Biology subjects

Scala, S.

Publications and source records attributed to Scala, S..

5 recordsLinked to original sources

bioRxiv2026

Targeting the Tumor-Stroma Crosstalk: An AI-Based Virtual Screening Strategy for Dual MET/SMO Inhibitors in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by a dense desmoplastic tumor microenvironment (TME) that limits drug penetration and promotes immune evasion. Effective treatment, therefore, requires simultaneous modulation of multiple signaling pathways. Here, we describe a directed polypharmacological strategy to identify dual modulators of c-MET and Smoothened (SMO), aiming to disrupt the protective stroma through SMO inhibition while directly suppressing tumor cell survival via c-MET targeting. An AI-guided virtual screening workflow combining the machine-learning platform PyRMD, trained on known c-MET and SMO ligands, with structure-based molecular docking was applied to a library of over 9 million compounds. This approach led to the identification of compound 21, an aminopyrimidine-benzamide-phenoxyquinoline derivative, as a dual c-MET/SMO inhibitor. Biochemical and cellular studies demonstrated that compound 21 selectively binds the SMO orthosteric site (pKi = 5.60), inhibits agonist-induced GLI (Glioma-associated oncogene) signaling (pIC50 = 5.50), and potently suppresses c-MET kinase activity (pIC50 = 6.94). Western blot analyses further revealed that compound 21 promotes ubiquitin-proteasome-mediated degradation of c-MET, eliminating receptor availability and limiting compensatory resistance signaling. In 3D heterotypic models comprising MIAPaCa2 pancreatic cancer cells and CAF154-hTERT fibroblasts, dual inhibition of SMO-mediated stromal support and c-MET-driven tumor progression resulted in greater cytotoxicity than the combination of the selective inhibitors Sonidegib and PHA-665752. Overall, compound 21 overcomes stromal-mediated resistance, enhances tumor cell death, and validates dual SMO/c-MET targeting as a promising single-agent therapeutic strategy for PDAC. One Sentence SummaryAn AI-identified dual SMO/c-MET inhibitor overcomes stromal resistance and degrades c-MET to suppress pancreatic cancer.

cancer biology↗

bioRxiv2023

Molecular and phenotypic blueprint of the hematopoietic compartment reveals proliferation stress as a driver of age-associated human stem cell dysfunctions

Hematopoietic stem/progenitor cell (HSPC) aging studies have been associated with myeloid skewing, reduced clonal output, and impaired regenerative capacity, but quantitative immunophenotypic and functional analysis across human aging is lacking. Here, we provide a comprehensive phenotypic, transcriptional, and functional dissection of human hematopoiesis across the lifespan. Although primitive HSPC numbers were stable during aging, overall cellularity was reduced, especially for erythroid and lymphoid lineages. Notably, HSPC from aged individuals had superior repopulating frequency than younger counterparts in xenografts; yet aged HSPC displayed epigenetic dysregulation of cell cycle, inflammatory signatures, and a reduced capacity to counteract activation-induced proliferative stress with concomitant accumulation of DNA damage and senescence-like features upon xenotransplantation. This phenotype was recapitulated by enforcing proliferative stress in vivo on cord blood (CB) HSPC. Overall, our work sheds light on dysregulated responses to activation-induced proliferation underlying HSPC aging and establishes CB xenotransplantation-based models as suitable for studying age-associated hematopoietic defects.

cell biology↗

bioRxiv2022

TRACKING HEMATOPOIETIC STEM CELL EVOLUTION IN A WISKOTT-ALDRICH CLINICAL TRIAL

Hematopoietic Stem Cells (HSC) are the cells that give rise to all other blood cells and, as such, they are crucial in the healthy development of individuals. Wiskott-Aldrich Syndrome (WAS) is a severe disorder affecting the regulation of hematopoietic cells and is caused by mutations in the WASP gene. We consider data from a revolutionary gene therapy clinical trial, where HSC harvested from 3 WAS patients bone marrow have been edited and corrected using viral vectors. Upon re-infusion into the patient, the HSC multiply and differentiate into other cell types. The aim is to unravel the cell multiplication and cell differentiation process, which has until now remained elusive. This paper models the replenishment of blood lineages resulting from corrected HSC via a multivariate, density-dependent Markov process and develops an inferential procedure to estimate the dynamic parameters given a set of temporally sparsely observed trajectories. Starting from the master equation, we derive a system of non-linear differential equations for the evolution of the first- and second-order moments over time. We use these moment equations in a generalized method-of-moments framework to perform inference. The performance of our proposal has been evaluated by considering different sampling scenarios and measurement errors of various strengths using a simulation study. We also compared it to another state-of-the-art approach and found that our method is statistically more efficient. By applying our method to the Wiskott-Aldrich Syndrome gene therapy data we found strong evidence for a myeloid-based developmental pathway of hematopoietic cells where fates of lymphoid and myeloid cells remain coupled even after the loss of erythroid potential. All code used in this manuscript can be found in the online Supplement, and the latest version of the code is available at github. com/dp3ll1n/SLCDP_v1.0.

bioinformatics↗

bioRxiv2020

SDF-1/CXCR4 inhibition prevents paradoxical generation of cisplatin-induced pro-metastatic niches

Platinum-based chemotherapy remains widely used in advanced non-small cell lung cancer (NSCLC) despite its ineffectiveness in long-term control of metastasis. Here, we uncover the interconnected pathways subtending cisplatin-induced metastasis promotion. We report that cisplatin treatment of tumor-free mice results in bone-marrow expansion of CCR2+CXCR4+Ly6Chigh inflammatory monocytes (IM) concomitantly with increased levels in the lungs of stromal SDF-1, the CXCR4 ligand. In experimental metastasis assays, cisplatin-induced IM favor tumor cells extravasation and expansion of CD133+CXCR4+ metastasis initiating cells (MICs), facilitating lung metastasis formation. At the primary tumor, cisplatin reduces tumor size but induces tumor release of SDF-1 triggering MICs expansion and recruitment of pro-invasive CXCR4+ macrophages. Co-recruitment of MICs and CCR2+CXCR4+ IM at SDF-1-enriched distant sites also promotes spontaneous metastasis. Combination treatment with a CXCR4 inhibitor prevents cisplatin-induced IM/MICs recruitment and interaction thus precluding metastasis overgrowth. Finally, we observe in NSCLC patients specimens that SDF-1 levels are higher in platinum-treated samples and correlate with worse outcome. Our findings suggest a possible novel combination therapy based on CXCR4 blockade to control metastatic disease, paradoxically promoted by cisplatin.

cancer biology↗

bioRxiv2020

A cell-autonomous PD-1/PD-L1 circuit promotes tumorigenicity of thyroid cancer cells by activating a SHP2/Ras/MAPK signalling cascade

The programmed cell death-1 (PD-1) and its ligands PD-L1 and PD-L2 are immune checkpoints. Typically, cancer cells express the PD-Ls that bind PD-1 on immune cells, inhibiting their anti-cancer activity. Recently, PD-1 expression has been found in cancer cells. We analysed expression and functions of PD-1 in thyroid cancer (TC). Human TC specimens (47%), but not normal thyroids, displayed PD-1 expression in epithelial cells, which significantly correlated with tumour stage and lymph-node metastasis. PD-1 overexpression/stimulation promoted TC cell proliferation and migration in culture. PD-1 recruited the SHP2 phosphatase, potentiated its phosphatase activity thus enhancing Ras activation by dephosphorylation of inhibitory tyrosine 32 and triggering the MAPK cascade. PD-1 inhibition decreased, while PD-1 overexpression facilitated, TC cell xenograft growth by affecting cell proliferation. PD-1 circuit blockade in TC, besides restoring anti-cancer immunity, could also directly impair TC cell growth by inhibiting the Ras/MAPK pathway.

cancer biology↗