Mutually exclusive teams-like patterns of gene regulation characterize phenotypic heterogeneity along the noradrenergic-mesenchymal axis in neuroblastoma DOI Creative Commons
Manas Sehgal, Sonali Nayak, Sarthak Sahoo

и другие.

Cancer Biology & Therapy, Год журнала: 2024, Номер 25(1)

Опубликована: Янв. 17, 2024

Neuroblastoma is the most frequent extracranial pediatric tumor and leads to 15% of all cancer-related deaths in children. Tumor relapse therapy resistance neuroblastoma are driven by phenotypic plasticity heterogeneity between noradrenergic (NOR) mesenchymal (MES) cell states. Despite importance this plasticity, dynamics molecular patterns associated with these bidirectional cell-state transitions remain relatively poorly understood. Here, we analyze multiple RNA-seq datasets at both bulk single-cell resolution, understand association NOR- MES-specific factors. We observed that NOR-specific expression largely mutually exclusive, exhibiting a "teams-like" behavior among genes involved, reminiscent our earlier observations lung cancer melanoma. This antagonism NOR MES phenotypes was also metabolic reprogramming immunotherapy targets PD-L1 GD2 as well experimental perturbations driving NOR-MES and/or MES-NOR transition. Further, were seen only genes, but not housekeeping possibly highlighting hallmark network topology enabling plasticity.

Язык: Английский

Immunosuppressive Traits of the Hybrid Epithelial/Mesenchymal Phenotype DOI Creative Commons
Sarthak Sahoo, Sonali Nayak, Kishore Hari

и другие.

Frontiers in Immunology, Год журнала: 2021, Номер 12

Опубликована: Дек. 15, 2021

Recent preclinical and clinical data suggests enhanced metastatic fitness of hybrid epithelial/mesenchymal (E/M) phenotypes, but mechanistic details regarding their survival strategies during metastasis remain unclear. Here, we investigate immune-evasive E/M states. We construct simulate the dynamics a minimalistic regulatory network encompassing known associations among regulators EMT (epithelial-mesenchymal transition) PD-L1, an established immune-suppressor. Our simulations for consisting SLUG, ZEB1, miR-200, CDH1 integrated with single-cell bulk RNA-seq analysis, elucidate that cells can have high levels similar to those seen in full phenotype, thus obviating need cancer undergo be immune-evasive. Specifically, breast cancer, show co-existence resistance anti-estrogen therapy increased PD-L1 levels. results underscore how emergent interconnected networks coordinate different axes cellular metastasis.

Язык: Английский

Процитировано

61
Landscape of epithelial–mesenchymal plasticity as an emergent property of coordinated teams in regulatory networks DOI Creative Commons
Kishore Hari,

Varun Ullanat,

Archana Balasubramanian

и другие.

eLife, Год журнала: 2022, Номер 11

Опубликована: Окт. 21, 2022

Elucidating the design principles of regulatory networks driving cellular decision-making has fundamental implications in mapping and eventually controlling cell-fate decisions. Despite being complex, these often only give rise to a few phenotypes. Previously, we identified two 'teams' nodes small cell lung cancer network that constrained phenotypic repertoire aligned strongly with dominant phenotypes obtained from simulations (Chauhan et al., 2021). However, it remained elusive whether exist other networks, how do they shape landscape. Here, demonstrate five different varying sizes governing epithelial-mesenchymal plasticity comprised players - one canonical drivers epithelial phenotype containing mesenchymal inducers. These are specific topology orchestrate bimodal landscape more frequent dynamically robust perturbations, relative intermediary/hybrid epithelial/mesenchymal ones. Our analysis reveals alone can contain information about corresponding distributions, thus obviating need simulate them. We propose as principle drive canalization diverse processes.

Язык: Английский

Процитировано

53
Killing SCLC: insights into how to target a shapeshifting tumor DOI Open Access
Kate D. Sutherland, Abbie S. Ireland, Trudy G. Oliver

и другие.

Genes & Development, Год журнала: 2022, Номер 36(5-6), С. 241 - 258

Опубликована: Март 1, 2022

Small cell lung cancer (SCLC) is a rapidly growing, highly metastatic, and relatively immune-cold subtype. Historically viewed in the laboratory clinic as single disease, new discoveries suggest that SCLC comprises multiple molecular subsets. Expression of MYC family members lineage-related transcription factors ASCL1, NEUROD1, POU2F3 (and, some studies, YAP1) define unique states have been associated with distinct responses to variety therapies. However, tumors exhibit high degree intratumoral heterogeneity, recent studies suggesting existence tumor plasticity phenotypic switching between subtype states. While correlated with, likely drives, therapeutic resistance, mechanisms underlying this are still largely unknown. Subtype also immune-related gene expression, which impacts response immune checkpoint blockade may reveal novel targets for alternative immunotherapeutic approaches. In review, we synthesize on how these processes impinge antitumor immunity.

Язык: Английский

Процитировано

52
City2vec: Urban knowledge discovery based on population mobile network DOI
Yan Zhang, Xiang Zheng, Marco Helbich

и другие.

Sustainable Cities and Society, Год журнала: 2022, Номер 85, С. 104000 - 104000

Опубликована: Июль 13, 2022

Язык: Английский

Процитировано

32
Unraveling non-genetic heterogeneity in cancer with dynamical models and computational tools DOI
Maalavika Pillai, Emilia Hojel, Mohit Kumar Jolly

и другие.

Nature Computational Science, Год журнала: 2023, Номер 3(4), С. 301 - 313

Опубликована: Апрель 24, 2023

Язык: Английский

Процитировано

23
Mapping Spatiotemporal Heterogeneity in Tumor Profiles by Integrating High-Throughput Imaging and Omics Analysis DOI Creative Commons

Pooja Annasaheb Patkulkar,

Ayalur Raghu Subbalakshmi,

Mohit Kumar Jolly

и другие.

ACS Omega, Год журнала: 2023, Номер 8(7), С. 6126 - 6138

Опубликована: Фев. 7, 2023

Intratumoral heterogeneity associates with more aggressive disease progression and worse patient outcomes. Understanding the reasons enabling emergence of such remains incomplete, which restricts our ability to manage it from a therapeutic perspective. Technological advancements as high-throughput molecular imaging, single-cell omics, spatial transcriptomics allow recording patterns spatiotemporal in longitudinal manner, thus offering insights into multiscale dynamics its evolution. Here, we review latest technological trends biological diagnostics well transcriptomics, both have witnessed burgeoning growth recent past terms mapping within tumor cell types stromal constitution. We also discuss ongoing challenges, indicating possible ways integrate across these methods systems-level map each systematic investigation implications for

Язык: Английский

Процитировано

18
Amino Acids Frequency and Interaction Trends: Comprehensive Analysis of Experimentally Validated Viral Antigen–Antibody Complexes DOI

Roylan Pais,

Anil Kumar Nagraj,

Riya Patel

и другие.

Molecular Biotechnology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 8, 2025

Язык: Английский

Процитировано

1
Systems-level network modeling deciphers the master regulators of phenotypic plasticity and heterogeneity in melanoma DOI Creative Commons
Maalavika Pillai, Mohit Kumar Jolly

iScience, Год журнала: 2021, Номер 24(10), С. 103111 - 103111

Опубликована: Сен. 9, 2021

Phenotypic (i.e. non-genetic) heterogeneity in melanoma drives dedifferentiation, recalcitrance to targeted therapy and immunotherapy, consequent tumor relapse metastasis. Various markers or regulators associated with distinct phenotypes have been identified, but, how does a network of interactions among these give rise multiple "attractor" states phenotypic switching remains elusive. Here, we inferred transcription factors (TFs) that act as master for gene signatures diverse cell-states melanoma. Dynamical simulations this predicted can settle into different "attractors" (TF expression patterns), suggesting TF dynamics the emergence heterogeneity. These recapitulate major observed explain de-differentiation trajectory upon BRAF inhibition. Our systems-level modeling framework offers platform understand trajectories transitions landscape regulatory identify novel therapeutic strategies targeting plasticity.

Язык: Английский

Процитировано

34
Increased prevalence of hybrid epithelial/mesenchymal state and enhanced phenotypic heterogeneity in basal breast cancer DOI Creative Commons
Sarthak Sahoo,

Soundharya Ramu,

Madhumathy G Nair

и другие.

iScience, Год журнала: 2024, Номер 27(7), С. 110116 - 110116

Опубликована: Май 27, 2024

Highlights•Luminal signature is closely associated with epithelial in breast cancer•Basal correlates well a hybrid epithelial-mesenchymal signature•Basal cancer exhibits higher heterogeneity patterns•Mathematical modeling of underlying gene networks explains observed heterogeneitySummaryIntra-tumoral phenotypic promotes tumor relapse and therapeutic resistance remains an unsolved clinical challenge. Decoding the interconnections among different biological axes plasticity crucial to understand molecular origins heterogeneity. Here, we use multi-modal transcriptomic data—bulk, single-cell, spatial transcriptomics—from cell lines primary samples, identify associations between transition (EMT) luminal-basal plasticity—two key processes that enable We show luminal strongly associates state, but basal epithelial/mesenchymal phenotype(s) Mathematical core regulatory representative crosstalk elucidate mechanistic underpinnings from data. Our systems-based approach integrating data analysis mechanism-based offers predictive framework characterize intra-tumor interventions restrict it.Graphical abstract

Язык: Английский

Процитировано

6
KLF4 Induces Mesenchymal–Epithelial Transition (MET) by Suppressing Multiple EMT-Inducing Transcription Factors DOI Open Access

Ayalur Raghu Subbalakshmi,

Sarthak Sahoo, Isabelle McMullen

и другие.

Cancers, Год журнала: 2021, Номер 13(20), С. 5135 - 5135

Опубликована: Окт. 13, 2021

Epithelial-Mesenchymal Plasticity (EMP) refers to reversible dynamic processes where cells can transition from epithelial mesenchymal (EMT) or (MET) phenotypes. Both these are modulated by multiple transcription factors acting in concert. While EMT-inducing (TFs)-TWIST1/2, ZEB1/2, SNAIL1/2/3, GSC, and FOXC2-are well-characterized, the MET-inducing TFs relatively poorly understood (OVOL1/2 GRHL1/2). Here, using mechanism-based mathematical modeling, we show that factor KLF4 delay onset of EMT suppressing EMT-TFs. Our simulations suggest overexpression promote a phenotypic shift toward more state, an observation suggested negative correlation with EMT-TFs transcriptomic-based scoring metrics cancer cell lines. We also influence modulating dynamics be strengthened its ability inhibit cell-state transitions at epigenetic level. Thus, through parallel paths act as putative MET-TF. associates patient survival across cancers context-specific manner, highlighting complex association EMP survival.

Язык: Английский

Процитировано

29