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Proteogenomic analysis of chemo-refractory high-grade serous ovarian cancer

Chowdhury, Shrabanti; Kennedy, Jacob J; Ivey, Richard G; Murillo, Oscar D; Hosseini, Noshad; Song, Xiaoyu; Petralia, Francesca; Calinawan, Anna; Savage, Sara R; Berry, Anna B; Reva, Boris; Ozbek, Umut; Krek, Azra; Ma, Weiping; da Veiga Leprevost, Felipe; Ji, Jiayi; Yoo, Seungyeul; Lin, Chenwei; Voytovich, Uliana J; Huang, Yajue; Lee, Sun-Hee; Bergan, Lindsay; Lorentzen, Travis D; Mesri, Mehdi; Rodriguez, Henry; Hoofnagle, Andrew N; Herbert, Zachary T; Nesvizhskii, Alexey I; Zhang, Bing; Whiteaker, Jeffrey R; Fenyo, David; McKerrow, Wilson; Wang, Joshua; Schürer, Stephan C; Stathias, Vasileios; Chen, X Steven; Barcellos-Hoff, Mary Helen; Starr, Timothy K; Winterhoff, Boris J; Nelson, Andrew C; Mok, Samuel C; Kaufmann, Scott H; Drescher, Charles; Cieslik, Marcin; Wang, Pei; Birrer, Michael J; Paulovich, Amanda G
To improve the understanding of chemo-refractory high-grade serous ovarian cancers (HGSOCs), we characterized the proteogenomic landscape of 242 (refractory and sensitive) HGSOCs, representing one discovery and two validation cohorts across two biospecimen types (formalin-fixed paraffin-embedded and frozen). We identified a 64-protein signature that predicts with high specificity a subset of HGSOCs refractory to initial platinum-based therapy and is validated in two independent patient cohorts. We detected significant association between lack of Ch17 loss of heterozygosity (LOH) and chemo-refractoriness. Based on pathway protein expression, we identified 5 clusters of HGSOC, which validated across two independent patient cohorts and patient-derived xenograft (PDX) models. These clusters may represent different mechanisms of refractoriness and implicate putative therapeutic vulnerabilities.
PMCID:10414761
PMID: 37541199
ISSN: 1097-4172
CID: 5594782

Exploiting Canonical TGFβ Signaling in Cancer Treatment

Liu, Qi; Chen, Genwen; Moore, Jade; Guix, Ines; Placantonokis, Dimitris; Barcellos-Hoff, Mary Helen
Transforming growth factor β (TGFβ) is a pleiotropic cytokine that plays critical roles to define cancer cell phenotypes, construct the tumor microenvironment, and suppress anti-tumor immune responses. As such, TGFβ is a lynchpin for integrating cancer cell intrinsic pathways and communication among host cells in the tumor and beyond that together affect responses to genotoxic, targeted, and immune therapy. Despite decades of preclinical and clinical studies, evidence of clinical benefit from targeting TGFβ in cancer remains elusive. Here, we review the mechanisms by which TGFβ acts to oppose successful cancer therapy, the reported prognostic and predictive value of TGFβ biomarkers, and the potential impact of inhibiting TGFβ in precision oncology. Paradoxically, the diverse mechanisms by which TGFβ impedes therapeutic response are a principal barrier to implementing TGFβ inhibitors because it is unclear which TGFβ mechanism is functional in which patient. Companion diagnostic tools and specific biomarkers of TGFβ targeted biology will be the key to exploiting TGFβ biology for patient benefit.
PMID: 34670783
ISSN: 1538-8514
CID: 5043352

Altered regulation of BRCA1 exon 11 splicing is associated with breast cancer risk in carriers of BRCA1 pathogenic variants

Ruiz de Garibay, Gorka; Fernandez-Garcia, Ignacio; Mazoyer, Sylvie; Leme de Calais, Flavia; Ameri, Pietro; Vijayakumar, Sangeetha; Martinez-Ruiz, Haydeliz; Damiola, Francesca; Barjhoux, Laure; Thomassen, Mads; Andersen, Lars V B; Herranz, Carmen; Mateo, Francesca; Palomero, Luis; Espín, Roderic; Gómez, Antonio; García, Nadia; Jimenez, Daniel; Bonifaci, Núria; Extremera, Ana I; Castaño, Julio; Raya, Angel; Eyras, Eduardo; Puente, Xose S; Brunet, Joan; Lázaro, Conxi; Radice, Paolo; Barnes, Daniel R; Antoniou, Antonis C; Spurdle, Amanda B; de la Hoya, Miguel; Baralle, Diana; Barcellos-Hoff, Mary Helen; Pujana, Miquel A
Germline pathogenic variants in BRCA1 confer a high risk of developing breast and ovarian cancer. The BRCA1 exon 11 (formally exon 10) is one of the largest exons and codes for the nuclear localization signals of the corresponding gene product. This exon can be partially or entirely skipped during pre-mRNA splicing, leading to three major in-frame isoforms that are detectable in most cell types and tissue, and in normal and cancer settings. However, it is unclear whether the splicing imbalance of this exon is associated with cancer risk. Here we identify a common genetic variant in intron 10, rs5820483 (NC_000017.11:g.43095106_43095108dup), which is associated with exon 11 isoform expression and alternative splicing, and with the risk of breast cancer, but not ovarian cancer, in BRCA1 pathogenic variant carriers. The identification of this genetic effect was confirmed by analogous observations in mouse cells and tissue in which a loxP sequence was inserted in the syntenic intronic region. The prediction that the rs5820483 minor allele variant would create a binding site for the splicing silencer hnRNP A1 was confirmed by pull-down assays. Our data suggest that perturbation of BRCA1 exon 11 splicing modifies the breast cancer risk conferred by pathogenic variants of this gene.
PMID: 34420246
ISSN: 1098-1004
CID: 5011032

Inflammation mediates the development of aggressive breast cancer following radiotherapy

Ma, Lin; Gonzalez-Junca, Alba; Zheng, Yufei; Ouyang, Haoxu; Illa-Bochaca, Irineu; Horst, Kathleen C; Krings, Gregor; Wang, Yinghao; Fernandez-Garcia, Ignacio; Chou, William; Barcellos-Hoff, Mary Helen
PURPOSE/OBJECTIVE:Women treated with radiotherapy before 30 years of age have increased risk of developing breast cancer at an early age. Here we sought to investigate mechanisms by which radiation promotes aggressive cancer. EXPERIMENTAL DESIGN/METHODS:null mammary transplants after irradiation of the target epithelium or host using immunocompetent and incompetent mice, some which were treated with aspirin. RESULTS:null mammary transplantation, cancers also established an iTME, which pointed to a critical role for myeloid cells. Consistent with this, irradiated mammary glands contained more macrophages and human cells co-cultured with polarized macrophages underwent dysplastic morphogenesis mediated by interferon γ. Treating mice with low-dose aspirin for 6 months post-irradiation prevented establishment of an iTME and resulted in less aggressive tumors. CONCLUSIONS:These data show that radiation acts via non-mutational mechanisms to promote markedly immunosuppressive features of aggressive, radiation-preceded breast cancers.
PMID: 33402361
ISSN: 1557-3265
CID: 4738832

Loss of TGFβ signaling increases alternative end-joining DNA repair that sensitizes to genotoxic therapies across cancer types

Liu, Qi; Palomero, Luis; Moore, Jade; Guix, Ines; Espín, Roderic; Aytés, Alvaro; Mao, Jian-Hua; Paulovich, Amanda G; Whiteaker, Jeffrey R; Ivey, Richard G; Iliakis, George; Luo, Daxian; Chalmers, Anthony J; Murnane, John; Pujana, Miquel Angel; Barcellos-Hoff, Mary Helen
Among the pleotropic roles of transforming growth factor-β (TGFβ) signaling in cancer, its impact on genomic stability is least understood. Inhibition of TGFβ signaling increases use of alternative end joining (alt-EJ), an error-prone DNA repair process that typically functions as a "backup" pathway if double-strand break repair by homologous recombination or nonhomologous end joining is compromised. However, the consequences of this functional relationship on therapeutic vulnerability in human cancer remain unknown. Here, we show that TGFβ broadly controls the DNA damage response and suppresses alt-EJ genes that are associated with genomic instability. Mechanistically based TGFβ and alt-EJ gene expression signatures were anticorrelated in glioblastoma, squamous cell lung cancer, and serous ovarian cancer. Consistent with error-prone repair, more of the genome was altered in tumors classified as low TGFβ and high alt-EJ, and the corresponding patients had better outcomes. Pan-cancer analysis of solid neoplasms revealed that alt-EJ genes were coordinately expressed and anticorrelated with TGFβ competency in 16 of 17 cancer types tested. Moreover, regardless of cancer type, tumors classified as low TGFβ and high alt-EJ were characterized by an insertion-deletion mutation signature containing short microhomologies and were more sensitive to genotoxic therapy. Collectively, experimental studies revealed that loss or inhibition of TGFβ signaling compromises the DNA damage response, resulting in ineffective repair by alt-EJ. Translation of this mechanistic relationship into gene expression signatures identified a robust anticorrelation that predicts response to genotoxic therapies, thereby expanding the potential therapeutic scope of TGFβ biology.
PMID: 33568520
ISSN: 1946-6242
CID: 4779862

Positron Emission Tomography Imaging of Functional TGFβ Activity and Benefit of TGFβ Inhibition in Irradiated Intracranial Tumors

Gonzalez-Junca, Alba; Reiners, Oliver; Borrero-Garcia, Luis D; Beckford-Vera, Denis; Lazar, Ann A; Chou, William; Braunstein, Steve; VanBrocklin, Henry; Franc, Benjamin L; Barcellos-Hoff, Mary Helen
INTRODUCTION/BACKGROUND:Transforming growth factor β (TGFβ) promotes cell survival by endorsing DNA damage repair and mediates an immunosuppressive tumor microenvironment. Thus, TGFβ activation in response to radiation therapy is potentially targetable because it opposes therapeutic control. Strategies to assess this potential in the clinic are needed. METHODS:Zr -fresolimumab, a humanized TGFβ neutralizing monoclonal antibody, as means to detect TGFβ activation in intracranial tumor models. TGFβ pathway activity was validated by immunodetection of phosphorylated SMAD2 and TGFβ target, tenascin. The contribution of TGFβ to radiation response was assessed by Kaplan Meier survival analysis of mice bearing intracranial murine tumor models, GL261 and SB28 glioblastoma and brain-adapted 4T1 breast cancer (4T1-BrA) treated with TGFβ neutralizing monoclonal antibody, 1D11, and/or focal radiation (10 Gy). RESULTS:Zr-fresolimumab PET imaging detected engineered, physiological and radiation-induced TGFβ activation, which was confirmed by immunostaining of biological markers. GL261 glioblastoma tumors had more PET signal compared to similar sized SB28 glioblastoma tumors, whereas widespread PET signal of 4T1-BrA intracranial tumors is consistent with its highly dispersed histological distribution. Survival of mice bearing intracranial tumors treated with 1D11 neutralizing antibody alone was similar to that of mice treated with control antibody whereas 1D11 improved survival when given in combination with focal radiation. The extent of survival benefit of combination of radiation and 1D11 was associated with the degree of TGFβ activity detected by PET. CONCLUSIONS:Zr -fresolimumab PET imaging detects radiation-induced TGFβ activation in tumors. Functional imaging indicated a range of TGFβ activity in intracranial tumors, but TGFβ blockade provided survival benefit only in the context of radiation treatment. These studies are further evidence that radiation-induced TGFβ activity opposes therapeutic response to radiation.
PMID: 33007434
ISSN: 1879-355x
CID: 4617382

Editorial: Cell Signaling Mediating Critical Radiation Responses [Editorial]

Herskind, Carsten; Barcellos-Hoff, Mary Helen
PMCID:8142942
PMID: 34041040
ISSN: 2234-943x
CID: 4888142

In Memoriam - Zena Werb 1945-2020 [Editorial]

Barcellos-Hoff, Mary Helen; Weaver, Valerie M
PMID: 32997280
ISSN: 1573-7039
CID: 4616932

Aggressive Mammary Cancers Lacking Lymphocytic Infiltration Arise in Irradiated Mice and Can be Prevented by Dietary Intervention

Omene, Coral; Ma, Lin; Moore, Jade; Ouyang, Haoxu; Illa-Bochaca, Irineu; Chou, William; Patel, Manan S; Sebastiano, Christopher; Demaria, Sandra; Mao, Jian-Hua; Karagoz, Kubra; Gatza, Michael L; Barcellos-Hoff, Mary Helen
Because the incidence of breast cancer increases decades after ionizing radiation exposure, aging has been implicated in the evolution of the tumor microenvironment and tumor progression. Here, we investigated radiation-induced carcinogenesis using a model in which the mammary glands of 10-month-old BALB/c mice were transplanted with Trp53-null mammary tissue three days after exposure to low doses of sparsely ionizing γ-radiation or densely ionizing particle radiation. Mammary transplants in aged irradiated hosts gave rise to significantly more tumors that grew more rapidly than those in sham-irradiated mice, with the most pronounced effects seen in mice irradiated with densely ionizing particle radiation. Tumor transcriptomes identified a characteristic immune signature of these aggressive cancers. Consistent with this, fast-growing tumors exhibited an immunosuppressive tumor microenvironment with few infiltrating lymphocytes, abundant immunosuppressive myeloid cells, and high cyclooxgenase-2 and TGFβ. Only aged irradiated hosts gave rise to tumors lacking cytotoxic CD8+ lymphocytes (defined here as immune desert), which also occurred in younger mice. These data suggested that host irradiation may promote immunosuppression. To test this, young chimera mice were fed chow containing a honeybee-derived compound with anti-inflammatory and immunomodulatory properties, caffeic acid phenethyl ester (CAPE). CAPE prevented the detrimental effects of host irradiation on tumor growth rate, immune signature, and immunosuppression. These data indicated that low-dose radiation, particularly densely ionizing radiation, promoted more aggressive cancers by suppressing antitumor immunity. Dietary intervention with a non-toxic immunomodulatory agent could prevent systemic effects of radiation that fuel carcinogenesis, supporting the potential of this strategy for cancer prevention.
PMID: 31831632
ISSN: 2326-6074
CID: 4234912

TGFβ blockade enhances radiotherapy abscopal efficacy effects in combination with anti-PD1 and anti-CD137 immunostimulatory monoclonal antibodies

Rodriguez-Ruiz, Maria E; Rodriguez, Inmaculada; Mayorga, Lina; Labiano, Tania; Barbes, Benigno; Etxeberria, Inaki; Ponz-Sarvise, Mariano; Azpilikueta, Arantza; Bolaños, Elixabet; Sanmamed, Miguel F; Berraondo, Pedro; Calvo, Felipe A; Barcellos-Hoff, Mary Helen; Perez-Gracia, Jose Luis; Melero, Ignacio
Radiotherapy can be synergistically combined with immunotherapy in mouse models, extending its efficacious effects outside of the irradiated field (abscopal effects). We previously reported that a regimen encompassing local radiotherapy in combination with anti-CD137 plus anti-PD-1 mAbs achieves potent abscopal effects against syngeneic transplanted murine tumors up to a certain tumor size. Knowing that TGF-beta expression or activation increases in irradiated tissues, we tested whether TGF-beta blockade may further enhance abscopal effects in conjunction with the anti-PD-1 plus anti-CD137 mAb combination. Indeed, TGFβ blockade with 1D11, a TGFβ neutralizing monoclonal antibody, markedly enhanced abscopal effects and overall treatment efficacy against subcutaneous tumors of either 4T1 breast cancer cells or large MC38 colorectal tumors. Increases in CD8 T cells infiltrating the non-irradiated lesion were documented upon combined treatment, which intensely expressed Granzyme-B as an indicator of cytotoxic effector capability. Interestingly, tumor tissue but not healthy tissue irradiation results in the presence of higher concentrations of TGFβ in the non-irradiated contralateral tumor which showed smad2/3 phosphorylation increases in infiltrating CD8 T cells. In conclusion, radiotherapy-induced TGF-beta hampers abscopal efficacy even upon combination with a potent immunotherapy regimen. Therefore TGF-beta blockade in combination with radioimmunotherapy results in greater efficacy.
PMID: 30683810
ISSN: 1538-8514
CID: 3683262