Biology subjects

Nirula, M.

Publications and source records attributed to Nirula, M..

6 recordsLinked to original sources

bioRxiv2026

Spatially Organized Tertiary Lymphoid Structures Emerge in Small Cell Lung Cancer and Associate with Improved Survival

Tertiary lymphoid structures (TLS) are ectopic immune aggregates associated with improved prognosis and response to immunotherapy in multiple solid tumors. However, their presence, spatial organization, and functional relevance in small cell lung cancer (SCLC), a malignancy characterized by profound immune evasion, remain poorly understood. Using imaging mass cytometry (IMC) across 320 regions of interest spanning primary lung tumor, tumor-adjacent lung, liver and lymph node metastasis, complemented by Visium HD spatial transcriptomics, we characterized the cellular architecture and molecular programs of TLS-like niches in SCLC. TLS-like niches were identified in a subset of SCLC samples, predominantly primary lung tumor tissues and adjacent lung, spanning a continuum from loose lymphoid aggregates to compact follicle-like immune structures. Organized TLS-like niches contained CD20+ B-cell cores, closely associated with CD4+ and CD8A+ T cells, proliferating lymphocytes, HLA-DR+ antigen-presenting compartments, and SMA+ stromal scaffolds, and were enriched for canonical TLS organizer signals (CXCL13, LTB, FDCSP). Patients with TLS-positive tumors demonstrated improved overall survival, and core TLS-associated transcriptional programs were associated with favorable survival in an independent bulk RNA-seq cohort. To our knowledge, this represents one of the first spatially resolved analyses of TLS-like immune architecture in SCLC, demonstrating that organized lymphoid immunity can emerge in this classically immune-evasive disease and is associated with improved survival.

cancer biology↗

bioRxiv2026

Proteomic Profiling Identifies CLDN3 as a Tumor-Selective Therapeutic Target in Small Cell Lung Cancer

Small cell lung cancer (SCLC) remains a highly lethal disease with limited targetable surface antigens beyond delta-like ligand 3 (DLL3). We sought to systematically identify and validate tumor-selective cell-surface targets in relapsed SCLC. To this end, we developed an integrated proteogenomic pipeline combining single-cell RNA sequencing, combinatorial optimization, mass spectrometry-based proteomics, and immunohistochemistry to systematically map the SCLC surfaceome of 49 tumors across 25 patients with relapsed SCLC. Using this approach we found claudin-3 (CLDN3) to be a consistently expressed and tumor-selective antigen, with broader coverage than DLL3, which is the current clinical benchmark. CLDN3 was highly expressed across various treatment states, while maintaining low expression in most nonmalignant tissues. Functional validation using a novel CLDN3-specific monoclonal antibody (ABN501) demonstrated NK cell-mediated cytotoxicity in vitro and tumor regression in vivo, as well as a favorable safety profile. These findings support clinical development of CLDN3-directed therapies and demonstrate the utility of integrated proteogenomic approaches for antigen discovery in solid tumors.

cancer biology↗

bioRxiv2026

Hepatobiliary Progenitor-like Reprogramming in Liver Metastases

Metastatic progression requires cancer cells to adapt to the unique constraints of distant organ microenvironments, yet the mechanisms that drive organ-specific adaptations remain poorly understood. Here, we show that the liver actively rewrites metastatic cancer cell identity, driving tumor cells toward a hepatobiliary progenitor-like state. Through integrated transcriptomic, proteomic, metabolomic, and epigenomic analyses of patient-derived rapid-autopsy samples and experimental models, we identify this state as selectively enriched in liver metastases. It is characterized by co-activation of hepatic and biliary/progenitor regulators HNF4A and SOX9 and is observed across multiple epithelial cancers, indicating a conserved response to the hepatic niche. Mechanistically, hepatocyte-derived TGF-{beta} and hypoxia converge to activate a HIF-1-ACLY axis, increasing nuclear acetyl-coenzyme A availability and histone acetylation at hepatic lineage regulatory elements to drive hepatobiliary reprogramming. This coordinated niche-response program can be captured transcriptionally and is associated with inferior overall survival. Disruption of this pathway suppresses hepatic reprogramming and impairs liver metastatic fitness. These findings identify the liver as an active determinant of metastatic cell fate, linking microenvironmental signaling to metabolic and chromatin remodeling programs that enable lineage plasticity. More broadly, they reveal organ-specific reprogramming as a fundamental principle of metastasis and a therapeutic vulnerability in liver metastases.

cancer biology↗

bioRxiv2025

Lamin A/C Deficiency Drives Genomic Instability and Poor Survival in Small-Cell Lung Cancer through Increased R-loop Accumulation

Lamin A/C (LMNA), a key component of the nuclear envelope, is essential for maintaining nuclear integrity and genome organization [1]. While LMNA dysregulation has been implicated in genomic instability across cancer and aging, the underlying mechanisms remain poorly understood [2]. Here, we investigate LMNAs role in small-cell lung cancer (SCLC), a highly aggressive malignancy characterized by extreme genomic instability [3, 4]. We demonstrate that LMNA depletion promotes R-loop accumulation, transcription-replication conflicts, replication stress, DNA breaks, and micronuclei formation. Mechanistically, LMNA loss disrupts nuclear pore complex distribution, reducing phenylalanine-glycine (FG)-nucleoporin incorporation and impairing RNA export efficiency. Furthermore, we show that LMNA expression is epigenetically repressed by EZH2 during SCLC differentiation from neuroendocrine (NE) to non-NE states. Clinically, low LMNA levels correlate with significantly worse survival in SCLC patients. These findings uncover a novel role for LMNA in safeguarding genome integrity and shaping tumor heterogeneity, with broad implications for cancer and aging. Significance StatementLamin A/C, a key structural component of the nuclear envelope, is frequently lost or mutated in cancer, laminopathies, and aging-related disorders. Lamin A/C loss is associated with genomic instability, but the underlying mechanisms remain incompletely understood. We demonstrate that LMNA loss drives genomic instability by promoting R-loop accumulation through disrupted nuclear pore dynamics and impaired RNA export. These findings reveal a previously unrecognized link between LMNA loss, nuclear envelope dysfunction, and genome instability. Targeting this pathway could help mitigate genomic instability in aging and laminopathies, while leveraging R-loop accumulation may enhance the efficacy of DNA-damaging therapies in cancer.

cancer biology↗

bioRxiv2024

Metastatic organotropism in small cell lung cancer

Metastasis is the leading cause of cancer-related deaths, yet its regulatory mechanisms are not fully understood. Small-cell lung cancer (SCLC) is the most metastatic form of lung cancer, with most patients presenting with widespread disease, making it an ideal model for studying metastasis. However, the lack of suitable preclinical models has limited such studies. We utilized rapid autopsy-derived tumors to develop xenograft models that mimic key features of SCLC, including histopathology, rapid and widespread development of metastasis to the liver, brain, adrenal, bone marrow, and kidneys within weeks, and response to chemotherapy. By integrating in vivo lineage selection with comprehensive bulk and single cell multiomic profiling of transcriptomes and chromatin accessibility, we identified critical cellular programs driving metastatic organotropism to the liver and brain, the most common sites of SCLC metastasis. Our findings reveal the key role of nuclear-cytoskeletal interactions in SCLC liver metastasis. Specifically, the loss of the nuclear envelope protein lamin A/C, encoded by the LMNA gene, increased nuclear deformability and significantly increased the incidence of liver metastasis. Human liver metastases exhibited reduced LMNA expression compared to other metastatic sites, correlating with poorer patient outcomes and increased mortality. This study introduces novel preclinical models for SCLC metastasis and highlights pathways critical for organ-specific metastasis, offering new avenues for the development of targeted therapies to prevent or treat metastatic disease.

cancer biology↗

bioRxiv2024

Microenvironment Shapes Cell State, Plasticity, and Heterogeneity of Small Cell Lung Cancer

Small-cell lung cancer (SCLC) is the most fatal form of lung cancer. Intra-tumoral heterogeneity, marked by neuroendocrine (NE) and non-neuroendocrine (non-NE) cell states, defines SCLC, but the drivers of SCLC plasticity are poorly understood. To map the landscape of SCLC tumor microenvironment (TME), we apply spatially resolved transcriptomics and quantitative mass spectrometry-based proteomics to metastatic SCLC tumors obtained via rapid autopsy. The phenotype and overall composition of non-malignant cells in the tumor microenvironment (TME) exhibits substantial variability, closely mirroring the tumor phenotype, suggesting TME-driven reprogramming of NE cell states. We identify cancer-associated fibroblasts (CAF) as a crucial element of SCLC TME heterogeneity, contributing to immune exclusion, and predicting exceptionally poor prognosis. Together, our work provides a comprehensive map of SCLC tumor and TME ecosystems, emphasizing their pivotal role in SCLCs adaptable nature, opening possibilities for re-programming the intercellular communications that shape SCLC tumor states.

cancer biology↗