Biology subjects

Izzo, L. T.

Publications and source records attributed to Izzo, L. T..

3 recordsLinked to original sources

bioRxiv2025

Transmembrane Serine Protease TMPRSS11B promotes an acidified tumor microenvironment and immune suppression in lung squamous cell carcinoma

Lung cancer is the leading cause of cancer-related deaths worldwide. Existing therapeutic options have limited efficacy, particularly for lung squamous cell carcinoma (LUSC), underscoring the critical need for the identification of new therapeutic targets. We previously demonstrated that the Transmembrane Serine Protease TMPRSS11B promotes transformation of human bronchial epithelial cells and enhances lactate export from LUSC cells. To determine the impact of TMPRSS11B activity on the host immune system and the tumor microenvironment (TME), we evaluated the effect of Tmprss11b depletion in a syngeneic mouse model. Tmprss11b depletion significantly reduced tumor burden in immunocompetent mice and triggered an infiltration of immune cells. RNA FISH analysis and spatial transcriptomics in the autochthonous Rosa26-Sox2-Ires-GfpLSL/LSL; Nkx2-1fl/fl; Lkb1fl/fl (SNL) model revealed an enrichment of Tmprss11b expression in LUSC tumors, specifically in Krt13+ hillock-like cells. Ultra-pH sensitive nanoparticle imaging and metabolite analysis identified regions of acidification, elevated lactate, and enrichment of M2-like macrophages in LUSC tumors. These results demonstrate that TMPRSS11B promotes an acidified and immunosuppressive TME and nominate this enzyme as a therapeutic target in LUSC.

cancer biology↗

bioRxiv2025

KLF4 promotes a KRT13+ hillock-like state in squamous lung cancer

Lung squamous cell carcinoma (LUSC) is a basal-like subtype of lung cancer with limited treatment options. While prior studies have identified tumour-propagating cell states in squamous tumours, the broader landscape of intra-tumoural heterogeneity within LUSC remains poorly understood. Here, we employ Sox2-driven mouse models, organoid cultures, and single-cell transcriptomic analyses to uncover previously unrecognized levels of cell fate diversity within LUSC. Specifically, we identify a KRT13+ hillock-like population of slower-dividing tumour cells characterized by immunomodulatory gene expression signatures. The tumour hillock-like state is conserved across multiple animal and human-derived models and is present in the majority of human LUSCs as well as head and neck and esophageal squamous tumours. Our findings shed light on the cellular origins of tumour hillock-like states: lung club cells give rise to tumours with luminal hillock-like populations, while basal-like tumour-propagating cells transition into basal hillock-like states, resembling lineage plasticity trajectories of the normal lung. Mechanistically, KLF4 promotes KRT13, a broadly conserved hillock-like state with enrichment of potential therapeutic targets, and resistance to platinum-based chemotherapy. Together, these results provide molecular insights into the lineage plasticity underlying intra-tumoural heterogeneity within LUSC, offering potential avenues for new therapeutic strategies.

cancer biology↗

bioRxiv2022

The carnitine shuttle links mitochondrial metabolism to histone acetylation and lipogenesis

Acetyl-CoA is a central metabolite used for lipid synthesis in the cytosol and histone acetylation in the nucleus, among other pathways. The two major precursors to acetyl-CoA in the nuclear-cytoplasmic compartment are citrate and acetate, which are processed to acetyl-CoA by ATP-citrate lyase (ACLY) and acyl-CoA synthetase short-chain 2 (ACSS2), respectively. While some evidence has suggested the existence of additional routes to nuclear-cytosolic acetyl-CoA, such pathways remain poorly defined. To investigate this, we generated cancer cell lines lacking both ACLY and ACSS2. Unexpectedly, and in contrast to observations in fibroblasts, ACLY and ACSS2 double knockout (DKO) cancer cells remain viable and proliferate, maintain pools of cytosolic acetyl-CoA, and are competent to acetylate proteins in both cytosolic and nuclear compartments. Using stable isotope tracing, we show that both glucose and fatty acids feed acetyl-CoA pools and histone acetylation in DKO cells. Moreover, we provide evidence for the carnitine shuttle and carnitine acetyltransferase (CrAT) as a substantial pathway to transfer two-carbon units from mitochondria to cytosol independent of ACLY. Indeed, in the absence of ACLY, glucose can feed fatty acid synthesis in a carnitine responsive and CrAT-dependent manner. This work defines a carnitine-facilitated route to produce nuclear-cytosolic acetyl-CoA, shedding light on the intricate regulation and compartmentalization of acetyl-CoA metabolism

cell biology↗