Drug resistance and metastasis account for more than 90% of all cancer deaths. This is particularly evident in gastric cancer, when patients commonly (60-70%) receive diagnoses after the cancer has spread to local lymph nodes and distant organs (liver, lung). Nearly all patients develop drug-resistant tumours and face a staggering 94% chance of death within five years. This is unacceptable, and we can do better.
Drugs that target cancer stem cells (CSCs) induce striking tumour regression in stomach cancer models, but inevitably spawn therapy-resistant cells that adopt aggressive phenotypes and accelerate tumour growth. This rationally suggests targeting stem cell plasticity is a possible way to overcome some of the limitations of directly targeting CSCs.
We show treating patient-derived tumour organoids (PDTOs) with chemotherapy (5-FU) or directly targeting Lgr5+ CSCs in metastatic gastric cancer mouse models induces a shift in the cell-state of cancer cells towards an undifferentiated/embryonic-like state. This finding is supported by previous collaborative work where we depleted Lgr5+ colon cancer stem cells, which induced a YAP-driven regenerative-like state that enable CSCs to switch cell-states and resist the effects of chemotherapy. Similarly, we show that YAP/TAZ signalling is highly enriched in gastric cancer cells that transition to an embryonic-like state. Consequently, targeted suppression of YAP/TAZ signalling in combination with chemotherapy closes-off adaptive signalling loops, thereby blocking fetal-like reversion of cancer cells, and subsequent resistance to chemotherapy. Together, these data indicate activation of YAP/TAZ signalling is linked to stomach cancer progression, and suggest YAP/TAZ plays a conserved role recalibrating the CSC hierarchy to promote and maintain non-Lgr5+ CSCs that are responsible for fuelling stomach cancer in response to treatment.