Biology subjects

Bhalla, A. D.

Publications and source records attributed to Bhalla, A. D..

3 recordsLinked to original sources

bioRxiv2026

Cross-species Study of Canine and Human Peripheral Nerve Sheath Tumors: Clinical and Molecular Perspectives

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas. An obstacle to treating MPNSTs is a lack of effective systemic therapies. Although over 70% of human MPNSTs have lost or inactivated the epigenome regulator polycomb repressive complex 2 (PRC2), its activity and contribution to canine PNST progression remain unclear. This study compared canine peripheral nerve sheath tumors (PNSTs) and human MPNSTs across biological and clinical features, including PRC2 activity. Immunohistochemical analysis was performed for a human tissue microarray of 54 neurofibromas and 139 MPNSTs, and 63 canine PNSTs for H3K27me3, a repressive histone mark deposited by intact PRC2, and H3K27ac, which increases globally upon H3K27me3 loss. To understand the genomic alterations present in canine PNSTs, we analyzed tumor mutation burden, copy number alteration, and transcriptomes of eight canine PNST/normal pairs. The results suggested that H3K27me3 loss and associated gain of H3K27ac epigenetically drive human and canine tumors. These findings warrant further studies to evaluate whether these epigenetic deregulations alter similar gene signatures across species.

cancer biology↗

bioRxiv2026

Spatially-Resolved Multiomic Atlas of Leiomyosarcoma Identifies Two Clinically Relevant Epigenetically-Driven Cell States

Leiomyosarcoma is a smooth muscle-derived malignancy marked by significant clinical heterogeneity. The extent and nature of cellular heterogeneity and molecular underpinnings remain poorly understood. To address this at transcriptomic and epigenomic levels, we performed single-nucleus multiome sequencing on untreated primary leiomyosarcoma tissues. Malignant cells segregated almost exclusively into two previously unrecognized and epigenetically distinct states: a dedifferentiated, mesenchymal-like subtype (MES) and a differentiated smooth muscle-enriched subtype (SMC). Chromatin accessibility profiling revealed strong enrichment of nuclear factor I (NFI) transcription factor motifs in MES cells, whereas AP-1 family motifs--most prominently FOSL2--were selectively accessible in SMC cells. Established leiomyosarcoma cell lines faithfully recapitulated these subtypes, and targeted depletion of NFI or AP-1 factors suppressed proliferation, invasion, and in vivo tumor growth, demonstrating functional dependency on these transcriptional programs. Spatial transcriptomics across 328 tissue cores from 128 leiomyosarcomas showed that immunosuppressive macrophages preferentially cluster around MES regions, revealing a subtype-specific tumor-immune niche. Clinically, MES-dominant tumors were associated with significantly worse patient outcomes. Through an epigenetic inhibitor screen, we identify and validate SMARCA4/2 inhibition as a promising therapeutic vulnerability for MES leiomyosarcomas. Together, this work defines two epigenetically driven, transcription factor-regulated, and clinically relevant states of leiomyosarcoma, revealing mechanistic underpinnings of tumor heterogeneity and uncovering actionable therapeutic strategies. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=93 HEIGHT=200 SRC="FIGDIR/small/726988v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@132928eorg.highwire.dtl.DTLVardef@133e3b7org.highwire.dtl.DTLVardef@1ab4398org.highwire.dtl.DTLVardef@e2de25_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2021

New cellular models of undifferentiated pleomorphic sarcoma and malignant peripheral nerve sheath tumor

Undifferentiated pleomorphic sarcoma (UPS) and malignant peripheral nerve sheath tumor (MPNST) are aggressive soft tissue sarcomas that do not respond well to current treatment modalities. The limited availability of UPS and MPNST cell lines makes it challenging to identify potential therapeutic targets in a laboratory setting. Understanding the urgent need for improved treatments for these tumors and the limited cellular models led us to generate additional cell lines to study these rare cancers further. Patient-derived tumors were used to establish 5 new UPS models, including one radiation-associated UPS--UPS060.1, UPS271.1, UPS511, UPS0103, and RIS620--and 3 new models of MPNST--MPNST007, MPNST3813E, and MPNST4970. This study examined the utility of the new cell lines as sarcoma models by assessing tumorigenic potential and mutation status for known sarcoma-related genes. All the cell lines formed colonies and migrated in vitro. The in vivo tumorigenic potential of each cell line was determined by either subcutaneous injection of cells or implantation of tumor tissue into immunocompromised mice. UPS060.1, UPS271.1, and UPS511 cells formed tumors in mice upon subcutaneous injection. UPS0103 and RIS620 tumor implants formed tumors in vivo, as did MPNST007 and MPNST3813E tumor implants. Mutation analysis of a panel of genes frequently mutated in sarcomas showed that two of the three MPNST cell lines had NF1 mutations. Two of the three MPNST cell lines had mutations in polycomb repressive complex 2 members. These new cellular models provide the scientific community with powerful tools for detailed studies of sarcomagenesis and investigate novel therapies for UPS and MPNST.

cancer biology↗