YAP drives fate conversion and chemoresistance of small cell lung cancer

Abstract

Small cell lung cancer (SCLC) has a high degree of plasticity and is characterized by a remarkable response to chemotherapy followed by the development of resistance. Here, we use a mouse SCLC model to show that intratumoral heterogeneity of SCLC is progressively established during SCLC tumorigenesis. YAP/TAZ and Notch are required for the generation of non-neuroendocrine (Non-NE) SCLC tumor cells, but not for the initiation of SCLC. YAP signals through Notch-dependent and Notch-independent pathways to promote the fate conversion of SCLC from NE to Non-NE tumor cells by inducing Rest expression. In addition, YAP activation enhances the chemoresistance in NE SCLC tumor cells, while the inactivation of YAP in Non-NE SCLC tumor cells switches cell death induced by chemotherapy drugs from apoptosis to pyroptosis. Our study demonstrates that YAP plays critical roles in the establishment of intratumoral heterogeneity and highlights the potential of targeting YAP for chemoresistant SCLC.

Mechanomimetic 3D Scaffolds as a Humanized In Vitro Model for Ovarian Cancer

“…Aside from intrinsic molecular mechanisms [ 121 ], tumor chemoresistance is also affected by the biochemical and physical properties of the tumor microenvironment [ 122 , 123 , 124 ]. Specifically, the chemotherapeutic response of ovarian cancer cells in vitro is markedly affected by substrate stiffness; for example, during an evaluation of ovarian cancer tumor response to standard chemotherapeutic drugs (cisplatin and paclitaxel), antiproliferation effects were directly proportional to the stiffness of the substrate, thus, ovarian cancer cell lines grown on softer substrates with a lower elastic modulus were less sensitive to chemotherapeutic agents [ 15 ].…”

Killing SCLC: insights into how to target a shapeshifting tumor

“…SCLC cells that are ASCL1-low (often expressing multiple EMT markers) tend to be more sensitive to ferroptosis induction ( Bebber et al 2021 ), reminiscent of studies suggesting mesenchymal fate is predictive of ferroptosis sensitivity in multiple cancer types ( Hangauer et al 2017 ; Viswanathan et al 2017 ; Jiang et al 2021 ). Recent studies also suggest SCLC can undergo pyroptosis ( Wu et al 2021 ). How SCLC molecular subsets are wired for sensitivity to diverse forms of cell death and how cell death processes impact immune response should be important areas of further study.…”

“…YAP1 can also be present in stromal cells, which makes it difficult to distinguish from tumor cells with bulk analysis approaches. However, YAP1 can be expressed in late stage tumors in multiple mouse models of SCLC ( Ireland et al 2020 ; Wu et al 2021 ) and has been detected in human SCLC circulating tumor cell-derived xenografts (CDX) at variable proportions ( Pearsall et al 2020 ). These data suggest that YAP1 could be the result of stromal contamination and/or could represent a late stage of SCLC progression.…”

“…These data suggest that YAP1 could be the result of stromal contamination and/or could represent a late stage of SCLC progression. Toward the latter possibility, recent functional studies show that ectopic expression of YAP1 or TAZ (WWTR1) can promote a non-NE fate ( Horie et al 2016 ; Wu et al 2021 ; Jin et al 2022 ). Conversely, recent studies suggest that YAP1 may serve as a prognostic biomarker for limited-stage disease and tumors exhibiting a T-cell inflamed phenotype ( Tlemsani et al 2020 ; Owonikoko et al 2021 ).…”

“…Notch pathway activity is a recurrent mechanism implicated in lineage switching in SCLC ( Lim et al 2017 ; Ireland et al 2020 ; Patel et al 2021 ; Wu et al 2021 ). ASCL1 and the Notch pathway have a mutually antagonistic relationship in lung development and cancer.…”