Publications by authors named "Shawna Hubert"

12 Publications

  • Page 1 of 1

Activation of PI3K/AKT Pathway Is a Potential Mechanism of Treatment Resistance in Small Cell Lung Cancer.

Clin Cancer Res 2021 Dec 17. Epub 2021 Dec 17.

Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China.

Purpose: Here, we have investigated treatment resistance mechanisms in small cell lung cancer (SCLC) by focusing on comparing the genotype and phenotype in tumor samples of treatment-resistant and treatment-sensitive SCLC.

Methods: We conducted whole-exome sequencing on paired tumor samples at diagnosis and relapse from 11 patients with limited-stage (LS)-SCLC and targeted sequencing of 1,021 cancer-related genes on cell-free DNA at baseline and paired relapsed samples from 9 additional patients with LS-SCLC. Furthermore, we performed label-free mass spectrometry-based proteomics on tumor samples from 28 chemo-resistant and 23 chemo-sensitive patients with extensive-stage (ES)-SCLC. The main findings were validated in chemo-sensitive versus chemo-resistant SCLC cell lines and analyses of transcriptomic data of SCLC cell lines from a public database.

Results: Genomic analyses demonstrated that at relapse of LS-SCLC, genes in the PI3K/AKT signaling pathway were enriched for acquired somatic mutations or high-frequency acquired copy-number variants. Pathway analysis on differentially upregulated proteins from ES-SCLC cohort revealed enrichment in the HIF-1 signaling pathway. Importantly, 7 of 62 PI3K/AKT pathway genes containing acquired somatic copy-number amplifications were enriched in HIF-1 pathway. Analyses of transcriptomic data of SCLC cell lines from public databases confirmed upregulation of PI3K/AKT and HIF-1 pathways in chemo-resistant SCLC cell lines. Furthermore, chemotherapy-resistant cell lines could be sensitive to PI3K inhibitors .

Conclusions: PI3K/AKT pathway activation may be one potential mechanism underlying therapeutic resistance of SCLC. This finding warrants further investigation and provides a possible approach to reverse resistance to chemo/radiotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-21-1943DOI Listing
December 2021

The histologic phenotype of lung cancers is associated with transcriptomic features rather than genomic characteristics.

Nat Commun 2021 12 6;12(1):7081. Epub 2021 Dec 6.

Department of Genomic Medicine, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.

Histology plays an essential role in therapeutic decision-making for lung cancer patients. However, the molecular determinants of lung cancer histology are largely unknown. We conduct whole-exome sequencing and microarray profiling on 19 micro-dissected tumor regions of different histologic subtypes from 9 patients with lung cancers of mixed histology. A median of 68.9% of point mutations and 83% of copy number aberrations are shared between different histologic components within the same tumors. Furthermore, different histologic components within the tumors demonstrate similar subclonal architecture. On the other hand, transcriptomic profiling reveals shared pathways between the same histologic subtypes from different patients, which is supported by the analyses of the transcriptomic data from 141 cell lines and 343 lung cancers of different histologic subtypes. These data derived from mixed histologic subtypes in the setting of identical genetic background and exposure history support that the histologic fate of lung cancer cells is associated with transcriptomic features rather than the genomic profiles in most tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-27341-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8648877PMC
December 2021

Cold and heterogeneous T cell repertoire is associated with copy number aberrations and loss of immune genes in small-cell lung cancer.

Nat Commun 2021 11 17;12(1):6655. Epub 2021 Nov 17.

Department of Thoracic/Head and Neck Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, Texas, 77030, USA.

Small-cell lung cancer (SCLC) is speculated to harbor complex genomic intratumor heterogeneity (ITH) associated with high recurrence rate and suboptimal response to immunotherapy. Here, using multi-region whole exome/T cell receptor (TCR) sequencing as well as immunohistochemistry, we reveal a rather homogeneous mutational landscape but extremely cold and heterogeneous TCR repertoire in limited-stage SCLC tumors (LS-SCLCs). Compared to localized non-small cell lung cancers, LS-SCLCs have similar predicted neoantigen burden and genomic ITH, but significantly colder and more heterogeneous TCR repertoire associated with higher chromosomal copy number aberration (CNA) burden. Furthermore, copy number loss of IFN-γ pathway genes is frequently observed and positively correlates with CNA burden. Higher mutational burden, higher T cell infiltration and positive PD-L1 expression are associated with longer overall survival (OS), while higher CNA burden is associated with shorter OS in patients with LS-SCLC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-26821-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8599854PMC
November 2021

Multiomics Analysis Reveals Distinct Immunogenomic Features of Lung Cancer with Ground-Glass Opacity.

Am J Respir Crit Care Med 2021 11;204(10):1180-1192

Department of Thoracic Surgery and.

Ground-glass opacity (GGO)-associated lung cancers are common and radiologically distinct clinical entities known to have an indolent clinical course and superior survival, implying a unique underlying biology. However, the molecular and immune characteristics of GGO-associated lung nodules have not been systemically studied. To provide mechanistic insights for the treatment of these radiologically distinct clinical entities. We initiated a prospective cohort study to collect and characterize pulmonary nodules with GGO components (nonsolid and part-solid nodules) or without GGO components, as precisely quantified by using three-dimensional image reconstruction to delineate the molecular and immune features associated with GGO. Multiomics assessment conducted by using targeted gene panel sequencing, RNA sequencing, TCR (T-cell receptor) sequencing, and circulating tumor DNA detection was performed. GGO-associated lung cancers exhibited a lower tumor mutation burden than solid nodules. Transcriptomic analysis revealed a less active immune environment in GGO components and immune pathways, decreased expression of immune activation markers, and less infiltration of most immune-cell subsets, which was confirmed by using multiplex immunofluorescence. Furthermore, T-cell repertoire sequencing revealed lower T-cell expansion in GGO-associated lung cancers. HLA loss of heterozygosity was significantly less common in lung adenocarcinomas with GGO components than in those without. Circulating tumor DNA analysis suggested that the release of tumor DNA to the peripheral blood was correlated with the tumor size of non-GGO components. Compared with lung cancers presenting with solid lung nodules, GGO-associated lung cancers are characterized by a less active metabolism and a less active immune microenvironment, which may be the mechanisms underlying their indolent clinical course. Clinical trial registered with www.clinicaltrials.gov (NCT03320044).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1164/rccm.202101-0119OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8759311PMC
November 2021

Immune evolution from preneoplasia to invasive lung adenocarcinomas and underlying molecular features.

Nat Commun 2021 05 11;12(1):2722. Epub 2021 May 11.

Department of Thoracic/Head and Neck Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA.

The mechanism by which anti-cancer immunity shapes early carcinogenesis of lung adenocarcinoma (ADC) is unknown. In this study, we characterize the immune contexture of invasive lung ADC and its precursors by transcriptomic immune profiling, T cell receptor (TCR) sequencing and multiplex immunofluorescence (mIF). Our results demonstrate that anti-tumor immunity evolved as a continuum from lung preneoplasia, to preinvasive ADC, minimally-invasive ADC and frankly invasive lung ADC with a gradually less effective and more intensively regulated immune response including down-regulation of immune-activation pathways, up-regulation of immunosuppressive pathways, lower infiltration of cytotoxic T cells (CTLs) and anti-tumor helper T cells (Th), higher infiltration of regulatory T cells (Tregs), decreased T cell clonality, and lower frequencies of top T cell clones in later-stages. Driver mutations, chromosomal copy number aberrations (CNAs) and aberrant DNA methylation may collectively impinge host immune responses and facilitate immune evasion, promoting the outgrowth of fit subclones in preneoplasia into dominant clones in invasive ADC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-22890-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113327PMC
May 2021

Characteristics and Outcomes of 35 Breast Cancer Patients Infected With COVID-19.

Front Oncol 2020 21;10:570130. Epub 2020 Oct 21.

Department of Geriatrics, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, China.

Since December 2019, a novel coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly engulfed the world. Cancer patients infected with COVID-19 are considered to carry higher severity of the disease and higher mortality rate than common COVID-19 patients in previous studies. However, due to the poor clinical information on COVID-19 patients with cancer, the evidences that supported this conclusion are insufficient. At present, rather limited reports have analyzed the clinical data of breast cancer patients infected with COVID-19. Therefore, in this retrospective study, we described the clinical characteristics and the outcomes of 35 COVID-19 patients with breast cancer and compared 55 COVID-19 patients without cancer and 81 COVID-19 patients with other types of cancer as controls. Our data showed that there were no differences in disease severity and outcomes between the COVID-19 patients with breast cancer and the common COVID-19 patients, which was in contrast to previous studies. In addition, compared with other types of cancer patients, asymptomatic infections and mild cases among breast cancer patients made up a substantially larger proportion. Our results indicated that the clinical characteristics of breast cancer patients were milder than those of other types of cancer patients, but there were no significant differences in outcomes between the two groups.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2020.570130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609864PMC
October 2020

Prognostic Value of Pro-Inflammatory Neutrophils and C-Reactive Protein in Cancer Patient With Coronavirus Disease 2019: A Multi-Center, Retrospective Study.

Front Pharmacol 2020 22;11:576994. Epub 2020 Oct 22.

Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

At present, the epidemic of the novel coronavirus disease 2019 (COVID-19) has quickly engulfed the world. Inflammatory cytokines are associated with the severity and outcomes of patients with COVID-19. However, the prognostic value of pro-inflammatory factors in cancer patients with COVID-19 are unknown. A multi-center, retrospective, cross-sectional study, based on five designated tertiary hospitals for the treatment of COVID-19 in Hubei Province, China. 112 cancer patients with COVID-19, and 105 COVID-19 patients without cancer were enrolled in the study between January 1st, 2020 and April 30th, 2020. The risk assessment of pro-inflammatory factors for disease severity and clinical adverse outcomes was identified by univariable and multivariable logistic regression models. Of the 112 cancer patients with COVID-19, 40 (35.7%) patients were in critical condition and 18 (16.1%) patients died unfortunately. Univariate and multivariate analysis demonstrated that hemoglobin level and pro-inflammatory neutrophils and C-reactive protein (CRP), can be used as independent factors affecting the severity of COVID-19; Meanwhile, pro-inflammatory neutrophils and CRP can be used as an independent influencing factor for adverse clinical outcome of death. Moreover, the dynamic changes of neutrophils and CRP were also presented, and compared with COVID-19 patients without cancer, cancer patients with COVID-19 showed higher neutrophil counts and CRP levels. In cancer patients with COVID-19, the significant increase in pro-inflammatory neutrophils and CRP indicated a more critical illness and adverse clinical outcome, and pro-inflammatory neutrophils and CRP played a greater adverse role compare with COVID-19 patients without cancer, which may be the cause of critical illness and adverse clinical outcomes of cancer patients with COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2020.576994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656194PMC
October 2020

Multiomics profiling of primary lung cancers and distant metastases reveals immunosuppression as a common characteristic of tumor cells with metastatic plasticity.

Genome Biol 2020 11 4;21(1):271. Epub 2020 Nov 4.

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: Metastasis is the primary cause of cancer mortality accounting for 90% of cancer deaths. Our understanding of the molecular mechanisms driving metastasis is rudimentary.

Results: We perform whole exome sequencing (WES), RNA sequencing, methylation microarray, and immunohistochemistry (IHC) on 8 pairs of non-small cell lung cancer (NSCLC) primary tumors and matched distant metastases. Furthermore, we analyze published WES data from 35 primary NSCLC and metastasis pairs, and transcriptomic data from 4 autopsy cases with metastatic NSCLC and one metastatic lung cancer mouse model. The majority of somatic mutations are shared between primary tumors and paired distant metastases although mutational signatures suggest different mutagenesis processes in play before and after metastatic spread. Subclonal analysis reveals evidence of monoclonal seeding in 41 of 42 patients. Pathway analysis of transcriptomic data reveals that downregulated pathways in metastases are mainly immune-related. Further deconvolution analysis reveals significantly lower infiltration of various immune cell types in metastases with the exception of CD4+ T cells and M2 macrophages. These results are in line with lower densities of immune cells and higher CD4/CD8 ratios in metastases shown by IHC. Analysis of transcriptomic data from autopsy cases and animal models confirms that immunosuppression is also present in extracranial metastases. Significantly higher somatic copy number aberration and allelic imbalance burdens are identified in metastases.

Conclusions: Metastasis is a molecularly late event, and immunosuppression driven by different molecular events, including somatic copy number aberration, may be a common characteristic of tumors with metastatic plasticity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13059-020-02175-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7640699PMC
November 2020

Concurrent use of aspirin with osimertinib is associated with improved survival in advanced EGFR-mutant non-small cell lung cancer.

Lung Cancer 2020 11 9;149:33-40. Epub 2020 Sep 9.

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, USA. Electronic address:

Background: Osimertinib is the treatment of choice for advanced EGFR-mutant non-small cell lung cancer (NSCLC). However, novel strategies to improve the duration of disease control are still urgently needed. Aspirin has been shown to decrease cancer incidence and improve outcomes in various malignancies. Therefore, we evaluated a cohort of patients who received osimertinib with or without concurrent use of aspirin to assess whether the addition of aspirin may lead to improved clinical outcomes.

Methods: MD Anderson Cancer Center GEMINI database was retrospectively queried for EGFR-mutant NSCLC patients who received osimertinib with or without concurrent use of aspirin for progression-free survival (PFS) and overall survival (OS).

Results: A total of 365 patients were identified including 77 which had concurrent use of aspirin. Patients in the aspirin-osimertinib group had significantly improved PFS (21.3 vs 11.6 months; HR, 0.52; 95 % CI, 0.38-0.70) and OS (Not reached vs 32.3 months; HR, 0.56; 95 % CI, 0.35-0.91) compared to osimertinib group. In subgroup analyses, the aspirin-associated PFS benefit was observed in patients with and without central nervous system (CNS) metastases, as well as in osimertinib first-line setting and in subsequent line setting. The median PFS in EGFR 19Del patients was longer than EGFR L858R patients with osimertinib, and when aspirin was added, the median PFS significantly improved in both groups regardless of lines of therapy. The benefit from aspirin was independent of age, gender, TP53 mutational status, or PD-L1 positivity.

Conclusion: Concurrent aspirin use with osimertinib in EGFR-mutant NSCLC patients was associated with improved survival, regardless of lines of therapy, CNS metastatic status, EGFR mutation type, age, gender, TP53, and PD-L1 status.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lungcan.2020.08.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577964PMC
November 2020

Impacts of Dietary Protein and Prebiotic Inclusion on Liver and Spleen Gene Expression in Hy-Line Brown Caged Layers.

Animals (Basel) 2020 Mar 9;10(3). Epub 2020 Mar 9.

Department of Poultry Science, Texas A&M University, College Station, TX 77843-2472, USA.

The ingredients of poultry feeds are chosen based on the least-cost formulation to meet nutritional requirements. However, this approach can lead to the introduction of anti-nutritional ingredients in the feed. The objective of this study was to evaluate the impacts of two diets (with or without prebiotic) on homeostatic genes in the liver and spleen of laying hens. Hy-Line Brown layers were raised either on a soybean meal or cottonseed meal-based diets with and without an added prebiotic (yeast cell wall), totaling four experimental diets. A total of 120, 63-week old layers were housed individually in a wire cage system. We investigated differences in the expression of select homeostatic marker genes in the liver and spleen of hens from each treatment. We then used the ΔΔCT and generalized linear models to assess significance. Results show that the inclusion of prebiotic yeast cell-wall (YCW) increased the expression of the gene in the liver tissue for both the soybean meal (SBM) and cottonseed meal (CSM) diets. For splenic tissue, the combination of YCW with the CSM diet increased the POR gene over six log2 fold. Altogether, our results suggest altered homeostasis, which can have consequences for health and performance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ani10030453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142900PMC
March 2020

The Role of Housing Environment and Dietary Protein Source on the Gut Microbiota of Chicken.

Animals (Basel) 2019 Dec 5;9(12). Epub 2019 Dec 5.

Department of Poultry Science, Texas A&M University, 2472 TAMU, College Station, TX 77845, USA.

The gut microbiota of chicken has received much attention due to its importance for bird health, food safety, and performance. In the United States, the impending transition to cage-free housing environments has raised many questions about its consequences for poultry health, productivity, and welfare. Therefore, we investigated how housing environments and feed composition affect the poultry gut microbiome. Such data is necessary to inform the design of production systems that promote health and food safety. In this study, we investigated the cecal microbiome of both caged and cage-free laying hens that were fed either an industry-standard soy-based versus a soy-free diet. Caged hens were housed in standard industry-style layer cages with one bird per cage, and cage-free hens were housed in a poultry barn with an outdoor enclosed yard with multiple hens per pen. Our study showed significant differences in the gut microbiota between cage-free and caged environments. Cage free housing generated higher diversity compared to caged housing. Furthermore, we observed a synergistic interaction of soy-based feed in cage-free housing, as the cage-free soy group showed the highest alpha diversity, whereas the caged-soy group showed the lowest diversity overall.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ani9121085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940977PMC
December 2019

Circadian disruption and divergent microbiota acquisition under extended photoperiod regimens in chicken.

PeerJ 2019 14;7:e6592. Epub 2019 Mar 14.

Poultry Science Department, Texas A&M University, College Station, TX, USA.

The gut microbiota is crucial for metabolic homeostasis, immunity, growth and overall health, and it is recognized that early-life microbiota acquisition is a pivotal event for later-life health. Recent studies show that gut microbiota diversity and functional activity are synchronized with the host circadian rhythms in healthy individuals, and circadian disruption elicits dysbiosis in mammalian models. However, no studies have determined the associations between circadian disruption in early life, microbiota colonization, and the consequences for microbiota structure in birds. Chickens, as a major source of protein around the world, are one of the most important agricultural species, and their gut and metabolic health are significant concerns. The poultry industry routinely employs extended photoperiods (>18 h light) as a management tool, and their impacts on the chicken circadian, its role in gut microbiota acquisition in early life (first 3 weeks of life), and consequences for later life microbiota structure remain unknown. In this study, the objectives were to (a) characterize circadian activity under two different light regimes in layer chicken (12/12 h' Light/Dark (LD) and 23/1 h LD), (b) characterize gut microbiota acquisition and composition in the first 4 weeks of life, (c) determine if gut microbiota oscillate in synchrony with the host circadian rhythm, and (d) to determine if fecal microbiota is representative of cecal microbiota in early life. Expression of clock genes (, , and ) was assayed, and fecal and cecal microbiotas were characterized using 16S rRNA gene amplicon analyses from birds raised under two photoperiod treatments. Chickens raised under 12/12 LD photoperiods exhibited rhythmic clock gene activity, which was absent in birds raised under the extended (23/1 LD) photoperiod. There was differential microbiota acquisition under different photoperiod regimes in newly hatched chicks. Gut microbiota members showed a similar oscillating pattern as the host, but this association was not as strong as found in mammals. Finally, the fecal microbiota was found to be not representative of cecal microbiota membership and structure in young birds. This is one of the first studies to demonstrate the use of photoperiods to modulate microbiota acquisition in newly hatched chicks, and show their potential as a tool to promote the colonization of beneficial microorganisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7717/peerj.6592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6421066PMC
March 2019
-->