Cancers Of Epithelial Origin Research Articles

EBV infection alters DNA methylation in primary human colon cells: A path to inflammation and carcinogenesis?

Epstein-Barr Virus (EBV) is associated with several types of human cancers, and changes in DNA methylation are reported to contribute to viral-driven carcinogenesis, particularly in cancers of epithelial origin. In a previous study, we demonstrated that EBV infects human primary colonic cells (HCoEpC) and replicates within these cells, leading to pro-inflammatory and pro-tumorigenic effects. Notably, these effects were mostly prevented by inhibiting viral replication with PAA. Interestingly, the EBV-induced effects correlated with the upregulation of DNMT1 and were counteracted by pretreating cells with 5-AZA, suggesting a role for DNA hypermethylation.Building on this background, the current study investigates the methylation changes induced by EBV infection in HCoEpC, both in the presence and absence of PAA, or ERK1/2 and STAT3 inhibitors, pathways known to be activated by EBV and involved in the dysregulation of methylation in tumor cells. The genome-wide methylation analysis conducted in this study allowed us to identify several biological processes and genes affected by these epigenetic changes, providing insights into the possible underlying mechanisms leading to the pathological effects induced by EBV. Specifically, we found that the virus induced significant methylation changes, with hypermethylation being more prevalent than hypomethylation. Several genes involved in embryogenesis, carcinogenesis, and inflammation were affected.

Expression and clinical significance of CLDN7 and its immune-related cells in breast cancer

BackgroundCLDN is a core component of tight junctions (TJs). Abnormal expressions of CLDNs are commonly detected in various types of tumors. CLDNs are of interest as a potential therapeutic target. CLDNs are closely associated with most cancers of epithelial origin, especially when CLDN7 promotes cancer cell metastasis, such as in gastric, cervical, and ovarian cancers.Its expression and prognosis in breast cancer (BC) remain unknown.The purpose of this study was to investigate the expression pattern of CLDN7 and related immune factors in BC and shed light on a better therapeutic avenue for BC patients.MethodThe cBioPortal, GEPIA, and TCGA databases were used to comprehensively assess the expression of CLDN7 in BC. The Kaplan-Meier Plotter (KMP) database was applied to examine the relationship among the CLDN7 overexpression (OE), prognosis, and overall survival (OS) of BC patients. Immunohistochemical staining was performed on 92 BC tissue samples and 20 benign breast tumors to verify the expression level of CLDN-7 protein and its correlation with clinicopathological features and prognosis. TIMER2.0 was used to analyze the correlation between the CLDN7 OE and immune gene activation using BC-related transcriptomic data. Enrichment analyses of CLDN7-related immune pathways were conducted using online databases. The risk of expression of CLDN7-related immune genes was assessed and differentially expressed (DE) genes were included in the construction of the risk prognosis nomogram.ResultsBoth database analysis and clinical sample validation results showed that CLDN7 was significantly overexpressed (OE) in BC, and the OE was correlated with poor DFS in BC patients (p < 0.05). TIMER2.0 analysis indicated that CLDN7 OE was negatively associated with the activation of B-cells, CD4+ T-cells, and CD8+ T-cells but positively with the M0 macrophages. Pathway enrichment analysis suggested that CLDN7-related immune factors were mostly involved in the NF-κB and T-cell receptor (TCR) signaling pathways. Univariate Cox regression was used to analyze the correlation between 52 CLDN7 related genes and OS, and 22 genes that are related to prognosis were identified. Prognostic genes were included in the prognostic nomogram of BC with a C-index of 0.76 to predict the 3-year and 5-year OS probabilities of BC individuals.ConclusionsThese findings provide evidence for the role of CLDN7-linked tumor immunity, suggesting that CLDN7 might be a potential immunotherapeutic target for BC, and its association with immune markers could shed light on the better prognosis of BC.

Mechanistic Characterization of Cancer-associated Fibroblast Depletion via an Antibody-Drug Conjugate Targeting Fibroblast Activation Protein.

The direct elimination of FAP-expressing CAFs disrupts the cross-talk with cancer cells leading to a proinflammatory response and alterations in the immune microenvironment and antitumor immune response.

Enfortumab vedotin plus pembrolizumab in the treatment of locally advanced or metastatic bladder cancer of variant histology: A phase II study.

TPS4615 Background: Bladder cancers of variant histology (BCVH) account for up to 25% of bladder cancer incidence and affected patients (pts) usually have poor outcomes. The treatment options are limited due to the underrepresentation or exclusion of BCVH pts from trials for locally advanced or metastatic urothelial cancer (mUC). Enfortumab vedotin (EV) is an antibody-drug conjugate specific for Nectin-4. In the EV 302 Phase III trial, EV+pembrolizumab (pembro) significantly prolonged overall survival (OS) compared to platinum-based chemotherapy in mUC (HR 0.47, 95% CI 0.38-0.58) and was recently FDA-approved as standard of care in 1L mUC. Translational studies from our center show Nectin-4 expression in many BCVH pts and data support immune-checkpoint inhibitor (ICI) activity in subsets of these pts. We hypothesize the presence of clinical activity of this combination in BCVH. Therefore, we designed this trial to assess the efficacy and safety of EV+pembro in locally advanced or metastatic BCVH (mBCVH). Methods: This is a Phase II, open-label, single-center trial at the Winship Cancer Institute of Emory University (NCT05756569) for pts with mBCVH. Pts will receive pembro 200mg IV on Day 1 and EV 1.25mg/Kg IV on Days 1 and 8 of a 21-day cycle for up to two years. The eligibility criteria include histologically confirmed variant histology or non-urothelial bladder cancer of epithelial origin including squamous cell carcinoma and adenocarcinoma (according to the WHO 2016 Classification), ECOG 0-1, and any line of therapy. Pts with neuroendocrine bladder cancer, non-epithelial cancers (e.g. sarcoma, lymphoma), prior ICI and/or EV treatment are excluded. Overall response rate (ORR) per RECIST 1.1 is the primary outcome and will be tested using Simon's two-stage design (n=25). The first interim analysis is planned after 15 patients. The desirable target is ORR≥30% relative to a null hypothesis of ORR ≤10%. This statistical design yields a type I error rate of 0.05 and a power of 80% for a true ORR≥30%. Key secondary outcomes include OS, progression-free survival, duration of response, and incidence of adverse events per CTCAE v5.0. Correlative biomarker analyses using blood- and tissue-based assays will be conducted during screening and at disease progression. The trial is currently open for enrollment. Clinical trial information: NCT05756569 .

Multi-omics integration identifies cell-state-specific repression by PBRM1-PIAS1 cooperation

PBRM1 is frequently mutated in cancers of epithelial origin. How PBRM1 regulates normal epithelial homeostasis, prior to cancer initiation, remains unclear. Here, we show that PBRM1's gene regulatory roles differ drastically between cell states, leveraging human skin epithelium (epidermis) as a research platform. In progenitors, PBRM1 predominantly functions to repress terminal differentiation to sustain progenitors' regenerative potential; in the differentiation state, however, PBRM1 switches toward an activator. Between these two cell states, PBRM1 retains its genomic binding but associates with differential interacting proteins. Our targeted screen identified the E3 SUMO ligase PIAS1 as a key interactor. PIAS1 co-localizes with PBRM1 on chromatin to directly repress differentiation genes in progenitors, and PIAS1's chromatin binding drastically diminishes in differentiation. Furthermore, SUMOylation contributes to PBRM1's repressive function in progenitor maintenance. Thus, our findings highlight PBRM1's cell-state-specific regulatory roles influenced by its protein interactome despite its stable chromatin binding.

Frequency and Management Outcome in Gynecological Malignancies

Objective: The study was done to find out the frequency of different gynaecological malignancies, histological types and management outcome of these malignancies. Material and Methods: This study was conducted in unit III of Obtetrics and Gynecology Department, Jinnah Hospital, Lahore. Duration of study was 2 years from January 2018 to December 2019 and sample size was 81. All the cases presented with gynaecological cancer was analysed retrospectively by reviewing record. Complete data was evaluated in term of frequency of malignancies and their percentages. Results: The most common site of gynaecological malignancy was cervical 35 cases (43.2%) followed by ovarian 30 cases(37%).Uterine wasthe 3rd most common tumour with 13 cases(16%).The vulval and vaginal cancers were found to be lowest with 01 case each (1.2%). There was one case of choriocarcinoma (1.2%). Conclusion: Cervical cancer was the commonest cancer with squamous cell histological type (80%) followed by ovarian cancer of epithelial origin (73.3%).

Clinical significance of detection of micrometastases in lymph nodes in ovarian cancer

Ovarian cancer of epithelial origin is the most common type of oncological process in this organ and is characterized by a high probability of fatal outcome. It is believed that this is due to insufficiently effective diagnosis of the prevalence and severity of this disease. This review presents data on the development of disease recurrence in a significant number of patients after cytoreductive surgery. According to some authors, the reason for the high risk of recurrence is the insufficient information content of the method of studying histological preparations of regional lymph nodes after staining with hematoxylin and eosin to detect small-sized metastases, including isolated tumor cells and micrometastases. To improve the accuracy of such diagnostics, it is recommended to supplement the study of multilevel sections of lymph nodes using routine staining with the use of immunohistochemistry and other methods using various antibodies to cytokeratins, along with other epithelial markers. The review provides an analysis of the opinions of various researchers on the prognostic significance of the detection of micrometastases in the lymph nodes, which can increase the effectiveness of therapy due to a more accurate assessment of the prevalence of the disease and correction of the tactics of treating patients with various oncological diseases.

Abstract 2601: Lrig1 is a haplo-insufficient tumor suppressor and Lrig1-expressing cells can function as cells-of-origin of tumor development

Abstract LRIG1, leucine-rich repeats and immunoglobulin-like domains protein 1, is deleted or downregulated in many cancer types and has been reported to function as a tumor suppressor. LRIG1 is preferentially expressed in adult stem/progenitor cells and regulates their biological properties and quiescence by repressing the ERBB signaling. We recently reported LRIG1 to be overexpressed in human prostate cancer and to function as a feedback tumor suppressor. Human LRIG1 transgenically expressed in the mouse prostate inhibited the development and growth of both Hi-Myc and TRAMP tumors. The relationship between Lrig1-expressing adult stem/progenitor cells and cells-of-origin for cancer remains poorly understood. To address this, we deleted the Pten tumor suppressor gene in Lrig1-expressing cells by crossing Lrig1-CreERT2 mouse with Ptenfl/fl animals followed by Cre activation via tamoxifen administration. This knockout of Pten in Lrig1-expressing cells allowed us to assess the tumor suppressive function of Lrig1 as Lrig1-CreERT2 is a knock-in model in which one allele of Lrig1 is inactivated. We also generated a Lrig1-lineage tracing mouse model to label endogenous Lrig1-expressing cells by crossing Lrig1-CreERT2 mouse with CAG-tdTomato animals. Cre recombinase in these animals was activated by tamoxifen and epithelial tissues were harvested and analyzed for tomato signal by fluorescent microscopy. Lrig1-lineage tracing model showed that Lrig1-expressing cells in mouse prostate and oral epithelia are of CK5+ and CK8- phenotype suggesting their basal lineage. Targeted deletion of Pten in the Lrig1-expressing cellular compartments resulted in hyperplasic lesions in oral mucosa as early as 4 weeks and prevalent papilloma by 8 weeks. Pten deletion in the mouse prostate led to hyperplasia and high-grade prostate intraepithelial neoplasia (HGPIN) in a time-dependent manner. Consistent with these hyperplastic and tumor phenotypes, we observed elevated Ki-67 and pAkt staining indicating increased cell proliferation. Since Lrig1-CreERT2 is a knock-in model in which one allele of Lrig1 is inactivated, our data suggest that even one allelic loss of Lrig1 promotes more aggressive tumor phenotypes compared to those reported earlier with Pten deletion in CK5+ basal cells (CK5-CreERT2:Ptenfl/fl) in which similar lesions in oral mucosa and prostate tissues developed only after 20-24 weeks of Pten deletion. These results suggested that LRIG1 is a haplo-insufficient tumor suppressor as mono-allelic deletion of Lrig1 is sufficient to promote the tumorigenic process in mouse epithelial tissues induced by Pten loss. Our study also suggests that the Lrig-1 expressing cells can function as the cells-of-origin of cancer. We propose that Lrig1 may be used as a prognostic marker in cancers of epithelial origin and higher levels may portend a better prognosis. Citation Format: Moyi Wang, Qiuhui Li, Amanda Tracz, Jason Kirk, Anmbreen Jamroze, Rahul Kumar, Dean G. Tang. Lrig1 is a haplo-insufficient tumor suppressor and Lrig1-expressing cells can function as cells-of-origin of tumor development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2601.

Regulation of the Epithelial to Mesenchymal Transition in Osteosarcoma.

The epithelial to mesenchymal transition (EMT) is a cellular process that has been linked to the promotion of aggressive cellular features in many cancer types. It is characterized by the loss of the epithelial cell phenotype and a shift to a more mesenchymal phenotype and is accompanied by an associated change in cell markers. EMT is highly complex and regulated via multiple signaling pathways. While the importance of EMT is classically described for carcinomas-cancers of epithelial origin-it has also been clearly demonstrated in non-epithelial cancers, including osteosarcoma (OS), a primary bone cancer predominantly affecting children and young adults. Recent studies examining EMT in OS have highlighted regulatory roles for multiple proteins, non-coding nucleic acids, and components of the tumor micro-environment. This review serves to summarize these experimental findings, identify key families of regulatory molecules, and identify potential therapeutic targets specific to the EMT process in OS.

An integrative approach for exploring the nature of fibroepithelial neoplasms

BackgroundMalignant phyllodes tumour (MPT) is a rare breast malignancy with epithelial and mesenchymal features. Currently, there are no appropriate research models or effective targeted therapeutic approaches for MPT.MethodsWe collected fresh frozen tissues from nine patients with MPT and performed whole-exome and RNA sequencing. Additionally, we established patient-derived xenograft (PDX) models from patients with MPT and tested the efficacy of targeting dysregulated pathways in MPT using the PDX model from one MPT.ResultsMPT has unique molecular characteristics when compared to breast cancers of epithelial origin and can be classified into two groups. The PDX model derived from one patient with MPT showed that the mouse epithelial component increased during tumour growth. Moreover, targeted inhibition of platelet-derived growth factor receptor (PDGFR) and phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) by imatinib mesylate and PKI-587 showed in vivo tumour suppression effects.ConclusionsThis study revealed the molecular profiles of MPT that can lead to molecular classification and potential targeted therapy, and suggested that the MPT PDX model can be a useful tool for studying the pathogenesis of fibroepithelial neoplasms and for preclinical drug screening to find new therapeutic strategies for MPT.

A phase 2, multicenter, open-label study evaluating trastuzumab deruxtecan (T-DXd) for the treatment of select human epidermal growth factor receptor 2 (HER2)-expressing solid tumors (DESTINY-PanTumor02) (296)

<b>Objectives:</b> Human epidermal growth factor receptor 2 (HER2) is an established therapeutic target in both breast and gastric cancer. However, HER2-targeting therapies are not approved beyond these malignancies despite a high prevalence of HER2 expression across cancers of epithelial origin. Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate consisting of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a topoisomerase I inhibitor payload. In a cohort of pretreated patients with multiple HER2-expressing tumors, T-DXd demonstrated promising antitumor activity, with an investigator-assessed confirmed objective response rate of 40.9% (9 of 22 patients) and median progression-free survival of 11.1 months (95% CI: 5.4-20.5 months; Tsurutani J, et al. <i>Cancer Discov</i>. 2020;10:688-701). Here we describe the phase II DESTINY-PanTumor02 trial evaluating T-DXd in patients with select HER2-expressing solid tumors. <b>Methods:</b> DESTINY-PanTumor02 (NCT04482309) is an open-label, multi-center, multi-cohort, phase II study evaluating T-DXd for the treatment of patients with select HER2-expressing locally advanced, unresectable, or metastatic tumors. The study will consist of seven cohorts of patients (<i>n</i>≈40 each) with urothelial bladder, biliary tract, cervical, endometrial, ovarian, pancreatic, or rare tumors (tumors excluding those in the other cohorts and breast, gastric, colorectal, and non-small cell lung cancer). Patients are required to have disease progression following ≥1 prior systemic treatment for advanced or metastatic disease or have no satisfactory alternative treatment options. Prior HER2-targeting therapy is allowed. The primary endpoint is investigator-assessed confirmed objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary endpoints include duration of response, disease control rate, progression-free survival (all per investigator assessment according to RECIST 1.1), overall survival, safety, pharmacokinetics, and immunogenicity. Previously presented at the ESMO Congress 2021, FPN:1869 TiP, Meric-Bernstam, et al. - Reused with permission.

Poly(I:C) transfection induces a pro-inflammatory cascade in murine mammary carcinoma and fibrosarcoma cells

ABSTRACT Germline-encoded pattern recognition receptors [PRRs] in mammalian cells function in the detection of molecular patterns associated with pathogen invasion or cellular damage. A PRR subset is activated by the atypical presence and location of double-stranded RNA [dsRNA] or its synthetic analogue polyinosinic-polycytidylic acid [poly(I:C)], triggering pro-inflammatory signalling and death in many cell types. Poly(I:C) has been tested as a sole or combination cancer therapy in preclinical studies and clinical trials. The purpose of this study was to evaluate the effects of poly(I:C) transfection via electroporation on cell lines from a cancer of epithelial origin, 4T1 mammary carcinoma, and a cancer of mesenchymal origin, WEHI 164 fibrosarcoma. The effects of the poly(I:C) delivery on cell metabolism implicate the induction of cell death. A pro-inflammatory response was demonstrated by mRNA upregulation and the secretion of Type I interferon and several cytokines and chemokines. The mRNAs of dsRNA sensor DExD/H-box helicase 58/retinoic acid-inducible gene I protein [Ddx58/RIG-I] and sensor/co-sensor DEAH-box helicase 9 [Dhx9] were not regulated, but the mRNAs of RNA sensors toll-like receptor 3 [TLR3], interferon-induced with helicase C domain 1/melanoma differentiation-associated protein 5 [Ifih1/MDA5] and Z-DNA binding protein 1 [Zbp1] and co-sensors DEAD (Asp-Glu-Ala-Asp) box polypeptide 60 [Ddx60] and interferon-inducible protein 204 [Ifi204] were upregulated in both cell lines. The mRNAs encoding signalling pathways components were present or upregulated in both cell types. These data demonstrate that RNA sensing effects can be amplified by electroporation delivery, potentially expanding the practicality of this immunotherapeutic approach.

Circulating tumor cells as a biomarker for monitoring: Disease progression, treatment response, and minimal residual disease.

e15021 Background: To analyze the role of Circulating tumor cells (CTC) as a confirmatory personalized biomarker for monitoring the disease progression, disease burden, and minimal residual disease in epithelial origin cancers. Methods: In this retrospective study, 127 patients with colorectal, breast, and ovarian cancer at stage III and IV were analyzed. The patients were at various stages of intensive chemo and radiotherapy while the CTCs were isolated and enumerated from 1.5 ml of blood. The decision to continue chemotherapy or change to oral metronomic therapy was based on the presence of circulating tumor cells in Stage III. While in stage IV, serial measurement of CTC guided therapy. CTCs were isolated using OncoDiscover platform possessing EpCAM antibody based immunomagnetic targeting of magnetic nanoparticles after RBC lysis. CTCs were imaged and identified as CK18+ and CD45- cells showing a well-defined nucleus using a motorized fluorescence microscope operational with a monochrome camera. CTCs were enumerated using automated image analysis software and counts were expressed as number per 1.5 ml of blood. Results: In this retrospective study we analyzed blood sample from 127 patients with the advanced stage epithelial cancers (breast- 50 %, ovarian -27 %, colorectal- 23 %) for the presence of CTCs. Amongst those, 52 % showed the presence of CTCs (breast- 52 %, ovarian -46 %, colorectal- 58 %). The CTC count ranged between 1-5 / 1.5 ml of blood with mean and median value of 2 and 1. Among the CTC positive population, majority had CTC count of 1 (44.4 %), while more than 2 CTCs were observed in 11 % of population. CTC clusters were detected in 13 % of population which predominantly were stage IV patients. 67 % among the follow up patients showed decrease in CTC count from the baseline due to the prescribed treatment, while 22 % patients showed increase in CTC count from the baseline. 11 % patients did not show change in CTC count from the baseline. When CTCs count was investigated as an independent variable to monitor the therapeutic response, it correlated well with the positive or negative outcome. In few representative cases, the reduction of CTC number from the basal value was indicative of an effective treatment. Exceptionally, in a representative colorectal cancer case, PET showed no primary as well secondary tumor burden, but the presence of CTCs in blood led further investigating an abdominal MRI that indicated multiple liver lesions suggesting micro-metastasis. Subsequent to SIRT treatment, the patient showed complete tumor regression and absence of CTCs in peripheral blood. Conclusions: Our data suggest that CTC can serve as a dynamic intermittent biomarker for monitoring the disease progression in advanced stages and assess the therapeutic response, thus emphasizing the role of CTCs in personalized cancer management.

Differential Impacts on Tensional Homeostasis of Gastric Cancer Cells Due to Distinct Domain Variants of E-Cadherin.

Simple SummaryTensional homeostasis describes the ability of cells and tissues to maintain their internal mechanical tension stable at a set point value. A breakdown of tensional homeostasis is the hallmark of disease progression, including cancers. In cancers of epithelial origin, this phenomenon is closely associated with dysfunction of E-cadherin. In this study, we investigated how E-cadherin mutations identified in patients with cancer affect tensional homeostasis. Our results show that mutations affecting the juxtamembrane and intracellular domains of E-cadherin are detrimental for tensional homeostasis of gastric cancer cells.In epithelia, breakdown of tensional homeostasis is closely associated with E-cadherin dysfunction and disruption of tissue function and integrity. In this study, we investigated the effect of E-cadherin mutations affecting distinct protein domains on tensional homeostasis of gastric cancer cells. We used micropattern traction microscopy to measure temporal fluctuations of cellular traction forces in AGS cells transfected with the wild-type E-cadherin or with variants affecting the extracellular, the juxtamembrane, and the intracellular domains of the protein. We focused on the dynamic aspect of tensional homeostasis, namely the ability of cells to maintain a consistent level of tension, with low temporal variability around a set point. Cells were cultured on hydrogels micropatterned with different extracellular matrix (ECM) proteins to test whether the ECM adhesion impacts cell behavior. A combination of Fibronectin and Vitronectin was used as a substrate that promotes the adhesive ability of E-cadherin dysfunctional cells, whereas Collagen VI was used to test an unfavorable ECM condition. Our results showed that mutations affecting distinct E-cadherin domains influenced differently cell tensional homeostasis, and pinpointed the juxtamembrane and intracellular regions of E-cadherin as the key players in this process. Furthermore, Fibronectin and Vitronectin might modulate cancer cell behavior towards tensional homeostasis.

Hydroxyapatite Nanoparticles as a Potential Long-Term Treatment of Cancer of Epithelial Origin

Hydroxyapatite Nanoparticles as a Potential Long-Term Treatment of Cancer of Epithelial Origin

Grainyhead-like (Grhl) Target Genes in Development and Cancer.

Grainyhead-like (GRHL) factors are essential, highly conserved transcription factors (TFs) that regulate processes common to both natural cellular behaviours during embryogenesis, and de-regulation of growth and survival pathways in cancer. Serving to drive the transcription, and therefore activation of multiple co-ordinating pathways, the three GRHL family members (GRHL1-3) are a critical conduit for modulating the molecular landscape that guides cellular decision-making processes during proliferation, epithelial-mesenchymal transition (EMT) and migration. Animal models and in vitro approaches harbouring GRHL loss or gain-of-function are key research tools to understanding gene function, which gives confidence that resultant phenotypes and cellular behaviours may be translatable to humans. Critically, identifying and characterising the target genes to which these factors bind is also essential, as they allow us to discover and understand novel genetic pathways that could ultimately be used as targets for disease diagnosis, drug discovery and therapeutic strategies. GRHL1-3 and their transcriptional targets have been shown to drive comparable cellular processes in Drosophila, C. elegans, zebrafish and mice, and have recently also been implicated in the aetiology and/or progression of a number of human congenital disorders and cancers of epithelial origin. In this review, we will summarise the state of knowledge pertaining to the role of the GRHL family target genes in both development and cancer, primarily through understanding the genetic pathways transcriptionally regulated by these factors across disparate disease contexts.

Abstract P1-06-02: Targeted deletion of Kindlin-2 in mouse mammary glands inhibits tumor growth, invasion and metastasis downstream of TGF-β/EGF oncogenic signaling pathway

Abstract Cancer metastasis is a complex process by which cancer cells migrate through the blood and the lymphatic systems to lodge and proliferate in distant sites and organs in the body. Metastasis is the main cause of death in patients suffering from cancer, including those patients with breast cancer. Breast cancer (BC) is the most frequently diagnosed malignancy in women and is one of the leading causes of death due to cancer invasion, metastasis, and resistance to therapies. Among its variants, triple-negative breast cancer (TNBC) is considered the most aggressive due to its early invasive and metastatic properties with poor prognosis. Kindlin-2, which is encoded by Fermitin family homolog 2 gene (FERMT2) has been associated with pathogenesis of several types of cancers of epithelial origin. Our previous studies have addressed the role of Kindlin-2 as a major regulator of the invasion-metastasis cascade in breast cancer by controlling several hallmarks of cancer in tumor cells. The contribution of mammary epithelial cell Kindlin-2 in the mammary glands to the process of tumor progression and metastasis has, however, not been investigated. Accordingly, we generated a floxed mouse strain by targeting the FREMT2 (K2lox/lox) locus using a CRISPR/Cas9-based editing strategy, followed by tissue-specific deletion of the Kindlin-2 in the basal subtype of the mammary epithelial cells (MECs) in the mouse mammary glands by crossing the K2lox/lox mice with K14-cre mice. Loss of Kindlin-2 in the basal MECs had no deleterious effects on mammary glands development, mouse development and fertility and lactation in mice bearing the Kindlin 2-deletetion phenotype and their progeny. However, in a syngeneic mouse model of BC, the loss of Kindlin-2 in MECs inhibited tumor growth and metastasis in mice inoculated with the aggressive murine TNBC E0771 cells when implanted directly in their mammary fat pads. Injecting the E0771 cells via the tail vein of Kindlin-2-deleted mice had, however, no effect on tumor colonization in the lungs, when compared to wild-type mice, clearly supporting a critical role of MECs Kindlin-2 in BC tumor growth and metastasis. Mechanistically, we found the MECs Kindlin-2-mediated inhibition of tumor growth and metastasis is through the regulation of the TGF-β/ERK MAP. kinase signaling axis, in a similar manner that our published studies showed that Kindlin-2 regulates this oncogenic pathway in the BC cells. Thus, our findings strongly suggest that Kindlin-2 supports BC oncogenesis in both the tumor cells and the MECs in the mammary glands, through the regulation of the TGF-β/EGF oncogenic signaling pathway. Therefore, therapeutic strategies targeting Kindlin-2 in both the cancer cells and the mammary glands may be necessary for a successful inhibition of BC tumors. Citation Format: Priyanka Rana, Wei Wang, Akram Alkrekchi, Katarzyna Bialkowska, Vesna Markovic, Edward F Plow, Elzbieta Pluskota, Khalid Sossey-Alaoui. Targeted deletion of Kindlin-2 in mouse mammary glands inhibits tumor growth, invasion and metastasis downstream of TGF-β/EGF oncogenic signaling pathway [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-06-02.

Inhibition of integrin αvβ6 sparks T-cell antitumor response and enhances immune checkpoint blockade therapy in colorectal cancer

BackgroundIntegrin αvβ6 is a heterodimeric cell surface protein whose cellular expression is determined by the availability of the integrin β6 subunit (ITGB6). It is expressed at very low levels in...

A phase 2, multicenter, open-label study evaluating trastuzumab deruxtecan (T-DXd) for the treatment of select human epidermal growth factor receptor 2 (HER2)-expressing solid tumors (DESTINY-PanTumor02).

TPS623 Background: Human epidermal growth factor receptor 2 (HER2) is an established therapeutic target in both breast and gastric cancer. However, HER2-targeting therapies are not approved beyond these malignancies despite a high prevalence of HER2 expression across cancers of epithelial origin. Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate consisting of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a topoisomerase I inhibitor payload. In a cohort of pretreated patients with multiple HER2-expressing tumors, T-DXd demonstrated promising antitumor activity, with an investigator-assessed confirmed objective response rate of 40.9% (9 of 22 patients) and median progression-free survival of 11.1 months (95% CI, 5.4-20.5 months; Tsurutani J, et al. Cancer Discov. 2020;10:688-701). Here we describe the phase 2 DESTINY-PanTumor02 trial evaluating T-DXd in patients with select HER2-expressing solid tumors. Methods: DESTINY-PanTumor02 (NCT04482309) is an open-label, multicenter, multicohort, phase 2 study evaluating T-DXd for the treatment of patients with select HER2-expressing locally advanced, unresectable, or metastatic tumors. The study will consist of 7 cohorts of patients (n≈40 each) with urothelial bladder, biliary tract, cervical, endometrial, ovarian, pancreatic, or rare tumors (tumors excluding those in the other cohorts and breast, gastric, colorectal, and non-small cell lung cancer). Patients are required to have disease progression following ≥1 prior systemic treatment for advanced or metastatic disease or have no satisfactory alternative treatment options. Prior HER2-targeting therapy is allowed. The primary endpoint is investigator-assessed confirmed objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary endpoints include duration of response, disease control rate, progression-free survival (all per investigator assessment according to RECIST 1.1), overall survival, safety, pharmacokinetics, and immunogenicity. Previously presented at the ESMO Congress 2021, FPN: 1869 TiP, Meric-Bernstam et al. Reused with permission. Clinical trial information: NCT04482309.

Expression and Impact of C1GalT1 in Cancer Development and Progression.

Simple SummaryC1GalT1 is one of the enzymes that catalyze the addition of sugar residues to proteins (protein glycosylation). It specifically controls the synthesis and formation of a special disaccharide structure Galβ1,3GalNAcα-, which occurs predominately in cancer but rarely in normal cells. Recent studies have shown that C1GalT1 is overexpressed in many common cancers including colon, breast, gastric, lung, head and neck, pancreatic, esophageal, prostate, and hepatocellular cancer. C1GalT1 overexpression is also often associated with poorer prognosis and poorer patient survival. This review summarizes our current understanding of the expression of C1GalT1 in various cancers and discusses the impact of C1GalT change on cancer cell activities in cancer development and progression.C1GalT1 (T-synthase) is one of the key glycosyltransferases in the biosynthesis of O-linked mucin-type glycans of glycoproteins. It controls the formation of Core-1 disaccharide Galβ1,3GalNAcα- (Thomsen–Friedenreich oncofetal antigen, T or TF antigen) and Core-1-associated carbohydrate structures. Recent studies have shown that C1GalT1 is overexpressed in many cancers of epithelial origin including colon, breast, gastric, head and neck, pancreatic, esophageal, prostate, and hepatocellular cancer. Overexpression of C1GalT1 is often seen to also be associated with poorer prognosis and poorer patient survival. Change of C1GalT1 expression causes glycosylation changes of many cell membrane glycoproteins including mucin proteins, growth factor receptors, adhesion molecules, and death receptors. This leads to alteration of the interactions of these cell surface molecules with their binding ligands, resulting in changes of cancer cell activity and behaviors. This review summarizes our current understanding of the expression of C1GalT1 in various cancers and discusses the impact of C1GalT change on cancer cell activities in cancer development and progression.