On the histopathological growth patterns of colorectal liver metastasis:a Study of Histology, Immunology, Genetics, and Prognosis

This thesis aims to validate and establish the histopathological growth patterns of colorectal cancer liver metastasis as a relevant biomarker, and to evaluate immunity and genetics as potential underlying biological mechanisms

In Vitro and In Vivo Models of Colorectal Cancer for Clinical Application

The Special Issue "In Vitro and In Vivo Models of Colorectal Cancer for Clinical Application", edited by Marta Baiocchi and Ann Zeuner for Cancers, collects original research papers and reviews, depicting the current state and the perspectives of CRC models for preclinical and translational research. Original research papers published in this issue focus on some of the hottest topics in CRC research, such as circulating tumor cells, epigenetic regulation of stemness states, new therapeutic targets, molecular CRC classification and experimental CRC models such as organoids and PDXs. Additionally, four reviews on CRC stem cells, immunotherapy and drug discovery provide an updated viewpoint on key topics linking benchtop to bedside research in CRC

The application of artificial intelligence and image analysis to novel prognostic classification systems of colorectal cancer

Summary: pp. IV-V

Evaluation of PD-L1 expression in various formalin-fixed paraffin embedded tumour tissue samples using SP263, SP142 and QR1 antibody clones

Background & objectives: Cancer cells can avoid immune destruction through the inhibitory ligand PD-L1. PD-1 is a surface cell receptor, part of the immunoglobulin family. Its ligand PD-L1 is expressed by tumour cells and stromal tumour infltrating lymphocytes (TIL). Methods: Forty-four cancer cases were included in this study (24 triple-negative breast cancers (TNBC), 10 non-small cell lung cancer (NSCLC) and 10 malignant melanoma cases). Three clones of monoclonal primary antibodies were compared: QR1 (Quartett), SP 142 and SP263 (Ventana). For visualization, ultraView Universal DAB Detection Kit from Ventana was used on an automated platform for immunohistochemical staining Ventana BenchMark GX. Results: Comparing the sensitivity of two different clones on same tissue samples from TNBC, we found that the QR1 clone gave higher percentage of positive cells than clone SP142, but there was no statistically significant difference. Comparing the sensitivity of two different clones on same tissue samples from malignant melanoma, the SP263 clone gave higher percentage of positive cells than the QR1 clone, but again the difference was not statistically significant. Comparing the sensitivity of two different clones on same tissue samples from NSCLC, we found higher percentage of positive cells using the QR1 clone in comparison with the SP142 clone, but once again, the difference was not statistically significant. Conclusion: The three different antibody clones from two manufacturers Ventana and Quartett, gave comparable results with no statistically significant difference in staining intensity/ percentage of positive tumour and/or immune cells. Therefore, different PD-L1 clones from different manufacturers can potentially be used to evaluate the PD- L1 status in different tumour tissues. Due to the serious implications of the PD-L1 analysis in further treatment decisions for cancer patients, every antibody clone, staining protocol and evaluation process should be carefully and meticulously validated

Anticancer Inhibitors

The word "cancer" is associated with at least 100 different pathologies, depending on the organ involved and the type of tumor developed. Cancer is a complex disease involving multiple pathogenetic mechanisms. Characterization of different types of cancers, which distinguishes them from healthy cells and other cancers, allows for the identification of specific targets for each individual tumor. The principle of chemotherapy is based on interference with the mechanisms that regulate the life and proliferation of cancer cells, causing their death. In recent years, there has been continuous progress in the development of therapeutic agents against cancer, which is ongoing.The Anticancer Inhibitors Special Issue focuses on new target-based anticancer agents that inhibit a specific target involved in the suppression of various types of cancer and the control of their chemoresistance.There is a collection of research and review articles on advances in drug discovery, design, and development of new inhibitor compounds with potency against various cancer types

Histopathology-selective spatial oncogenic phenotypes in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) constitutes over 85% of lung cancer. Histologically, NSCLC can be broadly classified into adenocarcinoma (AC), squamous cell carcinoma (SCC), large cell carcinoma (LCC), and adenosquamous carcinoma (ASC). AC represents about 65% of all NSCLC cases, and it can be further subdivided based on tumor size and primary growth patterns, such as papillary, acinar, and mucinous. The formation of NSCLC histotypes is orchestrated by cells of origin, genetic alterations, and microenvironmental properties. Although NSCLC carries significant heterogeneity, some genetic mutations, functional phenotypes, and therapeutic responses are associated with specific NSCLC histotypes. Therefore, understanding histotype-selective etiology becomes essential for mechanistic studies and therapeutic applications in the NSCLC research field. Image-based tissue phenotyping has been commonly used for histological classification. It also allows the direct visualization of the distribution and expression of functional molecules. Quantifying such in situ phenotypes can be applied to hypothesis-based functional studies or data-driven correlative analyses. The first part of this thesis developed a spatial image analysis tool package. The making of Spa-RQ, an open-source tool package for image registration and quantification, reflected on the need to perform spatial phenotyping using serial tissue sections in a standardized laboratory workflow. Subsequently, we applied Spa-RQ to identify the histotype-selective, rather than genetically defined activation of MAPK, AKT, and mTOR signaling pathways in murine and human NSCLC samples. The diverse co-activation patterns between these pathways in different tissue compartments, measured by marker expression overlapping using Spa-RQ, may associate with heterogeneous responses towards combinatorial targeted therapies. The second part of this thesis work investigated the histotype-selective functions of a potential therapeutic target. The lung developmental transcription factor SOX9 is silenced in normal adult lung epithelia while it is re-expressed in NSCLC tissues. Its oncogenicity is widely acknowledged but has thus far not been confirmed in NSCLC subtypes. Analyzing the correlation between SOX9 expression and histotype-specific clinical staging, survival, and invasiveness revealed a clinical significance for increased SOX9 expression only in non-mucinous ACs, despite its broad expression in ASC, SCC, and mucinous AC. Supporting this, by comparing the histotype spectra in mouse models following Sox9 loss, we identified a critical role of SOX9 in promoting lung papillary AC progression. On the other hand, its expression was not required for developing squamous and mucinous structure tissues. Finally, using spatial phenotyping, we explained such opposing roles of SOX9 in NSCLC subtypes by the different cells of origin and microenvironmental properties: SOX9 expression was required to form advanced AC from the lung alveolar progenitor cells; on the contrary, its expression was dispensable for SCC development and even interfered with squamous metastasis. Therefore, this work exposed SOX9 as a potential drug target specific to a subgroup of lung AC. In summary, the identification of histotype-selective functional oncogenic phenotypes, as achieved in this thesis, contributes to understanding the heterogeneous nature of tumorigenesis, cancer progression, and drug sensitivities.Non-small cell lung cancer (NSCLC) constitutes over 85% of lung cancer. Histologically, NSCLC can be broadly classified into adenocarcinoma (AC), squamous cell carcinoma (SCC), large cell carcinoma (LCC), and adenosquamous carcinoma (ASC). AC represents about 65% of all NSCLC cases, and it can be further subdivided based on tumor size and primary growth patterns, such as papillary, acinar, and mucinous. The formation of NSCLC histotypes is orchestrated by cells of origin, genetic alterations, and microenvironmental properties. Although NSCLC carries significant heterogeneity, some genetic mutations, functional phenotypes, and therapeutic responses are associated with specific NSCLC histotypes. Therefore, understanding histotype-selective etiology becomes essential for mechanistic studies and therapeutic applications in the NSCLC research field. Image-based tissue phenotyping has been commonly used for histological classification. It also allows the direct visualization of the distribution and expression of functional molecules. Quantifying such in situ phenotypes can be applied to hypothesis-based functional studies or data-driven correlative analyses. The first part of this thesis developed a spatial image analysis tool package. The making of Spa-RQ, an open-source tool package for image registration and quantification, reflected on the need to perform spatial phenotyping using serial tissue sections in a standardized laboratory workflow. Subsequently, we applied Spa-RQ to identify the histotype-selective, rather than genetically defined activation of MAPK, AKT, and mTOR signaling pathways in murine and human NSCLC samples. The diverse co-activation patterns between these pathways in different tissue compartments, measured by marker expression overlapping using Spa-RQ, may associate with heterogeneous responses towards combinatorial targeted therapies. The second part of this thesis work investigated the histotype-selective functions of a potential therapeutic target. The lung developmental transcription factor SOX9 is silenced in normal adult lung epithelia while it is re-expressed in NSCLC tissues. Its oncogenicity is widely acknowledged but has thus far not been confirmed in NSCLC subtypes. Analyzing the correlation between SOX9 expression and histotype-specific clinical staging, survival, and invasiveness revealed a clinical significance for increased SOX9 expression only in non-mucinous ACs, despite its broad expression in ASC, SCC, and mucinous AC. Supporting this, by comparing the histotype spectra in mouse models following Sox9 loss, we identified a critical role of SOX9 in promoting lung papillary AC progression. On the other hand, its expression was not required for developing squamous and mucinous structure tissues. Finally, using spatial phenotyping, we explained such opposing roles of SOX9 in NSCLC subtypes by the different cells of origin and microenvironmental properties: SOX9 expression was required to form advanced AC from the lung alveolar progenitor cells; on the contrary, its expression was dispensable for SCC development and even interfered with squamous metastasis. Therefore, this work exposed SOX9 as a potential drug target specific to a subgroup of lung AC. In summary, the identification of histotype-selective functional oncogenic phenotypes, as achieved in this thesis, contributes to understanding the heterogeneous nature of tumorigenesis, cancer progression, and drug sensitivity

The HBP1 tumor suppressor is a negative epigenetic regulator of MYCN driven neuroblastoma through interaction with the PRC2 complex

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