CDKN2A^Lowcancer cells outcompete macrophages for microenvironmental zinc to drive immunotherapy resistance

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 8, 2025

ABSTRACT Approximately 50% of cancers exhibit decreased CDKN2A expression ( Low ), which is linked to immune checkpoint blockade (ICB) resistance. While traditionally recognized as a tumor suppressor and cell cycle regulator, we have previously put forth new paradigm demonstrating its role in intracellular metabolic reprogramming. Whether the derangement due loss alters metabolites within microenvironment (TME) how that affects compartment ICB response has never been investigated. Here found cancer cells reorganize zinc compartmentalization by upregulating importer SLC39A9 plasma membrane, leading accumulation concurrent depletion TME. This competition for results zinc-starved macrophages, reduced phagocytic activity. Remarkably, restoring levels TME through dietary intervention re-educates macrophages pro-phagocytic phenotype, sensitizing tumors ICB. Unexpectedly, T are not required this response. Clinically, from patients signatures, corresponding phagocytosis signatures. Moreover, with low circulating time-to-event outcomes compared those higher levels. Our work reveals unrecognized mechanism outcompete zinc, directly disrupting their function efficacy.

Language: Английский

Therapeutic targeting de novo purine biosynthesis driven by β-catenin-dependent PPAT upregulation in hepatoblastoma

Cell Death and Disease, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 17, 2025

Abstract De novo purine biosynthesis (DNPS) was previously shown to be aberrantly activated in many cancers. However, the activity of DNPS pathway and its underlying regulatory mechanism hepatoblastoma (HB) remain poorly understood. Herein, we discovered that expression PPAT, rate-limiting enzyme DNPS, markedly upregulated HB, leading an augmented flux via thereby promoting both HB cell proliferation migration. Furthermore, found mutant β-catenin, a dominant driver transcriptionally PPAT expression, hence stimulating constituting druggable metabolic vulnerability HB. Consistently, pharmacological targeting using inhibitor lometrexol or genetic repressing enhanced blocked progression vitro vivo. Our findings suggest patients harboring β-catenin mutations consequent upregulation, may treated efficaciously with inhibitors like lometrexol. These novel bear major therapeutic implications for targeted precision medicine

Language: Английский

ATR promotes mTORC1 activation via de novo cholesterol synthesis in p16-low cancer cells

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Oct. 28, 2023

ABSTRACT DNA damage and cellular metabolism exhibit a complex interplay characterized by bidirectional feedback mechanisms. Key mediators of the response metabolic regulation include Ataxia Telangiectasia Rad3-related protein (ATR) mechanistic Target Rapamycin Complex 1 (mTORC1), respectively. Previous studies have established ATR as regulatory upstream factor mTORC1 during replication stress; however, precise mechanisms which is activated in this context remain poorly defined. Additionally, activity signaling axis unperturbed cells has not been extensively investigated. Here, we demonstrate that promotes across various models under basal conditions. This effect particularly enhanced following loss p16, previously associated with hyperactivation here found increased activity. Mechanistically, de novo cholesterol synthesis activation through upregulation lanosterol synthase (LSS), independently both CHK1 TSC complex. Furthermore, attenuation resulting from inhibition was rescued supplementation or multiple contexts. restoration corresponded localization mTOR to lysosome. Collectively, our findings novel connection linking modulation metabolism.

Language: Английский