Biology subjects

Cicchini, M.

Publications and source records attributed to Cicchini, M..

3 recordsLinked to original sources

bioRxiv2022

p53 restoration in small cell lung cancer identifies a latent Cyclophilin-dependent necrosis mechanism

The p53 tumor suppressor regulates multiple context-dependent tumor suppressive programs. Although p53 is mutated in [~]90% of small cell lung cancer (SCLC) tumors, how p53 mediates tumor suppression in this context is unknown. Here, using a mouse model of SCLC in which endogenous p53 expression can be conditionally and temporally regulated, we show that SCLC tumors maintain a requirement for p53 inactivation. However, we identified tumor subtype heterogeneity between SCLC tumors such that p53 reactivation induces a canonical senescence response in a subset of tumors, while, in others, p53 induces a non-apoptotic form of cell death that culminates in necrosis. We pinpointed the cyclophilin family of peptidyl prolyl cis-trans isomerases as critical determinants of a p53-induced transcriptional program that is specific to SCLC tumors and cell lines that are poised to undergo p53-mediated necrosis. Importantly, inhibition of cyclophilin isomerase activity suppresses SCLC subtype-specific p53-mediated death by limiting p53 transcriptional output without impacting chromatin binding. Our study demonstrates that intertumoral heterogeneity in SCLC can influence the biological response to p53 restoration, describes a novel mechanism of p53-regulated necrotic cell death, and uncovers new targets for the treatment of this most-recalcitrant tumor type.

cancer biology↗

bioRxiv2020

Requirement for PKC epsilon in KRAS-driven lung tumorigenesis

ABSTRACTNon-small cell lung cancer (NSCLC), the most frequent subtype of lung cancer, remains a highly lethal malignancy and one of the leading causes of cancer deaths worldwide. Mutant KRAS is the prevailing oncogenic driver of lung adenocarcinoma, the most common histological form of NSCLC. In this study, we examined the role of PKCε, an oncogenic kinase highly expressed in NSCLC and other cancers, in KRAS-driven tumorigenesis. Notably, database analysis revealed an association between PKCε expression and poor outcome in lung adenocarcinoma patients specifically having KRAS mutation. By generating a PKCε-deficient, conditionally activatable allele of oncogenic Kras (LSL-KrasG12D;PKCε−/− mice) we were able to demonstrate the requirement of PKCε for Kras-driven lung tumorigenesis in vivo, which is consistent with the impaired transformed growth observed in PKCε-deficient KRAS-dependent NSCLC cells. Moreover, PKCε-knockout mice were found to be less susceptible to lung tumorigenesis induced by benzo[a]pyrene, a carcinogen that induces mutations in Kras. Mechanistic analysis using RNA-Seq revealed little overlapping for PKCε and KRAS in the control of genes/biological pathways relevant in NSCLC, suggesting that a permissive role of PKCε in KRAS-driven lung tumorigenesis may involve non-redundant mechanisms. Our results thus highlight the relevance and potential of targeting PKCε for lung cancer therapeutics.Competing Interest StatementThe authors have declared no competing interest.View Full Text

cancer biology↗

bioRxiv2019

Copper is an essential regulator of the autophagic kinases ULK1/2 to drive lung adenocarcinoma

Targeting aberrant kinase activity in cancer relies on unmasking cellular inputs such as growth factors, nutrients, and metabolites that contribute to cancer initiation and progression1. While the transition metal copper (Cu) is an essential nutrient that is traditionally viewed as a static cofactor within enzyme active sites2, a newfound role for Cu as a modulator of kinase signaling is emerging3, 4. We discovered that Cu is required for the activity of the autophagic kinases ULK1/2 through a direct Cu-ULK1/2 interaction. Genetic loss of the Cu transporter Ctr1 or mutations in ULK1 that disrupt Cu-binding reduced ULK1/2-dependent signaling and autophagosome complex formation. Elevated intracellular Cu levels are associated with starvation induced autophagy and sufficient to enhance ULK1 kinase activity and in turn autophagic flux. Targeting autophagy machinery is a promising therapeutic strategy in cancers5, but is limited by the absence of potent inhibitors and the emergence of resistance. The growth and survival of lung tumors driven by KRASG12D is diminished in the absence of Ctr1, depends on ULK1 Cu-binding, and is associated with reduced autophagy levels and signaling. These findings suggest a new molecular basis for exploiting Cu-chelation therapy to forestall autophagy signaling to limit proliferation and survival in cancer.

cancer biology↗