Tauler, A. | Search bioRxiv

bioRxiv2025

LARP1 integrates MYC and mTOR signaling to enable anabolic growth during tumor initiation

Tumor initiation requires the integration of oncogenic signals with environmental cues to enable anabolic growth. Among oncogenic drivers, MYC is central to tumorigenesis, with its deregulation observed in more than 60% of human cancers. Oncogenic MYC profoundly rewires transcription, enabling cells to bypass cell cycle checkpoints and resetting metabolism. A cornerstone of this rewiring is the up regulation of biomass-producing pathways, particularly ribosome biogenesis. How and when MYC oncogenic program is translationally executed, either immediately or until a favorable metabolic context emerges, remains a central unanswered question in tumor initiation, limiting our understanding of tumor latency and early intervention windows. Here, we identify the RNA-binding protein LARP1 as a critical effector of MYC-driven transformation, connecting MYC oncogenic activity with mTOR signaling. Mechanistically MYC represses miR-26a/b, relieving post-transcriptional repression of LARP1 and leading to its up regulation. LARP1 associates with the translational machinery loading it with the anabolic translatome induced by MYC in a translationally poised state. Upon permissive mTOR signaling, and dependent on the phosphorylation of LARP1 at serines 689 and 697, this program is rapidly translated, fueling the biosynthetic processes essential for tumor development. Importantly, genetic deletion of LARP1 or pharmacological mTOR inhibition completely abrogates tumor initiation in a genetically engineered colorectal organoid model of MYC-driven tumorigenesis, underscoring the physiological relevance of this two-step mechanism. These findings reveal a fundamental mechanism underlying MYC oncogenesis, whereby LARP1 bridges the anabolic translatome primed by MYC with its metabolic execution controlled by mTOR. By temporally uncoupling transformation from metabolic permissiveness, this mechanism defines a critical checkpoint in early tumorigenesis and reveals a potential vulnerability for intercepting MYC-driven cancer before biomass expansion.

cancer biology↗

bioRxiv2019

Lysosomal degradation ensures accurate chromosomal segregation to prevent genomic instability

Lysosomes, as primary degradative organelles, are the end-point of different converging pathways including macroautophagy. To date, lysosome function has mainly focused on interphase cells, while their role during mitosis remains controversial. Mitosis dictates the faithful transmission of genetic material among generations, and perturbations of mitotic division lead to chromosomal instability, a hallmark of cancer. Heretofore, correct mitotic progression relies on the orchestrated degradation of mitotic factors, which was mainly attributed to ubiquitin-triggered proteasome-dependent degradation. Here, we show that mitotic transition does not only rely on proteasome-dependent degradation, as impairment of lysosomes increases mitotic timing and leads to mitotic errors, thus promoting chromosomal instability. Furthermore, we identified several putative lysosomal targets in mitotic cells. Among them, WAPL, a cohesin regulatory protein, emerged as a novel p62-interacting protein for targeted lysosomal degradation. Finally, we characterized an atypical nuclear phenotype, the toroidal nucleus, as a novel biomarker for genotoxic screenings. Our results establish lysosome-dependent degradation as an essential event to prevent genomic instability.

cell biology↗