Biology subjects

Borah, A. A.

Publications and source records attributed to Borah, A. A..

4 recordsLinked to original sources

bioRxiv2025

Integrative analysis of mRNA stability regulation uncovers a metastasis-suppressive program in breast cancer

Heterogeneity in cancer gene expression is typically linked to genetic and epigenetic alterations, yet post-transcriptional regulation likely influences these patterns as well. However, the quantitative contribution of post-transcriptional mechanisms to cancer transcriptome dynamics remains unclear. Here, we systematically measured mRNA dynamics across diverse breast cancer models, revealing that mRNA stability significantly shapes gene expression variability. To decipher the regulatory grammar underlying these dynamics, we developed GreyHound, an interpretable multimodal deep-learning framework integrating RNA sequence features and RNA-binding protein (RBP) expression. GreyHound identified an extensive network of RBPs and their regulons underlying variations in mRNA stability. Among these, we uncovered a metastasis-suppressive regulatory axis centered on the RNA-binding protein RBMS3 and its post-transcriptional control of the redox regulator TXNIP. Functional and molecular analyses revealed that RBMS3 depletion resulted in targeted transcript destabilization, which was associated with poor clinical outcomes and enhanced metastatic potential in xenograft models. Using in vivo epistasis studies, we confirmed that RBMS3 regulation of TXNIP mRNA stability drives this metastasis-suppressive program. These findings position the RBMS3-TXNIP regulatory axis as a key post-transcriptional mechanism in breast cancer and illustrate how interpretable models of RNA dynamics can uncover hidden regulatory programs in disease.

cancer biology↗

bioRxiv2025

Human Papilloma Virus does not fully inactivate p53 in HNSCC

Head and neck squamous cell carcinoma (HNSCC) is a major global health challenge. Inactivation of the tumor suppressor p53 is the most frequent molecular event in this malignancy. p53 inactivation occurs either through TP53 mutations in human papilloma virus (HPV)-negative cases or via HPV-mediated p53 degradation in HPV-positive (HPV+) cases, where most tumors retain a wild-type (WT) TP53 allele. This underscores the critical role of p53-regulated processes in HNSCC pathogenesis. Clinically, HPV+ HNSCC is associated with significantly better outcomes than HPV-negative cases. However, despite HPV E6-mediated degradation of p53, approximately 10% of HPV+ HNSCC tumors harbor TP53 mutations, suggesting an additional selective pressure to suppress p53 signaling. In this study, we demonstrate that HPV+ TP53-WT HNSCC cells have residual, tumor suppressive p53 activity. Specifically, analysis of human tumor data reveals that among HPV+ HNSCC cases, those with WT TP53 have significantly better survival outcomes than both HPV+ cases with TP53 mutations and HPV-negative cases. Experimentally, genetic ablation of WT p53 in HPV+ HNSCC cells increased proliferation, migration, and invasion. Transcriptomic analysis revealed that p53 continues to regulate gene expression despite the presence of HPV. Further, human tumors with HPV+ TP53-WT status exhibit tumor-suppressive methylation patterns, fewer chromosomal alterations, and suppression of PI3K-AKT signaling compared to HPV+ TP53-mutant tumors. Importantly, loss of WT p53 in HPV+ HNSCC cells increased the levels of PI3K catalytic subunit p110, reduced expression of the molecular PI3K-AKT inhibitor INPP5D and enhanced sensitivity to pharmacologic PI3K inhibition. Together, our findings challenge the prevailing view that p53 is completely inactivated in HPV+ HNSCC and reveal tumor suppressive, p53-driven mechanisms that persist in these tumors. These insights highlight a potential role for TP53-based stratification in guiding treatment decisions and suggest new therapeutic vulnerabilities in HPV+ HNSCC.

cancer biology↗

bioRxiv2022

Partial gene suppression improves identification of cancer vulnerabilities when CRISPR-Cas9 knockout is pan-lethal

Hundreds of genome-wide loss-of-function screens have been performed, as part of efforts such as The Cancer Dependency Map, to create a catalog of genetic dependencies in a diverse set of cancer contexts. In recent years, large-scale screening efforts have shifted perturbation technology from RNAi to CRISPR-Cas9, due to the superior efficacy and specificity of CRISPR-Cas9-mediated approaches. However, questions remain about the extent to which partial suppression of gene targets could result in selective dependency across cell lines, potentially revealing a larger set of targetable cancer vulnerabilities than can be identified using CRISPR knockout alone. Here, we use CRISPR-Cas9 and RNAi screening data for more than 400 shared cell lines to represent knockout and partial suppression genetic perturbation modalities and evaluate the utility of each for therapeutic target discovery and the inference of gene function. We find that CRISPR screens identify more dependencies, and yield more accurate predictive models and co-dependency relationships overall. However, RNAi outperforms CRISPR in identifying associations (omics, drug, co-dependencies) with genes that are common dependencies for most cell lines (pan-dependencies). As pan-dependencies occur frequently in the CRISPR dataset (~2,000 genes), using results from both RNAi and CRISPR analyses facilitates the discovery of predictive models and associated co-dependencies for a wider range of gene targets than could be detected using either dataset alone. These findings can aid in the interpretation of contrasting results obtained from CRISPR and RNAi screens and reinforce the importance of partial gene suppression methods in building a cancer dependency map.

cancer biology↗

bioRxiv2020

Transcriptional subtype-specific microenvironmental crosstalk and tumor cell plasticity in metastatic pancreatic cancer

Bulk transcriptomic studies have defined classical and basal-like gene expression subtypes in pancreatic ductal adenocarcinoma (PDAC) that correlate with survival and response to chemotherapy; however, the underlying mechanisms that govern these subtypes and their heterogeneity remain elusive. Here, we performed single-cell RNA-sequencing of 23 metastatic PDAC needle biopsies and matched organoid models to understand how tumor cell-intrinsic features and extrinsic factors in the tumor microenvironment (TME) shape PDAC cancer cell phenotypes. We identify a novel cancer cell state that co-expresses basal-like and classical signatures, demonstrates upregulation of developmental and KRAS-driven gene expression programs, and represents a transitional intermediate between the basal-like and classical poles. Further, we observe structure to the metastatic TME supporting a model whereby reciprocal intercellular signaling shapes the local microenvironment and influences cancer cell transcriptional subtypes. In organoid culture, we find that transcriptional phenotypes are plastic and strongly skew toward the classical expression state, irrespective of genotype. Moreover, we show that patient-relevant transcriptional heterogeneity can be rescued by supplementing organoid media with factors found in the TME in a subtype-specific manner. Collectively, our study demonstrates that distinct microenvironmental signals are critical regulators of clinically relevant PDAC transcriptional states and their plasticity, identifies the necessity for considering the TME in cancer modeling efforts, and provides a generalizable approach for delineating the cell-intrinsic versus -extrinsic factors that govern tumor cell phenotypes.

cancer biology↗