Since the initial discovery of the oncogenic activity of WNT1 in mouse mammary glands, our appreciation for the complex roles for WNT signalling pathways in cancer has increased dramatically. WNTs and their downstream effectors regulate various processes that are important for cancer progression, including tumour initiation, tumour growth, cell senescence, cell death, differentiation and metastasis. Although WNT signalling pathways have been difficult to target, improved drug-discovery platforms and new technologies have facilitated the discovery of agents that can alter WNT signalling in preclinical models, thus setting the stage for clinical trials in humans.

WNT signalling pathways as therapeutic targets in cancer

WNT–β-catenin signalling is involved in a multitude of developmental processes and the maintenance of adult tissue homeostasis by regulating cell proliferation, differentiation, migration, genetic stability and apoptosis, as well as by maintaining adult stem cells in a pluripotent state. Not surprisingly, aberrant regulation of this pathway is therefore associated with a variety of diseases, including cancer, fibrosis and neurodegeneration. Despite this knowledge, therapeutic agents specifically targeting the WNT pathway have only recently entered clinical trials and none has yet been approved. This Review examines the problems and potential solutions to this vexing situation and attempts to bring them into perspective.

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Can we safely target the WNT pathway

Since their identification in 1994, cancer stem cells (CSCs) have been objects of intensive study. Their properties and mechanisms of formation have become a major focus of current cancer research, in part because of their enhanced ability to initiate and drive tumour growth and their intrinsic resistance to conventional therapeutics. The discovery that activation of the epithelial-to-mesenchymal transition (EMT) programme in carcinoma cells can give rise to cells with stem-like properties has provided one possible mechanism explaining how CSCs arise and presents a possible avenue for their therapeutic manipulation. Here we address recent developments in CSC research, focusing on carcinomas that are able to undergo EMT. We discuss the signalling pathways that create these cells, cell-intrinsic mechanisms that could be exploited for selective elimination or induction of their differentiation, and the role of the tumour microenvironment in sustaining them. Finally, we propose ways to use our current knowledge of the complex biology of CSCs to design novel therapies to eliminate them.

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Tackling the cancer stem cells — what challenges do they pose?

Precision medicine is about matching the right drugs to the right patients. Although this approach is technology agnostic, in cancer there is a tendency to make precision medicine synonymous with genomics. However, genome-based cancer therapeutic matching is limited by incomplete biological understanding of the relationship between phenotype and cancer genotype. This limitation can be addressed by functional testing of live patient tumour cells exposed to potential therapies. Recently, several 'next-generation' functional diagnostic technologies have been reported, including novel methods for tumour manipulation, molecularly precise assays of tumour responses and device-based in situ approaches; these address the limitations of the older generation of chemosensitivity tests. The promise of these new technologies suggests a future diagnostic strategy that integrates functional testing with next-generation sequencing and immunoprofiling to precisely match combination therapies to individual cancer patients.

Precision medicine for cancer with next-generation functional diagnostics

Mechanical strain regulates the development, organization, and function of multicellular tissues, but mechanisms linking mechanical strain and cell-cell junction proteins to cellular responses are poorly understood. Here, we showed that mechanical strain applied to quiescent epithelial cells induced rapid cell cycle reentry, mediated by independent nuclear accumulation and transcriptional activity of first Yap1 and then β-catenin. Inhibition of Yap1- and β-catenin-mediated transcription blocked cell cycle reentry and progression through G1 into S phase, respectively. Maintenance of quiescence, Yap1 nuclear exclusion, and β-catenin transcriptional responses to mechanical strain required E-cadherin extracellular engagement. Thus, activation of Yap1 and β-catenin may represent a master regulator of mechanical strain-induced cell proliferation, and cadherins provide signaling centers required for cellular responses to externally applied force.

http://science.sciencemag.org/content/sci/348/6238/1024.full.pdf

Mechanical strain induces E-cadherin–dependent Yap1 and β-catenin activation to drive cell cycle entry

Misregulated β-catenin responsive transcription (CRT) has been implicated in the genesis of various malignancies, including colorectal carcinomas, and it is a key therapeutic target in combating various cancers. Despite significant effort, successful clinical implementation of CRT inhibitory therapeutics remains a challenging goal. This is, in part, because of the challenge of identifying inhibitory compounds that specifically modulate the nuclear transcriptional activity of β-catenin while not affecting its cytoskeletal function in stabilizing adherens junctions at the cell membrane. Here, we report an RNAi-based modifier screening strategy for the identification of CRT inhibitors. Our data provide support for the specificity of these inhibitory compounds in antagonizing the transcriptional function of nuclear β-catenin. We show that these inhibitors efficiently block Wnt/β-catenin–induced target genes and phenotypes in various mammalian and cancer cell lines. Importantly, these Wnt inhibitors are specifically cytotoxic to human colon tumor biopsy cultures as well as colon cancer cell lines that exhibit deregulated Wnt signaling.

https://www.pnas.org/content/pnas/108/15/5954.full.pdf

An RNAi-based chemical genetic screen identifies three small-molecule inhibitors of the Wnt/wingless signaling pathway

Background/Aim: To assess the impact of drug selection upon the treatment of advanced and metastatic non- small cell lung cancer (NSCLC), we applied a functional platform that measures drug-induced cell death in human tumor primary-culture micro-spheroids isolated from surgical specimens. Patients and Methods: At diagnosis, microspheroids isolated by mechanical and enzymatic disaggregation were examined for drug-induced cell-death by morphology and staining characteristics. Drugs were administered using standard protocols. Thirty-one patients, who received at least one cycle of therapy, were evaluable. All patients signed informed consent. Results: Twenty out of 31 patients responded (64.5%), 1 completely and 19 partially, providing a two-fold improvement over historical control of 30% (p=0.00015), a median time-to-progression of 8.5 months and a median overall survival of 21.3 months. Conclusion: This functional platform is feasible and provides a favorable objective response rate, time-to-progression and survival in advanced, metastatic, untreated NSCLC, and warrants further evaluation. Bronchogenic carcinoma is the leading cause of cancer- related death in the US with 160,340 estimated deaths in 2012. The majority of patients present with non-small cell lung cancer. While the 1-year survival for advanced lung cancer has improved from 35% to 42% over the past 3 decades (1), the 5-year survival for stage III & IV disease

Steve S. Evans

Papers

An RNAi-based chemical genetic screen identifies three small-molecule inhibitors of the Wnt/wingless signaling pathway

Functional Profiling to Select Chemotherapy in Untreated, Advanced or Metastatic Non-small Cell Lung Cancer