Abstract NG08: Functional interrogation of cell plasticity in cancer

Abstract

Abstract The enormous complexity of cancer etiology and its rapidly evolving nature render it among the top threats against human health of our time. My research pertains to the molecular determinants of cellular plasticity in cancer, applying principles of cell and development biology, combined with mouse genetics tools and functional genomics approaches. During development, stem cells undergo stepwise fate restrictions with the end point being a diverse array of fully differentiated organs. Meanwhile, many of our adult tissues reserve stem cells to orchestrate postnatal remodeling and repair damage. Such regenerative capabilities are essential for organismal survival; however, it poses vulnerability to individuals undergoing prolonged stress where stem cells are subjected to exhaustion or malignant transformation. When contrasting regenerative behaviors across different stress conditions, one finds striking phenotypic convergence. A typically one-way-street developmental paradigm from pluripotency or multipotency to unipotency is temporally reversed during regeneration and tissue repair, and completely overthrown by cancer. Skin represents an outstanding model to address questions in cancer plasticity. It harbors resident stem cells that are abundant and genetically tractable. Its epithelium has two distinct lineages, hair follicle (HF) and epidermis (Epd), each harboring their own resident stem cells (SCs) fueling their homeostatic turnover. Upon injury, both Epd- and HF-SCs near the wound site mobilize toward it, re-epithelializing the wound bed and restoring the barrier. SCs from each lineage when acquiring oncogenic mutations also participates in malignant progression; one of such is squamous cell carcinomas (SCCs), a highly deadly cancer frequently occurring in head and neck, esophagus, lung, cervix, and skin. Skin SCCs highly resemble many of the SCCs including those of the head and neck at pathological and molecular levels, hence are excellent models to study SCCs. Testing the long postulated hypothesis ‘cancer is a wound that never heals', I found stressed SCs adopt a highly plastic state termed ‘lineage infidelity' - wide spread co-opt of otherwise lineage restricted genes - to cope with stress, drive wound repair and SCC progression (Ge et al, Cell, 2017). My study identified three defining properties of lineage infidelity. One, it is manifested as prevalent co-expression in the same cell of fate markers that are otherwise confined to opposite lineages. Two, markers of lineage infidelity are functionally required to cope with stress. Of note, rather than an intermediate stage on route to SC differentiation and fate transition, lineage infidelity describes a functional state where cell identity genes are purposely re-wired from a homeostatic network into a stress-specific one, hence representing a cancer specific vulnerability. Three, lineage infidelity occurs regardless of SC origin, and across different types of stress, hence is a core mechanism SCs use to steer fate choices under stress. Besides individually characterizing SC fate determinants in cancer, I have also developed in vivo functional screens for drivers of SCC progression, in this case, microRNAs. My proof-of-principle study had uncovered a cohort of novel oncomiRs that functionally promote SCC progression in mouse in vivo and in human tumor xenografts, exhibiting prognosis values in human patients (Ge et al, Nat Cell Biol, 2016). My strategy of ultrasound-guided in utero lentiviral microinjections allows rapid, stable and skin SC specific transgene integration, enabling functional genomics at a hitherto unparalleled speed and precision. Combining it with CRISPR, I have performed lineage specific and inducible gene knockout and overexpression to study SC plasticity in vivo. I am therefore uniquely positioned to apply in vivo functional genomics and study cancer plasticity. My long-term career goal is to leverage the basic knowledge I learn from studying cancer plasticity, and exploit novel cancer targets including the non-coding genome and regulatory RNAs, to therapeutically benefit patients with malignant diseases. Citation Format: Yejing Ge, Elaine Fuchs. Functional interrogation of cell plasticity in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr NG08.