Biology subjects

Dhawan, A.

Publications and source records attributed to Dhawan, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Serum IgM crosslinks hepatitis B subviral particles into supramolecular immune complexes

Hepatitis B virus (HBV)-infected cells release hepatitis B surface antigen (HBsAg)-rich subviral particles (SVPs) in large excess over infectious virions. SVPs bind antibodies against HBsAg (anti-HBs), including neutralizing antibodies, but the physical products of antibody capture in human blood are uncharacterized. Here we used cryo-electron tomography (cryo-ET) to image HBsAg-enriched serum from a patient with severe acute Hepatitis B and observed three-dimensional assemblies of intact IgM-SVP immune complexes. These associations persisted at a lower particle density and were validated by a spatial-randomization null model. Subtomogram averaging and single-particle cryo-electron microscopy (cryo-EM) identified three serum IgM Fc-core assemblies, IgM-J-CD5L, IgM-J and IgM-J-SC, with cryo-EM maps reaching 2.8 angstrom resolution. Mapping these Fc core assemblies into tomograms revealed full-length IgM engaging individual SVPs through several Fab arms and bridging neighboring particles into immune complex networks containing multiple IgM molecules and SVPs. Thus, serum IgM uses multivalent Fab interactions to crosslink HBsAg-rich SVPs into supramolecular immune complexes. This observation extends the SVP decoy model from passive antibody sequestration to higher-order particle organization.

molecular biology↗

bioRxiv2025

Extensive and differential platinum chemotherapy mutagenesis in children

Childhood cancer survivors often develop long-term adverse effects, which may be caused by direct mutagenesis of cytotoxic agents. Some of these agents generate distinctive DNA imprints (mutational signatures), as exemplified by platinum chemotherapeutics. Here, we examined chemotherapy mutagenesis in paediatric tissues by deploying a duplex sequencing method (NanoSeq), which enables mutation calling from single DNA molecules. We surveyed whole genomes of paediatric liver, blood and other tissues, obtained from surgical resections and at post-mortem. Platinum signatures pervaded all tissues extensively, elevating mutation burdens of paediatric tissues to levels seen in adults. Remarkably, we found a tissue-specific mutational signature in the liver. We examined the functional potential of mutations by gene focused NanoSeq, which revealed that platinum agents cause a vast repertoire of cancer causing variants across normal tissues, such as leukaemogenic mutations in blood. This finding may conceivably link cancer treatment in childhood to mutation-driven long term sequelae.

cancer biology↗

bioRxiv2025

Context-Dependent miRNA Regulatory Landscapes in Breast Cancer Uncovered by Network Community Structure

MicroRNAs (miRNAs) regulate gene expression through many-to-many interactions that are cooperative, context-dependent, and challenging to interpret from individual miRNA-target pairs alone. Yet, no framework simultaneously captures the cooperative, systems-level, and context-specific dimensions of miRNA regulation across the heterogeneous subtypes of a breast cancer. Here, we integrated paired miRNA and mRNA expression profiles from 1,161 breast cancers from The Cancer Genome Atlas (TCGA) with experimentally validated miRNA-target interactions and protein interaction networks to define cooperative miRNA regulatory modules in breast cancer. Community-resolved analysis of the resulting networks identified 16 functionally coherent miRNA modules associated with core cancer processes. To capture pathway-level network context beyond direct targets, we quantified the proximity of miRNA target sets to pathway proteins within a breast cancer-specific protein interaction network. This framework identified cooperative miRNA modules associated with cell cycle progression, DNA repair, PTEN/TP53-related signaling, and epithelial-mesenchymal transition. Subtype-resolved network analysis further showed that most inferred miRNA functions are strongly context dependent, not being associated in all of basal-like, HER2-enriched, luminal A, and luminal B tumors. In contrast, a limited set of pathway-level associations was conserved across subtypes. Among these, the miR-29 family (miR-29a/b/c-3p) emerged as a consistent regulator of collagen remodeling, extracellular matrix organization, PDGF signaling, and EMT. Notably, this functional conservation persisted despite subtype-specific variation in the underlying target genes. Together, these results define the cooperative miRNA modules that post-transcriptional regulate breast cancer subtypes, identify the miR-29 family as a candidate pan-subtype therapeutic target for EMT-driven metastasis, and establish a generalizable computational framework for resolving miRNA programs across heterogeneous cancers.

cancer biology↗

bioRxiv2025

Platelets drive immune suppression and glioblastoma growth in a sex-dependent manner via PAR4 signaling

Sex differences in cancer outcome, including that of glioblastoma (GBM), are shaped by biological, hormonal, and immunological factors and impact disease progression, treatment responses, survival, and tumor microenvironment (TME) interactions. Platelets regulate the immune responses and tumor progression in many cancers, but it is not clear how they contribute to these sex-based differences by affecting the dynamics of the TME. Here, we show that GBM patients exhibit heightened platelet reactivity driven by PAR4 signaling. In murine GBM models, both pharmacological inhibition of PAR4 using BMS986120 and genetic deletion of PAR4 significantly prolong survival in females but not males. This survival advantage is estrogen dependent: it is preserved in chromosomal male-hormonal female mice within the four-core genotype model and is rescued in ovariectomized mice treated with estrogen. The survival benefit is TME specific and is mediated by platelet-driven enhancement of CD8 T cell infiltration into the tumor. Inhibition of platelet PAR4 signaling increases calcium signaling through an estrogen-dependent interaction between PAR4 and estrogen receptor {beta} (ER{beta})--a receptor interaction not previously described. PAR4-activated platelets within the TME suppress CD8 T cell function, and depletion of CD8 T cells abolishes both the tumor-induced platelet reactivity and the survival benefit conferred by PAR4 inhibition. These findings establish platelet-mediated PAR4 signaling as a critical driver of tumor progression and identify sex-specific immune responses as key to therapeutic efficacy.

cancer biology↗

bioRxiv2025

Astrocyte reprogramming drives tumor progression and chemotherapy resistance in agent-based models of breast cancer brain metastases

Breast cancer brain metastases (BCBM) affect nearly 90,000 patients annually in the United States and carry a significant risk of mortality. As metastatic lesions develop, the unique milieu of the brain microenvironment shapes disease progression and therapeutic response. Among resident brain cells, astrocytes are both the most common, and are increasingly recognized as key regulators of this process, yet their precise role remains poorly defined. Here, we present a hybrid agent-based model (ABM) to simulate tumor-astrocyte interactions on a two-dimensional lattice. In our model, metastatic tumor cells induce phenotypic reprogramming of astrocytes from an antito a pro-metastatic state, thereby enhancing tumor proliferation. We systematically evaluate how variations in astrocyte density, spatial distribution, and chemotherapy impact tumor expansion and spatial morphology, quantified by fractal dimension, lacunarity, and eccentricity. Our simulations reveal that astrocyte reprogramming accelerates tumor progression and contributes to increased morphological complexity and chemotherapeutic resistance.

cancer biology↗

bioRxiv2025

The mutational landscape defines the proteome and spatial organization of tumor, stroma and immune cells in ovarian cancer

High-grade serous ovarian cancer (HGSOC) is a highly aggressive and lethal form of ovarian cancer. Challenges to diagnosis and treatment include a lack of effective screening methods for early detection, the absence of cancer-specific symptoms, and the development of chemoresistance. The genomic instability of HGSOC, further complicated by homologous recombination deficiency (HRD), leads to heterogeneity in HGSOC tumors and patient response to treatment. This makes it challenging to develop a single, effective diagnostic and treatment approach for this disease. Proteogenomic studies have provided some insight into HGSOC biology, but a deeper understanding of the tumor proteome through chemotherapy and disease recurrence is needed. Here we have profiled the proteome of tumors from 29 HGSOC patients before and after multiple rounds of chemotherapy. The proteome of HGSOC tumors remained unchanged for individual patients even after numerous rounds of chemotherapy. Differential expression analysis revealed known and novel proteins associated with chemoresistance and HRD status, further supported by similar changes at the genetic and epigenetic levels. We found that HRD affected proteins related to immune pathways. HRD was also associated with more shared T cell receptor (TCR) CDR3 repertoires of tumor-infiltrating T cells and increased neoantigen counts. ERAP1, a protein involved in peptide trimming before antigen presentation to immune cells via MHC-class I, was overexpressed in homologous recombination proficient (HRP) tumors and negatively correlated to neoantigen count. Its potential role in immune suppression in HRP tumors makes it an attractive therapeutic target that may be effective in combination with immunotherapy, particularly for HRP tumors. 26-plex immunostaining of HGSOC whole tissues further revealed significant differences in the spatial proximities of immune cells to each other and to tumor cells based on HRD status. Through proteomic and imaging analysis, this work has shown that the immune landscape of HGSOC tumors is influenced by homologous recombination status and identified candidate drivers of HGSOC biology.

cancer biology↗

bioRxiv2025

Female Anterior Cruciate Ligaments Exhibit a Muted Mechanobiological Response to Mechanical Loading

Female athletes are significantly more likely to tear their anterior cruciate ligament (ACL) compared to their male counterparts. While there are several potential reasons for this, previous data from our lab demonstrated that female ACL explants have an impaired remodeling response to loading, which may prevent the repair of fatigue damage and lead to increased ACL rupture. The objective of this study was to identify the mechanisms driving the impaired remodeling of female ACLs to cyclic loading, including the role of estrogen. ACLs were harvested from male and female New Zealand white rabbits and cyclically loaded in a tensile bioreactor followed by bulk RNA-sequencing. Additional ACL explants treated with or without estradiol were analyzed using RT-qPCR to determine the regulatory effect of estrogen on markers for tissue remodeling and inflammatory cytokines with cyclic loading. We found that female ACLs exhibited significantly fewer differentially expressed genes (DEGs) in response to loading compared to male ACLs. Additionally, multiple mechanotransduction pathways were enriched with loading only in the male ACLs. While a few estrogen-related pathways were enriched in both male and female ACLs with loading, the expression of tissue remodeling markers was not different between estrogen treatment and vehicle control. Together, our findings highlight specific mechanotransduction pathways that may be responsible for the muted biological response of female ACLs to load, which provides a potential explanation for the increased rate of ACL tears in women.

bioengineering↗

bioRxiv2024

Homologous recombination promotes mitotic death to suppress the innate immune response

Double strand breaks (DSBs) can initiate mitotic catastrophe, a complex oncosuppressive phenomenon characterized by cell death during or after cell division. Through single-cell analysis of extended live imaging, we unveiled how cell cycle-regulated DSB repair guides disparate mitotic catastrophe outcomes. Our data reveal that toxic double Holliday junctions (dHjs) generated during homologous recombination (HR) promote non-immunogenic intrinsic apoptosis in the immediate mitosis after S or G2-phase DSB induction. Conversely, the combined activity of non-homologous end joining (NHEJ), microhomology mediated end joining (MMEJ), and single strand annealing (SSA) enable G1 phase cells to tolerate high DSB loads at the cost of aberrant cell division, innate immune response activation and delayed extrinsic lethality. Targeting NHEJ, MMEJ, or SSA promotes HR-dependent mitotic death, while suppressing mitotic death fosters a robust immunogenic response. Together the data indicate that a temporal repair hierarchy, coupled with cumulative DSB load, serves as a reliable predictor of mitotic catastrophe outcomes. In this pathway, HR suppress the innate immune response by promoting mitotic lethality.

cell biology↗

bioRxiv2024

Allograft and Autograft Anterior Cruciate Ligament Reconstructions Exhibit a Similar Biological Response to Cyclic Loading

ObjectiveAnterior cruciate ligament (ACL) reconstruction is one of the most commonly performed orthopaedic procedures. While outcomes are similar in the general patient population, the rerupture rate of non-irradiated allografts are 3-4 times higher than autografts in young active individuals. Previous studies suggest that the difference in clinical performance between graft types is due to impaired remodeling in allografts in response to loading. The objective of this study was to compare the remodeling response of autografts and allografts to cyclic loading. Furthermore, given that allografts are a foreign object and that immune cell signaling affects fibroblast mechanobiology, we compared markers of the immune cell composition between graft types. MethodsACL reconstructions were performed on New Zealand white rabbits, harvested 8 weeks post-surgery, and cyclically loaded to 2 MPa in a tensile bioreactor. Expression of markers for anabolic and catabolic tissue remodeling, as well as inflammatory cytokines and immune cells, were quantified using quantitative reverse transcription polymerase chain reaction. ResultsWe found that the expression of markers for tissue remodeling were not different between allografts and autografts. Similarly, we found that the expression of markers for immune cells were not different between allografts and autografts. ConclusionsThese data suggest that the poor clinical outcomes and impaired remodeling of allograft reconstructions compared to autografts is not due to a difference in graft mechanobiology.

bioengineering↗

bioRxiv2024

miR-644a is a tumor cell-intrinsic mediator of sex bias in glioblastoma

BackgroundBiological sex is an important risk factor for glioblastoma (GBM), with males having a higher incidence and poorer prognosis. The mechanisms for this sex bias are thought to be both tumor intrinsic and tumor extrinsic. MicroRNAs (miRNAs), key post-transcriptional regulators of gene expression, have been previously linked to sex differences in various cell types and diseases, but their role in the sex bias of GBM remains unknown. MethodsWe leveraged previously published paired miRNA and mRNA sequencing of 39 GBM patients (22 male, 17 female) to identify sex-biased miRNAs. We further interrogated a separate single-cell RNA sequencing dataset of 110 GBM patients to examine whether differences in miRNA target gene expression were tumor cell intrinsic or tumor cell extrinsic. Results were validated in a panel of patient-derived cell models. ResultsWe identified 10 sex-biased miRNAs (adjusted < 0.1), of which 3 were more highly expressed in males and 7 more highly expressed in females. Of these, miR-644a was higher in females, and increased expression of miR-644a target genes was significantly associated with decreased overall survival (HR 1.3, p = 0.02). Furthermore, analysis of an independent single-cell RNA sequencing dataset confirmed sex-specific expression of miR-644a target genes in tumor cells (p < 10-15). Among patient derived models, miR-644a was expressed a median of 4.8-fold higher in females compared to males. ConclusionsOur findings implicate miR-644a as a candidate tumor cell-intrinsic regulator of sex-biased gene expression in GBM. Key PointsO_LImiR-644a is more highly expressed in female GBM patients. C_LIO_LILower miR-644a target gene expression is associated with improved overall survival. C_LIO_LImiR-644a target genes are higher in male GBM cells but not in other cell types. C_LI Importance of the StudyMicroRNAs (miRNAs) are non-coding RNAs that regulate gene expression at the post-transcriptional level and were previously linked to glioblastoma (GBM) growth and therapeutic resistance. miRNAs play a role in the sex bias of various cell types and diseases, but how miRNAs contribute to sex differences in GBM is not well elucidated. We show that 10 miRNAs are differentially expressed between males and females and identify miR-644a as more highly expressed in female GBM patients. Using single-cell RNA-seq data, we demonstrate that sex differences in miR-644a target gene expression are tumor cell-intrinsic. Likewise, decreased miR-644a target gene expression is associated with improved overall patient survival. Our findings reveal miR-644a as a novel sex-biased miRNA in GBM, and a possible target for sex-specific precision therapies with limited collateral damage.

cancer biology↗

bioRxiv2023

Brain Connectivity Changes in Meditators and Novices during Yoga Nidra: A Novel fMRI Study

Yoga Nidra practice aims to induce a deeply relaxed state akin to sleep while maintaining heightened awareness. Despite the growing interest in its clinical applications, a comprehensive understanding of the underlying neural correlates of the practice of Yoga Nidra (YN) remains largely unexplored. In this novel fMRI investigation, we aim to discover the differences between wakeful resting states and states attained during YN practice. The study included individuals experienced in meditation and/or yogic practices, referred to as meditators (n=30), and novice controls (n=31). The GLM analysis, based on audio instructions, demonstrated activation related to auditory cues without concurrent Default Mode Network (DMN) deactivation. Additionally, meditators exhibited heightened bilateral thalamic activation compared to novices. DMN seed based Functional connectivity (FC) analysis revealed significant reductions in connectivity among meditators during YN as compared to controls. We did not find differences between the two groups during the pre and post resting state scans. Moreover, when DMN-FC was compared between the YN state and resting state, meditators showed distinct decoupling, whereas controls showed increased DMN-FC. Finally, meditators exhibit a remarkable correlation between reduced DMN connectivity during Yoga Nidra and self-reported hours of cumulative meditation and yoga practice. Together, these results suggest a unique neural modulation of the DMN in meditators during Yoga Nidra which results in being restful yet aware, aligned with their subjective experience of the practice. The study deepens our understanding of the neural mechanisms of Yoga Nidra, revealing distinct DMN connectivity decoupling in meditators and its relationship with meditation and yoga experience. These findings have interdisciplinary implications for neuroscience, psychology, and yogic disciplines.

neuroscience↗

bioRxiv2022

Cyclic Loading Induces Anabolic and Catabolic Gene Expression in ACLs in a Load-Dependent and Sex-Specific Manner

Anterior cruciate ligament (ACL) injuries are historically thought to be a result of a single acute overload or traumatic event. However, recent studies suggest that ACL failure may be a consequence of fatigue damage. Additionally, the remodeling response of ACLs to fatigue loading is unknown. Therefore, the objective of this study was to investigate the remodeling response of ACLs to cyclic loading. Furthermore, given that women have an increased rate of ACL rupture, we investigated whether this remodeling response is sex specific. ACLs were harvested from male and female New Zealand white rabbits and cyclically loaded in a tensile bioreactor mimicking the full range of physiological loading (2, 4, and 8 MPa). Expression of markers for anabolic and catabolic tissue remodeling, as well as inflammatory cytokines, was quantified using RT-qPCR. We found that the expression of markers for tissue remodeling of the ACL is dependent on the magnitude of loading and is sex specific. Male ACLs activated a tissue remodeling response to cyclic loading below 4 MPa loads but turned off remodeling at 8 MPa. These data support the hypothesis that noncontact ACL injury is a consequence of failed tissue remodeling and inadequate repair of microtrauma resulting from fatigue loading. Conversely, female ACLs downregulate genes responsible for tissue remodeling in response to cyclic loading at all magnitudes, which may explain the increased rate of ACL tears in women. Together, these data provide insight into the remodeling response of ACLs in vivo and potentially offer novel approaches for preventing ACL rupture.

bioengineering↗

bioRxiv2022

FAK drives resistance to therapy in HPV-negative head and neck cancer in a p53-dependent manner.

Radiation and platinum-based chemotherapy form the backbone of therapy in HPV-negative head and neck squamous cell carcinoma (HNSCC). We have correlated focal adhesion kinase (FAK/PTK2) expression with radioresistance and worse outcome in these patients. However, the importance of FAK in driving radioresistance and its effects on chemoresistance in these patients remain unclear. We performed an in vivo shRNA screen using targetable libraries to address these questions and identified FAK as an excellent target for both radio- and chemosensitization. Because TP53 is mutated in over 80% of HPV-negative HNSCC, we hypothesized that mutant TP53 may facilitate FAK-mediated therapy resistance. FAK inhibitor increased sensitivity to radiation, increased DNA damage and repressed homologous recombination and non-homologous end joining repair in mutant, but not wild-type, TP53 HPV-negative HNSCC cell lines. Mutant TP53 cisplatin-resistant cell line had increased FAK phosphorylation compared to wild-type, and FAK inhibition partially reversed cisplatin resistance. To validate these findings, we utilized a HNSCC cohort to show that FAK copy number and gene expression were associated with worse disease-free survival in mutant TP53, but not wild-type TP53, HPV-negative HNSCC tumors. Thus, FAK may represent a targetable therapeutic sensitizer linked to a known genomic marker of resistance.

cancer biology↗

bioRxiv2021

Dicer-to-Argonaute switch controls biogenesis of oncogenic miRNA

miRNAs are post-transcriptional regulators of gene expression, controlling biological processes from development to pathogenesis. We asked whether the reshaped functional miRNA landscape in cancers is driven by altered transcription of its precursors, or altered biogenesis and maturation of miRNAs. Integrated analysis of genomic and transcriptomic data in 9,111 samples across 10 cancer types and healthy tissues revealed a recurrent genomic switch from DICER-dependent to non-canonical Argonaute-mediated, DICER-independent, miRNA biogenesis. Experimental validation in AGO2-amplified clinical samples and cancer cell lines confirmed that canonical miRNAs can undergo maturation in a DICER-independent manner, and that elevated Argonaute levels promote selective maturation of the oncogenic miR-106b/25 cluster as shown by the altered ratio of mature miRNA to immature pri-miRNA levels. The preferential maturation of these oncogenic miRNAs, whose processing bypasses DICER1, promotes cancer progression and predicts poor prognosis. This highlights the evolution of non-canonical AGO2-dependent oncomiR processing as a novel driver pathway in cancer.

genomics↗

bioRxiv2021

Acetyl-CoA metabolism drives epigenome change and contributes to carcinogenesis risk in fatty liver disease

The rate of nonalcoholic fatty liver disease (NAFLD)-associated hepatocellular carcinoma (HCC) is increasing worldwide, but the steps in precancerous hepatocytes which lead to HCC driver mutations are not well understood. Here we provide evidence that metabolically-driven histone hyperacetylation in steatotic hepatocytes can increase DNA damage to initiate carcinogenesis. Genome-wide histone acetylation is increased in steatotic livers of rodents fed high fructose or high fat diet. In vitro, steatosis relaxes chromatin and increases DNA damage marker {gamma}H2AX, which is reversed by inhibiting acetyl-CoA production. Steatosis-associated acetylation and {gamma}H2AX are enriched at gene clusters in telomere-proximal regions which contain HCC tumor suppressors in hepatocytes and human fatty livers. Regions of metabolically-driven epigenetic change also have increased levels of DNA mutation in non-cancerous tissue from NAFLD patients. Finally, genome-scale network modelling indicates that redox balance is a key contributor to this mechanism. Thus abnormal histone hyperacetylation is a potential initiating event in HCC carcinogenesis.

cancer biology↗

bioRxiv2020

Identifying states of collateral sensitivity during the evolution of therapeutic resistance in Ewings sarcoma

Advances in the treatment of Ewings sarcoma (EWS) are desperately needed, particularly in the case of metastatic disease. A deeper understanding of collateral sensitivity, where the evolution of therapeutic resistance to one drug aligns with sensitivity to another drug, may improve our ability to effectively target this disease. For the first time in a solid tumor, we produced a temporal collateral sensitivity map that demonstrates the evolution of collateral sensitivity and resistance in EWS. We found that the evolution of collateral resistance was predictable with some drugs, but had significant variation in response to other drugs. Using this map of temporal collateral sensitivity in EWS, we can see that the path towards collateral sensitivity is not always repeatable, nor is there always a clear trajectory towards resistance or sensitivity. Identifying transcriptomic changes that accompany these states of transient collateral sensitivity could improve treatment planning for EWS patients.

evolutionary biology↗

bioRxiv2019

Network potential identifies therapeutic miRNA cocktails in Ewings Sarcoma

MicroRNA (miRNA)-based therapies are an emerging class of targeted therapeutics with many potential applications. Ewing Sarcoma patients could benefit dramatically from personalized miRNA therapy due to inter-patient heterogeneity and a lack of druggable (to this point) targets. However, because of the broad effects miRNAs may have on different cells and tissues, trials of miRNA therapies have struggled due to severe toxicity and unanticipated immune response. In order to overcome this hurdle, a network science-based approach is well-equipped to evaluate and identify miRNA candidates and combinations of candidates for the repression of key oncogenic targets while avoiding repression of essential housekeeping genes. We first characterized 6 Ewing sarcoma cell lines using mRNA sequencing. We then estimated a measure of tumor state, which we term network potential, based on both the mRNA gene expression and the underlying protein-protein interaction network in the tumor. Next, we ranked mRNA targets based on their contribution to network potential. We then identified miRNAs and combinations of miRNAs that preferentially act to repress mRNA targets with the greatest influence on network potential. Our analysis identified TRIM25, APP, ELAV1, RNF4, and HNRNPL as ideal mRNA targets for Ewing sarcoma therapy. Using predicted miRNA-mRNA target mappings, we identified miR-3613-3p, let-7a-3p, miR-300, miR-424-5p, and let-7b-3p as candidate optimal miRNAs for preferential repression of these targets. Ultimately, our work, as exemplified in the case of Ewing sarcoma, describes a novel pipeline by which personalized miRNA cocktails can be designed to maximally perturb gene networks contributing to cancer progression. Author SummaryPrecision medicine in cancer aims to find the right treatment, for the right patient, at the right time. Substantial variation between patient tumors, even of the same disease site, has limited the application of precision medicine in the clinic. In this study, we present novel computational tools for the identification of targets for cancer therapy using widely available sequencing data. We used a network-science based approach that leveraged multiple types of omic data to identify functionally relevant disease targets. Further, we developed algorithms to identify potential miRNA-based therapies that inhibit these predicted disease targets. We applied this pipeline to a novel Ewing Sarcoma transcriptomics data-set as well as publicly available patient data from the St. Jude Cloud. We identified a number of promising therapeutic targets for this rare disease, including EWSR1, the proposed driver of Ewing Sarcoma development. These novel data and methods will provide researchers with new tools for the development of precision medicine treatments in a variety of cancer systems.

systems biology↗

bioRxiv2018

Resistance to ALK targeting therapies as a gradual Darwinian adaptation to inhibitor specific selective pressures

Despite high initial efficacy, therapies that target oncogenic kinases eventually fail in advanced, metastatic cancers. This failure in initially responsive tumors is the direct result of the evolution of drug resistance under therapy-imposed selective pressures. In contrast to the massive body of experimental research on the molecular mechanisms of resistance, understanding of its evolutionary origins and dynamics remains fragmented. Using a combination of experimental studies and mathematical modeling, we sought to dissect the evolution of resistance to different clinical ALK inhibitors in an experimental model of ALK positive NSCLC. We found that resistance can originate from heterogeneous, weakly resistant, sub-populations with variable sensitivity to different ALK inhibitors. Instead of the commonly assumed stochastic single hit (epi) mutational transition, or drug-induced reprogramming, we found evidence of a hybrid scenario, of gradual, multifactorial development through acquisition of multiple cooperating genetic and epigenetic adaptive changes, amplified by selection. Additionally, we found that intermediate resistance phenotypes might present unique, temporally restricted collateral sensitivities, absent in therapy naive or fully resistant cells, suggesting new opportunities for therapeutic interference.

cancer biology↗