Selective Translation of Cell Fate Regulators Mediates Tolerance to Broad Oncogenic Stress

Abstract

Highlights d Epidermis manages widespread oncogenic stress by inhibiting progenitor renewal d HRAS induces aberrant translation and alters progenitor behavior through eIF2B5 d eIF2B5 coordinates cell fate with proliferation through distinct translation networks d eIF2B5-regulated ubiquitin ligase FBXO32 blocks renewal to restrain aberrant growth

Cancer Plasticity: The Role of mRNA Translation

“…Similarly, in transdifferentiated (EMT) breast cancer cells, overproduction of extracellular matrix components leads to endoplasmic reticulum (ER) stress and activation of the PERK/eIF2α axis, which is paralleled by invasion and metastasis [31]. In the epidermis, an eIF2B5-mediated translational program leads to loss of progenitor self-renewal, which limits tumor initiation and growth [32]. Collectively, these observations suggest a multifaceted role of the ISR in cancer cell phenotypic switching.…”

Proteomics reveal cap-dependent translation inhibitors remodel the translation machinery and translatome

“…As the most energy-consuming cellular investment (Li et al, 2014), the complexity of eukaryotic protein synthesis machinery (Jackson et al, 2010) provides intricate, precise control over protein production during cellular state transition (Ho and Lee, 2016;Liu et al, 2016). Accumulating evidence (Cai et al, 2020;de la Parra et al, 2018;Landon et al, 2014;Lee et al, 2015;Liu et al, 2016;Schwanha ¨usser et al, 2011;Vogel and Marcotte, 2012), including ours (Balukoff et al, 2020;Ho et al, , 2018Ho et al, , 2020, demonstrates the predominance of translation efficiency (TE) and translation machinery adaptations over transcript-level fluctuations in determining protein output (translatome) and phenotype in human cells responding to physiologic stimuli. In this study, we address whether this paradigm also applies to therapeutic interventions, especially those traditionally thought to elicit translational inhibition as their sole mode of action.…”

Injury suppresses Ras cell competitive advantage through enhanced wild-type cell proliferation

“…Constitutive activation of Ras oncogenes has been identified as the initial genetic event in 3-30% of human cutaneous squamous cell carcinomas (cSCCs) (3)(4)(5)(6) and in experimentally induced cSCCs in mice (7,8). In mouse models with mosaic epithelial expression of the constitutive active form of Hras (Hras G12V/+ ), mutant cells outcompete wild-type cells and expand in the uninjured skin epidermis (9)(10)(11). Although activated-Hras mutant cells are tolerated within otherwise wild-type and uninjured skin epithelium (9)(10)(11), injury has been shown to cooperate with oncogenic mutations to trigger tumorigenesis in various mouse models (12)(13)(14)(15)(16)(17)(18)(19)(20)(21).…”

“…In mouse models with mosaic epithelial expression of the constitutive active form of Hras (Hras G12V/+ ), mutant cells outcompete wild-type cells and expand in the uninjured skin epidermis (9)(10)(11). Although activated-Hras mutant cells are tolerated within otherwise wild-type and uninjured skin epithelium (9)(10)(11), injury has been shown to cooperate with oncogenic mutations to trigger tumorigenesis in various mouse models (12)(13)(14)(15)(16)(17)(18)(19)(20)(21). We considered that the expansion of Hras G12V/+ cells in the epidermis could represent a vulnerability upon injury; Hras G12V/+ cells could futher expand and lead to tumors.…”