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1.
Cell Rep ; 42(12): 113286, 2023 12 26.
Article in English | MEDLINE | ID: mdl-37995179

ABSTRACT

Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer and presents clinically with a high degree of biological heterogeneity and distinct clinical outcomes. The current paradigm of LUAD etiology posits alveolar epithelial type II (AT2) cells as the primary cell of origin, while the role of AT1 cells in LUAD oncogenesis remains unknown. Here, we examine oncogenic transformation in mouse Gram-domain containing 2 (Gramd2)+ AT1 cells via oncogenic KRASG12D. Activation of KRASG12D in AT1 cells induces multifocal LUAD, primarily of papillary histology. Furthermore, KRT8+ intermediate cell states were observed in both AT2- and AT1-derived LUAD, but SCGB3A2+, another intermediate cell marker, was primarily associated with AT1 cells, suggesting different mechanisms of tumor evolution. Collectively, our study reveals that Gramd2+ AT1 cells can serve as a cell of origin for LUAD and suggests that distinct subtypes of LUAD based on cell of origin be considered in the development of therapeutics.


Subject(s)
Adenocarcinoma of Lung , Lung Neoplasms , Animals , Mice , Adenocarcinoma of Lung/genetics , Adenocarcinoma of Lung/pathology , Cell Transformation, Neoplastic/metabolism , Lung Neoplasms/pathology , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins p21(ras)/metabolism
2.
Cancer Res ; 83(1): 34-48, 2023 01 04.
Article in English | MEDLINE | ID: mdl-36283023

ABSTRACT

Triple-negative breast cancer (TNBC) is an aggressive disease that disproportionately affects African American (AA) women. Limited targeted therapeutic options exist for patients with TNBC. Here, we employ spatial transcriptomics to interrogate tissue from a racially diverse TNBC cohort to comprehensively annotate the transcriptional states of spatially resolved cellular populations. A total of 38,706 spatial features from a cohort of 28 sections from 14 patients were analyzed. Intratumoral analysis of spatial features from individual sections revealed heterogeneous transcriptional substructures. However, integrated analysis of all samples resulted in nine transcriptionally distinct clusters that mapped across all individual sections. Furthermore, novel use of join count analysis demonstrated nonrandom directional spatial dependencies of the transcriptionally defined shared clusters, supporting a conserved spatio-transcriptional architecture in TNBC. These findings were substantiated in an independent validation cohort comprising 17,861 spatial features representing 15 samples from 8 patients. Stratification of samples by race revealed race-associated differences in hypoxic tumor content and regions of immune-rich infiltrate. Overall, this study combined spatial and functional molecular analyses to define the tumor architecture of TNBC, with potential implications in understanding TNBC disparities. SIGNIFICANCE: Spatial transcriptomics profiling of a diverse cohort of triple-negative breast cancers and innovative informatics approaches reveal a conserved cellular architecture across cancers and identify proportional differences in tumor cell composition by race.


Subject(s)
Transcriptome , Triple Negative Breast Neoplasms , Humans , Female , Triple Negative Breast Neoplasms/pathology , Gene Expression Profiling , Black or African American , Gene Expression Regulation, Neoplastic
3.
Genes (Basel) ; 12(9)2021 09 11.
Article in English | MEDLINE | ID: mdl-34573384

ABSTRACT

KRAS mutations are one of the most common oncogenic drivers in non-small cell lung cancer (NSCLC) and in lung adenocarcinomas in particular. Development of therapeutics targeting KRAS has been incredibly challenging, prompting indirect inhibition of downstream targets such as MEK and ERK. Such inhibitors, unfortunately, come with limited clinical efficacy, and therefore the demand for developing novel therapeutic strategies remains an urgent need for these patients. Exploring the influence of wild-type (WT) KRAS on druggable targets can uncover new vulnerabilities for the treatment of KRAS mutant lung adenocarcinomas. Using commercially available KRAS mutant lung adenocarcinoma cell lines, we explored the influence of WT KRAS on signaling networks and druggable targets. Expression and/or activation of 183 signaling proteins, most of which are targets of FDA-approved drugs, were captured by reverse-phase protein microarray (RPPA). Selected findings were validated on a cohort of 23 surgical biospecimens using the RPPA. Kinase-driven signatures associated with the presence of the KRAS WT allele were detected along the MAPK and AKT/mTOR signaling pathway and alterations of cell cycle regulators. FoxM1 emerged as a potential vulnerability of tumors retaining the KRAS WT allele both in cell lines and in the clinical samples. Our findings suggest that loss of WT KRAS impacts on signaling events and druggable targets in KRAS mutant lung adenocarcinomas.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Drug Resistance, Neoplasm/genetics , Lung Neoplasms , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins p21(ras)/genetics , A549 Cells , Alleles , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Biomarkers, Pharmacological/analysis , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Cell Line, Tumor , Extracellular Signal-Regulated MAP Kinases/drug effects , Extracellular Signal-Regulated MAP Kinases/metabolism , Gene Regulatory Networks/drug effects , Gene Regulatory Networks/genetics , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , MTOR Inhibitors/pharmacology , MTOR Inhibitors/therapeutic use , Mutation , Oncogene Protein v-akt/drug effects , Oncogene Protein v-akt/metabolism , Pharmacogenomic Testing , Protein Kinase Inhibitors/pharmacology , Retrospective Studies , Signal Transduction/drug effects , Signal Transduction/genetics
4.
Mol Cell ; 81(8): 1631-1639, 2021 04 15.
Article in English | MEDLINE | ID: mdl-33826920

ABSTRACT

Spatial transcriptional profiling provides gene expression information within the important anatomical context of tissue architecture. This approach is well suited to characterizing solid tumors, which develop within a complex landscape of malignant cells, immune cells, and stroma. In a single assay, spatial transcriptional profiling can interrogate the role of spatial relationships among these cell populations as well as reveal spatial patterns of relevant oncogenic genetic events. The broad utility of this approach is reflected in the array of strategies that have been developed for its implementation as well as in the recent commercial development of several profiling platforms. The flexibility to apply these technologies to both hypothesis-driven and discovery-driven studies allows widespread applicability in research settings. This review discusses available technologies for spatial transcriptional profiling and several applications for their use in cancer research.


Subject(s)
Gene Expression Profiling/methods , Neoplasms/genetics , Transcription, Genetic/genetics , Animals , Gene Expression/genetics , Humans
5.
Theranostics ; 7(9): 2477-2494, 2017.
Article in English | MEDLINE | ID: mdl-28744329

ABSTRACT

Herein, we report the use of a theranostic nanocarrier (Folate-HBPE(CT20p)) to deliver a therapeutic peptide to prostate cancer tumors that express PSMA (folate hydrolase 1). The therapeutic peptide (CT20p) targets and inhibits the chaperonin-containing TCP-1 (CCT) protein-folding complex, is selectively cytotoxic to cancer cells, and is non-toxic to normal tissue. With the delivery of CT20p to prostate cancer cells via PSMA, a dual level of cancer specificity is achieved: (1) selective targeting to PSMA-expressing prostate tumors, and (2) specific cytotoxicity to cancer cells with minimal toxicity to normal cells. The PSMA-targeting theranostic nanocarrier can image PSMA-expressing cells and tumors when a near infrared dye is used as cargo. Meanwhile, it can be used to treat PSMA-expressing tumors when a therapeutic, such as the CT20p peptide, is encapsulated within the nanocarrier. Even when these PSMA-targeting nanocarriers are taken up by macrophages, minimal cell death is observed in these cells, in contrast with doxorubicin-based therapeutics that result in significant macrophage death. Incubation of PSMA-expressing prostate cancer cells with the Folate-HBPE(CT20p) nanocarriers induces considerable changes in cell morphology, reduction in the levels of integrin ß1, and lower cell adhesion, eventually resulting in cell death. These results are relevant as integrin ß1 plays a key role in prostate cancer invasion and metastatic potential. In addition, the use of the developed PSMA-targeting nanocarrier facilitates the selective in vivo delivery of CT20p to PSMA-positive tumor, inducing significant reduction in tumor size.


Subject(s)
Antigens, Surface/metabolism , Antineoplastic Agents/administration & dosage , Drug Carriers/administration & dosage , Glutamate Carboxypeptidase II/metabolism , Molecular Targeted Therapy/methods , Nanoparticles/administration & dosage , Prostatic Neoplasms/diagnosis , Prostatic Neoplasms/drug therapy , Animals , Cell Line, Tumor , Cell Survival/drug effects , Disease Models, Animal , Heterografts , Humans , Male , Mice, Nude , Neoplasm Transplantation , Peptides/administration & dosage , Treatment Outcome , Tumor Cells, Cultured/cytology , Tumor Cells, Cultured/drug effects , Tumor Cells, Cultured/physiology
6.
Oncotarget ; 8(66): 110273-110288, 2017 Dec 15.
Article in English | MEDLINE | ID: mdl-29299146

ABSTRACT

Identifying new druggable targets is desired to meet the needs for effective cancer treatments. To this end, we previously reported the efficacy of a therapeutic peptide called CT20p that displays selective cytotoxicity through inhibition of a multi-subunit, protein-folding complex called Chaperonin-Containing TCP-1 (CCT). To investigate the role of CCT in cancer progression, we examined protein levels of CCT subunits in liver, prostate, and lung cancer using human tissue microarrays. We found that these cancers expressed higher levels of CCT2 as compared to normal tissues. Small cell lung cancer (SCLC) stood out as having statistically significant difference in CCT2. Higher levels of CCT2 in tumors from lung cancer patients were also associated with decreased survival. Using SCLC cell lines, we observed detectable amounts of CCT subunits and cells were susceptible to killing by CT20p. Treatment with CT20p, delivered to cells using polymeric nanoparticles, was cytotoxic to all SCLC cell lines, decreasing the levels of CCT client proteins like STAT3. In contrast, treatment with a STAT3 inhibitor was effective in one of the SCLC cell lines. While we found that CCT levels could vary in cell lines, normal tissues had low levels of CCT and minimal toxicity to liver or kidney function was observed in mice treated with CT20p. These results indicate that in SCLC, changes in CCT levels could be used as a biomarker for diagnosis and that targeting CCT for inhibition with CT20p is a promising treatment approach for those cancers such as SCLC that currently lack targeted therapeutics.

7.
Clin Cancer Res ; 22(17): 4366-79, 2016 Sep 01.
Article in English | MEDLINE | ID: mdl-27012814

ABSTRACT

PURPOSE: Metastatic disease is a leading cause of death for patients with breast cancer, driving the need for new therapies. CT20p is a peptide previously discovered by our group that displays cancer-specific cytotoxicity. To design the optimal therapeutic use of the peptide, we identified the intracellular target of CT20p in breast cancer cells, correlating expression patterns of the target with susceptibility to CT20p. EXPERIMENTAL DESIGN: Using polymeric nanoparticles to deliver CT20p, we assessed cytoskeletal changes, cell migration, adhesion, and viability in cells treated with the peptide. Protein pull-down experiments, coupled to mass spectrometry, enabled identification of the peptide's intracellular target. Biochemical and histologic techniques validated target identity in human cell lines and breast cancer tissue microarrays and revealed susceptibility patterns to CT20p. RESULTS: Chaperonin containing TCP-1 (CCT) was identified as the intracellular target of CT20p. Cancer cells susceptible to CT20p had increased CCT, and overexpression of CCTß, a subunit of the CCT complex, enhanced susceptibility to CT20p. Susceptible cells displayed reduced tubulin, a substrate of CCT, and inhibition of migration upon CT20p treatment. CCTß levels were higher in invasive ductal carcinomas than in cancer adjacent tissues and increased with breast cancer stage. Decreased breast cancer patient survival correlated with genomic alternations in CCTß and higher levels of the chaperone. CONCLUSIONS: Increased CCT protein in breast cancer cells underlies the cytotoxicity of CT20p. CCT is thus a potential target for therapeutic intervention and serves as a companion diagnostic to personalize the therapeutic use of CT20p for breast cancer treatment. Clin Cancer Res; 22(17); 4366-79. ©2016 AACR.


Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/metabolism , Chaperonin Containing TCP-1/metabolism , Peptides/pharmacology , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/metabolism , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/mortality , Cell Adhesion/drug effects , Cell Line, Tumor , Cell Movement/drug effects , Cell Survival/drug effects , Chaperonin Containing TCP-1/chemistry , Chaperonin Containing TCP-1/genetics , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Nanoparticles , Peptides/administration & dosage , Peptides/metabolism , Polymers , Prognosis , Protein Binding , Protein Subunits/metabolism
8.
J Fluoresc ; 21(3): 1223-30, 2011 May.
Article in English | MEDLINE | ID: mdl-21243414

ABSTRACT

We report two-photon fluorescence microscopy (2PFM) imaging and in vitro cell viability of a new, efficient, lysosome-selective system based on a two-photon absorbing (2PA) fluorescent probe (I) encapsulated in Pluronic® F-127 micelles. Preparation of dye I was accomplished via microwave-assisted synthesis, resulting in improved yields and reduced reaction times. Photophysical characterization revealed notable 2PA efficiency of this probe.


Subject(s)
Fluorescence , Fluorescent Dyes/chemical synthesis , Lysosomes/metabolism , Micelles , Molecular Imaging/methods , Animals , Cell Survival , Humans , Poloxamer
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