Extensive three-dimensional intratumor proteomic heterogeneity revealed by multiregion sampling in high-grade serous ovarian tumor specimens

Hunt, Allison L.; Bateman, Nicholas W.; Barakat, Waleed; Makohon-Moore, Sasha C.; Hood, Brian L.; Conrads, Kelly A.; Zhou, Ming; Calvert, Valerie; Pierobon, Mariaelena; Loffredo, Jeremy; Litzi, Tracy; Oliver, Julie; Mitchell, D. L.; Gist, Glenn; Rojas, Christine; Blanton, Brian; Robinson, Emma; Odunsi, Kunle; Sood, Anil K.; Casablanca, Yovanni; Darcy, Kathleen M.; Shriver, Craig D.; Petricoin, Emanuel F.; Rao, Uma; Maxwell, G. Larry; Conrads, Thomas P.

doi:10.1016/j.isci.2021.102757

Cited by 26 publications

(74 citation statements)

References 75 publications

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“…Some evidence supports the existence of spatially distinct intratumoral subpopulations, suggesting that such resolution may be possible with systematic workflows capable of elucidating the organization and spatial distribution of such subpopulations. In support of this, recent studies using spatial profiling techniques have demonstrated stark differences in biological activity between spatially separated regions of solid tumors and tumor microenvironments [14,17,19–21]. Notably, spatially heterogeneous tumoral subpopulations have been identified at the protein level, with the degree of proteomic heterogeneity predictive of therapeutic response [14,15].…”

Section: Addressing Spatial Proteomic Intratumoral Heterogeneitymentioning

confidence: 99%

“…In support of this, recent studies using spatial profiling techniques have demonstrated stark differences in biological activity between spatially separated regions of solid tumors and tumor microenvironments [14,17,19–21]. Notably, spatially heterogeneous tumoral subpopulations have been identified at the protein level, with the degree of proteomic heterogeneity predictive of therapeutic response [14,15]. While these comprehensive high‐resolution spatial analyses emphasize the need for routine spatial profiling, their current forms are often not feasible to be used routinely in clinical practice due to cost, subjectivity in region selection by different observers, and practical considerations.…”

Section: Addressing Spatial Proteomic Intratumoral Heterogeneitymentioning

confidence: 99%

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Integrating computational pathology and proteomics to address tumor heterogeneity

Dent

Diamandis

2022

The Journal of Pathology

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Despite numerous advances in our molecular understanding of cancer biology, success in precision medicine trials has remained elusive for many malignancies. Emerging evidence now supports that these challenges are partly driven by proteogenomic discordances across molecular readouts and heterogeneous biology that is spatially distributed across tumors. Here we discuss these key limitations and how integrating the promise of mass-spectrometry-based global proteomics and computational imaging can help prioritize and direct regional sampling to help overcome these important challenges of biologic variation in cancer.

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Section: Addressing Spatial Proteomic Intratumoral Heterogeneitymentioning

confidence: 99%

Section: Addressing Spatial Proteomic Intratumoral Heterogeneitymentioning

confidence: 99%

Integrating computational pathology and proteomics to address tumor heterogeneity

Dent

Diamandis

2022

The Journal of Pathology

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“…As described in the preanalytical section, tumor samples frequently exhibit distinct subclones within tumors, and any given result will be a synthesis of these subclones according to their relative proportions [ 66 , 67 , 68 ]. By definition, a biopsy represents only a fraction of the tissue at the site.…”

Section: Hrd Evaluation In Clinics: Current Limitationsmentioning

confidence: 99%

Toward More Comprehensive Homologous Recombination Deficiency Assays in Ovarian Cancer Part 2: Medical Perspectives

Quesada

Fabbro

Solassol

2022

Cancers

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High-grade serous ovarian cancer (HGSOC) is the most frequent and aggressive form of ovarian cancer, representing an important challenge for clinicians. Half of HGSOC cases have homologous recombination deficiency (HRD), which has specific causes (mainly alterations in BRCA1/2, but also other alterations encompassed by the BRCAness concept) and consequences, both at molecular (e.g., genomic instability) and clinical (e.g., sensitivity to PARP inhibitor) levels. Based on its prevalence and clinical impact, HRD status merits investigation. To date, three PARP inhibitors have received FDA/EMA approval. For some approvals, the presence of specific molecular alterations is required. Three companion diagnostic (CDx) assays based on distinct technical and medical considerations have received FDA approval to date. However, their use remains controversial due to their technical and medical limitations. In this companion and integrated review, we take a “bench-to-bedside” perspective on HRD definition and evaluation in the context of HGSOC. Part 1 of the review adopts a molecular perspective regarding technical considerations and the development of CDx. Part 2 focuses on the clinical impact of HRD evaluation, primarily through currently validated CDx and prescription of PARP inhibitors, outlining achievements, limitations and medical perspectives.

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“…Cells of interest in a tissue section are recognized by a microscope, cut out by a laser, and then collected for subsequent analysis. Hunt et al (2021) [ 19 ] demonstrated the benefits of investigating tumor tissue applying LCM in a 3-dimensional fashion. In this manner, detailed insights into tumor microenvironment heterogeneity are obtained, thereby getting access to prognostic signatures (biomarkers) and molecular cancer pathophysiology [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

“…Hunt et al (2021) [ 19 ] demonstrated the benefits of investigating tumor tissue applying LCM in a 3-dimensional fashion. In this manner, detailed insights into tumor microenvironment heterogeneity are obtained, thereby getting access to prognostic signatures (biomarkers) and molecular cancer pathophysiology [ 19 ]. However, LCM is very time-consuming.…”

Section: Introductionmentioning

confidence: 99%

Tissue Sampling and Homogenization with NIRL Enables Spatially Resolved Cell Layer Specific Proteomic Analysis of the Murine Intestine

Voß

Moritz

Pelczar

et al. 2022

IJMS

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For investigating the molecular physiology and pathophysiology in organs, the most exact data should be obtained; if not, organ-specific cell lines are analyzed, or the whole organ is homogenized, followed by the analysis of its biomolecules. However, if the morphological organization of the organ can be addressed, then, in the best case, the composition of molecules in single cells of the target organ can be analyzed. Laser capture microdissection (LCM) is a technique which enables the selection of specific cells of a tissue for further analysis of their molecules. However, LCM is a time-consuming two-dimensional technique, and optimal results are only obtained if the tissue is fixed, e.g., by formalin. Especially for proteome analysis, formalin fixation reduced the number of identifiable proteins, and this is an additional drawback. Recently, it was demonstrated that sampling of fresh-frozen (non-fixed) tissue with an infrared-laser is giving higher yields with respect to the absolute protein amount and number of identifiable proteins than conventional mechanical homogenization of tissues. In this study, the applicability of the infrared laser tissue sampling for the proteome analysis of different cell layers of murine intestine was investigated, using LC–MS/MS-based differential quantitative bottom-up proteomics. By laser ablation, eight consecutive layers of colon tissue were obtained and analyzed. However, a clear distinguishability of protein profiles between ascending, descending, and transversal colon was made, and we identified the different intestinal-cell-layer proteins, which are cell-specific, as confirmed by data from the Human Protein Atlas. Thus, for the first time, sampling directly from intact fresh-frozen tissue with three-dimensional resolution is giving access to the different proteomes of different cell layers of colon tissue.

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Extensive three-dimensional intratumor proteomic heterogeneity revealed by multiregion sampling in high-grade serous ovarian tumor specimens

Cited by 26 publications

References 75 publications

Integrating computational pathology and proteomics to address tumor heterogeneity

Integrating computational pathology and proteomics to address tumor heterogeneity

Toward More Comprehensive Homologous Recombination Deficiency Assays in Ovarian Cancer Part 2: Medical Perspectives

Tissue Sampling and Homogenization with NIRL Enables Spatially Resolved Cell Layer Specific Proteomic Analysis of the Murine Intestine

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