Biology subjects

Pedamallu, C. S.

Publications and source records attributed to Pedamallu, C. S..

3 recordsLinked to original sources

bioRxiv2021

Transcriptional and Functional Activity of Canine Hemangiosarcoma to Support Hematopoiesis Demonstrate Bone Marrow Nurse Cell Ontogeny

Hemangiosarcoma and angiosarcoma are soft-tissue sarcomas of blood vessel-forming cells in dogs and humans, respectively. These vasoformative sarcomas are aggressive and highly metastatic, with disorganized, irregular blood-filled vascular spaces. Our objective was to define molecular programs which support the niche that enables progression of canine hemangiosarcoma and human angiosarcoma. Dog-in-mouse hemangiosarcoma xenografts recapitulated the vasoformative and highly angiogenic morphology and molecular characteristics of primary tumors. Blood vessels in the tumors were complex and disorganized, and they were lined by both donor and host cells, a trait that was not observed in xenografts from canine osteosarcoma and lymphoma. In some cases, the xenografted hemangiosarcoma cells created exuberant myeloid hyperplasia and gave rise to lymphoproliferative tumors of mouse origin. We did not uncover a definitive transmissible etiology, but our functional analyses indicate that hemangiosarcoma cells generate a microenvironment that supports expansion and differentiation of hematopoietic progenitor populations. We conclude that canine hemangiosarcomas, and possibly human angiosarcomas, originate from stromal cells that are part of the bone marrow niche and that these cells may also support the growth of hematopoietic tumors. SignificanceWe demonstrate that molecular programs supporting expansion of immune and inflammatory cells in hemangiosarcoma resemble those of bone marrow niche cells, providing insights into the potential roles of these cells - whether physiological or pathological - in creating a permissive environment for the progression of hematopoietic malignancies.

cancer biology↗

bioRxiv2019

LSF small molecule inhibitors phenocopy LSF-targeted siRNAs causing mitotic defects and senescence in cancer cells

BackgroundThe oncogene LSF (encoded by TFCP2) has been proposed as a novel therapeutic target for multiple cancers. LSF overexpression in patient tumors correlates with poor prognosis in particular for both hepatocellular carcinoma and colorectal cancer. The limited treatment outcomes for these diseases underscore the need for molecularly targeting novel mechanisms. LSF small molecule inhibitors, Factor Quinolinone Inhibitors (FQIs), have exhibited robust anti-tumor activity in multiple mouse models, with no observable toxicity. MethodsCell proliferation and cell cycle progression were analyzed after loss of LSF activity, using HeLa cells as a model cancer cell line responsive to FQI1. In addition, results were compared after treatment with either FQI1 or siRNA targeting LSF to test for biological specificity of targeting LSF by FQI1. ResultsCellular phenotypes observed upon FQI1 treatment were due specifically to the loss of LSF activity, as siRNA targeting LSF produced highly similar phenotypes. Inhibition of LSF activity by either mechanism induced a strong delay prior to metaphase during progression through mitosis, with condensed, but unaligned, chromosomes. This mitotic disruption resulted in improper cellular division leading to multiple outcomes: multi-nucleation, apoptosis, and cellular senescence. ConclusionsSpecific inhibition of LSF by small molecules or siRNA results in mitotic defects, leading to cell death or senescence - consequences that are desirable in combating cancer. Taken together, these findings not only confirm that LSF is a promising target for cancer treatment, but also that FQIs are promising compounds for obtaining therapeutic effects for multiple LSF-driven cancers with unmet medical need.

cancer biology↗

bioRxiv2017

Pan-cancer study of heterogeneous RNA aberrations

We present the most comprehensive catalogue of cancer-associated gene alterations through characterization of tumor transcriptomes from 1,188 donors of the Pan-Cancer Analysis of Whole Genomes project. Using matched whole-genome sequencing data, we attributed RNA alterations to germline and somatic DNA alterations, revealing likely genetic mechanisms. We identified 444 associations of gene expression with somatic non-coding single-nucleotide variants. We found 1,872 splicing alterations associated with somatic mutation in intronic regions, including novel exonization events associated with Alu elements. Somatic copy number alterations were the major driver of total gene and allele-specific expression (ASE) variation. Additionally, 82% of gene fusions had structural variant support, including 75 of a novel class called \"bridged\" fusions, in which a third genomic location bridged two different genes. Globally, we observe transcriptomic alteration signatures that differ between cancer types and have associations with DNA mutational signatures. Given this unique dataset of RNA alterations, we also identified 1,012 genes significantly altered through both DNA and RNA mechanisms. Our study represents an extensive catalog of RNA alterations and reveals new insights into the heterogeneous molecular mechanisms of cancer gene alterations.

genomics↗