Biology subjects

Malladi, S.

Publications and source records attributed to Malladi, S..

5 recordsLinked to original sources

bioRxiv2026

A single chromosome 3p break initiates clear cell renal cell carcinoma evolution

Clear cell renal cell carcinoma (ccRCC) is initiated by chromosome 3p loss, yet chromosome losses impose a profound fitness burden on normal cells. How renal epithelial cells tolerate this deleterious aneuploidy during early tumorigenesis remains unclear. Analysis of 949 ccRCC genomes reveals two major classes of chromosome 3p alterations: simple deletions and complex rearrangements surrounding a terminal breakpoint - a pattern we term breakpoint-confined chromothripsis. We modeled both alterations in non-transformed human renal proximal tubule epithelial cells by introducing a single DNA double-strand break on chromosome 3p. Despite an initial fitness disadvantage, chromosome 3p loss drives adaptive genomic evolution that recapitulates recurrent ccRCC-associated aneuploidies, including 5q gain and 14q loss. These alterations alleviate the fitness constraints of 3p loss and promote metabolic reprogramming, clonal expansion, and malignant transformation, producing tumors with features of ccRCC. Thus, a single chromosome break initiates the evolutionary trajectory of ccRCC by creating a fitness bottleneck that selects for recurrent aneuploidies.

cancer biology↗

bioRxiv2024

Microfluidic Formation of Ultrathin, Handleable Collagen Sheets Exhibiting Toe-heel Tensile Behavior

The extracellular matrix (ECM) of cardiovascular tissues displays a non-linear, strain-dependent elastic modulus, attributed to the hierarchical organization of collagen. At low loads, these tissues exhibit compliance, permitting contraction or dilation, while at high loads, they stiffen considerably, increasing their mechanical strength by at least tenfold. Although collagen gels are widely used in 3D cell culture, tissue engineering, and biofabrication, current engineering techniques fail to replicate this hierarchical organization at the microscale. As a result, they lack both the non-linear tensile behavior and the physiologically relevant strength of native tissues. To address this limitation, we present templated collagen sheets that are 1.8 microns thin and 10 mm wide that demonstrate non-linear tensile behavior. Collagen sheets are obtained from an acidic collagen solution via a microfluidic flow focusing process, incorporating and subsequently removing emulsified oil droplets (mean diameters 2.1 microns and 5.0 microns, volume concentration 2.25%). Templated collagen sheets exhibit a two-fold increase in fibril alignment dispersion compared with non-templated ones. When assessed along their length, the Youngs modulus of templated sheets increases 62-fold at 90% failure strain, closely matching the properties of native load-bearing tissues. We anticipate that these ultrathin templated collagen sheets will have broad applications as a substrate material for the bottom-up fabrication of load-bearing biomaterials and tissue structures for in vitro applications and implantation.

bioengineering↗

bioRxiv2024

Estimating adequate contact rates and time of Highly Pathogenic Avian Influenza virus introduction into individual United States commercial poultry flocks during the 2022/24 epizootic

Following confirmation of the first case of the ongoing U.S. HPAI H5N1 epizootic in commercial poultry on February 8, 2022, the virus has continued to devastate the U.S. poultry sector and the pathogen has since managed to cross over to livestock and a few human cases have also been reported. Efficient outbreak management benefits greatly from timely detection and proper identification of the pathways of virus introduction and spread. In this study, using changes in mortality rates as a proxy for HPAI incidence in a layer, broiler and turkey flock, mathematical modeling techniques, specifically the Approximate Bayesian Computation algorithm in conjunction with a stochastic within-flock HPAI transmission model, were used to estimate the time window of pathogen introduction into the flock (TOI) and adequate contact rate (ACR) based on the daily mortality and diagnostic test results. The estimated TOI was then used together with the day when the first positive sample was collected to calculate the most likely time to first positive sample (MTFPS) which reflects the time to HPAI detection in the flock. The estimated joint (i.e., all species combined) median of the MTFPS for different flocks was six days, the joint median most likely ACR was 6.8 newly infected birds per infectious bird per day, the joint median R0was 13 and the joint median number of test days per flock was two. These results were also grouped by species and by epidemic phase and discussed accordingly. We conclude that findings from this and related studies are beneficial for the different stakeholders in outbreak management and combining TOI analysis with complementary approaches such as phylogenetic analyses is critically important for improved understanding of disease transmission pathways. The estimated parameters can also inform models used for surveillance design, risk analysis, and emergency preparedness.

bioinformatics↗

bioRxiv2022

Functional Characterization of lncRNA152 as an Angiogenesis-Inhibiting Tumor Suppressor in Triple-Negative Breast Cancers

AO_SCPLOWBSTRACTC_SCPLOWLong non-coding RNAs have been implicated in many of the hallmarks of cancer. Herein, we found that the expression of lncRNA152 (lnc152; a.k.a. DRAIC), which we annotated previously, is highly upregulated in luminal breast cancer (LBC) and downregulated in triple-negative breast cancer (TNBC). Knockdown of lnc152 promotes cell migration and invasion in LBC cell lines. In contrast, ectopic expression of lnc152 inhibits growth, migration, invasion, and angiogenesis in TNBC cell lines. In mice, lnc152 inhibited the growth of TNBC cell xenografts, as well as metastasis of TNBC cells in an intracardiac injection model. Transcriptome analysis of the xenografts indicated that lnc152 downregulates genes controlling angiogenesis. Using pull down assays coupled with LC-MS/MS, we identified RBM47, a known tumor suppressor in breast cancer, as a lnc152-interacting protein. The effects of lnc152 in TNBC cells are mediated, in part, by regulating the expression of RBM47. Collectively, our results demonstrate that lnc152 is an angiogenesis-inhibiting tumor suppressor that attenuates the aggressive cancer-related phenotypes found in TNBC. SO_SCPLOWTATEMENTC_SCPLOWO_SCPCAP C_SCPCAPO_SCPLOWOFC_SCPLOW SO_SCPLOWIGNIFICANCEC_SCPLOWThis study identifies lncRNA152 as an angiogenesis-inhibiting tumor suppressor that attenuates the aggressive cancer-related phenotypes found in TNBC by upregulating the expression of the tumor suppressor RBM47. As such, lncRNA152 may serve as a biomarker to track aggressiveness of breast cancer, as well as therapeutic target for treating TNBC.

cancer biology↗

bioRxiv2021

WNK1 Enhances Migration and Invasion in Breast Cancer Models

Metastasis is the major cause of mortality in breast cancer patients. Many signaling pathways have been linked to cancer invasiveness, but blockade of few protein components has succeeded in reducing metastasis. Thus, identification of proteins contributing to invasion that are manipulable by small molecules may be valuable in inhibiting spread of the disease. The protein kinase WNK1 (with no lysine (K) 1) has been suggested to induce migration of cells representing a range of cancer types. Analyses of mouse models and patient data have implicated WNK1 as one of a handful of genes uniquely linked to invasive breast cancer. Here we present evidence that inhibition of WNK1 slows breast cancer metastasis. We show that depletion or inhibition of WNK1 reduces migration of several breast cancer cell lines in wound healing assays and decreases invasion in collagen matrices. Furthermore, WNK1 depletion suppresses expression of AXL, a tyrosine kinase implicated in metastasis. Finally, we demonstrate that WNK inhibition in mice attenuates tumor progression and metastatic burden. These data showing reduced migration, invasion, and metastasis upon WNK1 depletion in multiple breast cancer models suggest that WNK1 contributes to the metastatic phenotype and that WNK1 inhibition may offer a therapeutic avenue for attenuating progression of invasive breast cancers.

cancer biology↗