New insights into regenerative programs driving cancer plasticity

Plasticity—the ability of cells to undergo phenotypic transitions—drives cancer progression and treatment resistance. Thus, plasticity is one of the most fundamental problems in cancer biology and one of the foremost challenges in clinical cancer management today. To date, targeting cancer plasticity has not succeeded in the clinic due to the lack of a fundamental understanding of the underlying mechanisms. Our recent published and ongoing work indicates that plasticity in lung cancer, pancreas cancer, and other carcinomas is concentrated in a minority subset of cancer cells, termed high plasticity cell states (HPCSs). Over the past several years, we have generated mouse models that allow for detection, longitudinal lineage-tracing, and ablation of the HPCS and other defined cancer cell states in lung and pancreas tumors in vivo. Using these systems, we have uncovered the HPCS cells are dedifferentiated but possess high capacity for cell state transitions, giving rise to both differentiated and advanced-stage cancer cells in situ in tumors. Longitudinal lineage tracing using secreted luciferases reveals HPCS-derived cells harbor more robust capacity for growth when compared to bulk cancer cells or another defined cancer cell state predicted to possess low plasticity. Suicide gene-mediated ablation of the HPCS in early-stage lesions abrogates tumor progression, whereas ablating HPCS cells in established tumors robustly reduces tumor burden. Leveraging these models, we have demonstrated that the HPCS gives rise to treatment-resistant cell states, whereas ablation of the HPCS abrogated resistance to chemotherapy and oncoprotein-targeted therapy. Furthermore, we show that the HPCS is a critical driver of a stromal cell circuit that drives immunosuppression, and cytoablation of the HPCS cells renders tumors vulnerable to immune attack. Interestingly, we find an HPCS-like state is ubiquitous in regenerating epithelia and carcinomas of multiple other tissues, revealing a convergence of plasticity programs in healthy and malignant epithelial tissues. In parallel studies, we have uncovered unexpected molecular drivers of this cell state, which operate system-wide in epithelial regenerative processes. These molecular mechanisms offer multiple therapeutic entry points, which may enable targeting of malignant plasticity in cancer patients. This work establishes the HPCS as a critical hub enabling reciprocal transitions between cancer cell states, including acquisition of states adapted to cancer therapies, and a critical driver of immunosuppressive tumor stroma. Targeting the HPCS may suppress cancer progression and eradicate treatment resistance.