alter their metabolism and ability to apoptose under these conditions, and consequently, reciprocal signals should be co-targeted to efficiently kill these tumour cells.
Figure 2: Working model of reciprocal tumour-stroma signaling. Expression of mutant KRas in tumour cells lead to changes in their cellular signaling network alongside increased secretion of paracrine acting growth factors, cytokines and morphogens. Neighboring genetically normal stromal cells respond to these changes and consequently adapt an ‘activated’ phenotype, which contribute to the desmoplastic reaction by increased expression of extracellular matric proteins and growth factors. These changes to the extracellular environment are hypothesized to elicit a subsequent change to the signaling in the tumour cells, leading the increased aggressive behavior and resistance to therapy.
In parallel we have developed approaches to identify stromal cell (fibroblast) dependencies, which has lead to the identification of a novel putative target that is undergoing further characterization (generously funded by Pancreas Cancer Research Fund - PCRF)
Our latest paper on reciprocal signalling explained (Tape et al. Cell)