Biology subjects

Calo, A.

Publications and source records attributed to Calo, A..

4 recordsLinked to original sources

bioRxiv2026

Nanomechanical phenotyping uncovers a non-canonical smooth muscle-like hypercontractility program in lung squamous cell carcinoma myofibroblasts

Myofibroblast-like cancer-associated fibroblasts (myCAFs) drive the stiff, tumor-promoting microenvironment, yet their mechanical phenotype in non-small cell lung cancer (NSCLC) remains undefined. myCAFs from major NSCLC subtypes (lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC)) were examined combining atomic force microscopy and traction force microscopy with molecular and signaling analyses. LUAD-myCAFs displayed canonical myofibroblast features, including elevated stiffness, traction forces, ROCK-MYPT1 signaling, and -SMA-rich stress fibers. Unexpectedly, LUSC-myCAFs amplified these nanomechanical features despite reduced ROCK-MYPT1 signaling and comparable -SMA levels. Instead, they exhibited a smooth muscle cell (SMC)-like contractile program characterized by enhanced SM-MHC(MYH11) expression colocalized with -SMA, ERK1/2-RLC hyperactivation, and DNA methylation reprogramming including SMC-contractility regulators. LUSC-myCAF hypercontractility was linked with reduced proliferative capacity and smaller intratumoral vessel lumens, consistent with the low CAF density and enhanced hypoxia patterns reported in LUSC. SMC markers were enriched and associated with adverse outcomes selectively in LUSC, highlighting the relevance of SMC-like myCAFs in LUSC progression. These findings unveil subtype-specific myCAF programs in NSCLC, and identify -SMA/SM-MHC(MYH11) myCAFs as key determinants of tumor mechanics, providing a rationale for the survival benefits of antihypertensive drugs targeting SMC hypercontractility. Moreover, they demonstrate that nanomechanical phenotyping can uncover translationally relevant myCAF phenotypes invisible to molecular profiling.

biophysics↗

bioRxiv2025

Structural basis and mechanism of action of NrdR, a bacterial master regulator of ribonucleotide reduction

Ribonucleotide reductases (RNRs) are the essential enzymes responsible for synthesizing dNTPs, the building blocks of DNA. In bacteria, the entire RNR network is controlled by the master regulator NrdR. As a regulator of an essential pathway with no eukaryotic equivalent, NrdR is a promising antimicrobial target. Recent studies have outlined a mechanism of action for NrdR, in which ATP and dATP induce changes in the protein quaternary structure, regulating RNR repression. However, due to a lack of functional studies linking the known structures to their biological roles, the role of NrdR is not yet fully understood. Here, we conducted a comprehensive study of NrdR in Escherichia coli and Pseudomonas aeruginosa. We delimited the NrdR regulon, combining transcriptomics and motif-based sequence analysis. We crystallized NrdR and obtained structural data on nucleotide binding and its relation to the stability of protein-protein interfaces involved in NrdR oligomerization. We examined the quaternary structures of NrdR using SEC-MALS and atomic force microscopy and correlated structure to function using point mutations, EMSAs, and in vitro transcription assays. Overall, our results demonstrate the mechanism used by NrdR to modulate its quaternary structure and activity and provide structural data that pave the way for targeted antimicrobial therapies.

molecular biology↗

bioRxiv2022

Reprogrammed Schwann cells organize into dynamic tracks that promote pancreatic cancer invasion

Nerves are a component of the tumor microenvironment contributing to cancer progression, but the role of cells from nerves in facilitating cancer invasion remains poorly understood. Here we show that Schwann cells (SCs) activated by cancer cells collectively function as Tumor Activated Schwann cell Tracks (TASTs) that promote cancer cell migration and invasion. Non-myelinating SCs form TASTs and have cell gene expression signatures that correlate with diminished survival in patients with pancreatic ductal adenocarcinoma. In TASTs, dynamic SCs form tracks that serve as cancer pathways and apply forces on cancer cells to enhance cancer motility. These SCs are activated by c-Jun, analogous to their reprogramming during nerve repair. This study reveals a mechanism of cancer cell invasion that co-opts a wound repair process and exploits the ability of SCs to collectively organize into tracks. These findings establish a novel paradigm of how cancer cells spread and reveal therapeutic opportunities. SIGNIFICANCEHow the tumor microenvironment participates in pancreatic cancer progression is not fully understood. Here, we show that Schwann cells are activated by cancer cells and collectively organize into tracks that dynamically enable cancer invasion in a c-Jun dependent manner.

cancer biology↗

bioRxiv2020

Cytotoxic lymphocytes use mechanosurveillance to target biophysical vulnerabilities in cancer

Immune cells identify cancer cells by recognizing characteristic biochemical features indicative of oncogenic transformation. Cancer cells have characteristic mechanical features, as well, but whether these biophysical properties also contribute to destruction by the immune system is not known. In the present study, we found that enhanced expression of myocardin related transcription factors (MRTFs), which promote migration and metastatic invasion, paradoxically compromised lung colonization by melanoma and breast carcinoma cells in an immune-mediated manner. Cancer cells with increased MRTF signaling were also more sensitive to immune checkpoint blockade therapy in mice and humans. The basis for this vulnerability was not biochemical, but biophysical. MRTF expression strengthened the actin cytoskeleton, increasing the rigidity of cancer cells and thereby making them more vulnerable to cytotoxic T lymphocytes and natural killer cells. These results reveal a mechanical dimension of immunosurveillance, which we call mechanosurveillance, that is particularly relevant to the targeting of metastatic disease.

immunology↗