establishment-characterization-patient-derived-gastric-organoids-from

Establishment and Characterization of Patient-derived Gastric Organoids from Biopsies of Benign Gastric Body and Antral Epithelium

Gastric patient-derived organoids (PDOs) offer a unique tool for studying gastric biology and pathology. Consequently, these PDOs find increasing use in a ...

Columbia University Irving Medical Center

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WITHDRAWN: FOXC1 modulates stem-like cell properties and chemoresistance through hedgehog and EMT signaling in gastric adenocarcinoma.

Gastric adenocarcinoma is one of the most common and lethal cancers worldwide and is associated with a high frequency of nodal metastasis. The value of multimodality therapy is well-established, but gastric resection and locoregional lymph node dissection are important mainstays in potentially curative therapy. However, there has been considerable regional variation in surgical approach and debate regarding the ideal extent of gastric resection, gastric reconstruction, and extent of lymphadenectomy. This chapter outlines the current evidence in the surgical management of gastric adenocarcinoma. The advent of minimally invasive approaches to gastric operations is also discussed.

Extent of gastrectomy and lymphadenectomy for gastric adenocarcinoma.

Randomized trials in the East have established minimally invasive gastrectomy as possibly superior for short-term outcomes and noninferior for long-term survival. Smaller randomized studies from Western countries have supported these findings. However, there are marked disparities in morbidity, mortality, and overall survival noted between Eastern and Western studies. In this article, we review the literature comparing open and minimally invasive gastrectomy in the East and West, and describe the possible reasons for differences in outcomes.

Open and minimally invasive gastrectomy in Eastern and Western patient populations: A review of the literature and reasons for differences in outcomes.

Retroperitoneal and pelvis sarcomas are uncommon tumors for which complete surgical resection is the mainstay of treatment. However, achieving complete gross resection with microscopically negative margins is challenging, and local recurrence rates can be high. Patients often succumb to uncontrolled local disease. Radiation therapy offers a potential means for sterilizing microscopic residual disease, although its use continues to be controversial. Chemotherapy alone or in combination with radiation continues to be investigated as an adjunct to surgery, along with immunotherapy and targeted therapies. In this review, we discuss the current management of retroperitoneal and pelvis sarcomas, focusing on studies of surgery and radiation therapy to maximize local control.

Treatment for local control of retroperitoneal and pelvis sarcomas: A review of the literature.

Germline mutation of CDH1 is rare and leads to hereditary diffuse gastric cancer (DGC).

Short and long-term outcomes of prophylactic total gastrectomy in 54 consecutive individuals with germline pathogenic mutations in the CDH1 gene.

Gastric adenocarcinoma is by far the most common form of gastric cancer (GC) and is a highly lethal form of cancer arising from the gastric epithelium. GC is an important area of focus of the medical community, given its often late-stage of diagnosis and associated high mortality rate. While surgery and chemotherapy remain the primary treatments, attention has been drawn to the use of immunologic therapies, which have shown promise in the treatment of other malignancies. The role for immune-based therapies has become clearer as we obtain a greater understanding of the role of the immune system in gastric cancer formation and growth. A variety treatment to augment the immune system are under evaluation in clinical trials, and these include immune checkpoint inhibitors, antibody-drug conjugates, and immune cell-based therapies. Here, we review the immune landscape and immune-based therapies for GC.

Gastric Cancer and the Immune System: The Key to Improving Outcomes?

Patients (pts) with locally advanced gastric adenocarcinoma (LAGA) often receive neoadjuvant chemotherapy. A minority of patients do not respond to chemotherapy and thus may benefit from upfront surgery. Patient-derived organoids (PDOs) are an in vitro model that may mimic the chemotherapy response of the original tumors.

Patient-Derived Organoids from Locally Advanced Gastric Adenocarcinomas Can Predict Resistance to Neoadjuvant Chemotherapy.

Gastric cancer is the third most common cause of cancer-related death worldwide. Diffuse-type gastric cancer (DGC) is a particularly aggressive subtype that is both difficult to detect and treat. DGC is distinguished by weak cell-cell cohesion, most often due to loss of the cell adhesion protein E-cadherin, a common occurrence in highly invasive, metastatic cancer cells. In this study, we demonstrate that loss-of-function mutation of E-cadherin in DGC cells results in their increased sensitivity to the non-apoptotic, iron-dependent form of cell death, ferroptosis. Homophilic contacts between E-cadherin molecules on adjacent cells suppress ferroptosis through activation of the Hippo pathway. Furthermore, single nucleotide mutations observed in DGC patients that ablate the homophilic binding capacity of E-cadherin reverse the ability of E-cadherin to suppress ferroptosis in both cell culture and xenograft models. Importantly, although E-cadherin loss in cancer cells is considered an essential event for epithelial-mesenchymal transition and subsequent metastasis, we found that circulating DGC cells lacking E-cadherin expression possess lower metastatic ability, due to their increased susceptibility to ferroptosis. Together, this study suggests that E-cadherin is a biomarker predicting the sensitivity to ferroptosis of DGC cells, both in primary tumor tissue and in circulation, thus guiding the usage of future ferroptosis-inducing therapeutics for the treatment of DGC.

E-cadherin is a biomarker for ferroptosis sensitivity in diffuse gastric cancer.

Dermatofibrosarcoma protuberans (DFSP) is an uncommon, locally aggressive cutaneous malignancy. Complete resection is the primary treatment but there is debate over the optimal method. Wide local excision was traditionally the standard of care; however, National Comprehensive Cancer Network guidelines now recommend Mohs micrographic surgery as the preferred approach. Medical therapy with imatinib can be used in advanced or unresectable disease. This review will discuss the current management of DFSP, focusing on optimal surgical approach.

Surgical management of dermatofibrosarcoma protuberans.

Our previous work showed that KRAS activation in gastric cancer cells leads to activation of an epithelial-to-mesenchymal transition (EMT) program and generation of cancer stem-like cells (CSCs). Here we analyze how this KRAS activation in gastric CSCs promotes tumor angiogenesis and metastasis. Gastric cancer CSCs were found to secrete pro-angiogenic factors such as vascular endothelial growth factor A (VEGF-A), and inhibition of KRAS markedly reduced secretion of these factors. In a genetically engineered mouse model, gastric tumorigenesis was markedly attenuated when both KRAS and VEGF-A signaling were blocked. In orthotropic implant and experimental metastasis models, silencing of KRAS and VEGF-A using shRNA in gastric CSCs abrogated primary tumor formation, lymph node metastasis, and lung metastasis far greater than individual silencing of KRAS or VEGF-A. Analysis of gastric cancer patient samples using RNA sequencing revealed a clear association between high expression of the gastric CSC marker CD44 and expression of both KRAS and VEGF-A, and high CD44 and VEGF-A expression predicted worse overall survival. In conclusion, KRAS activation in gastric CSCs enhances secretion of pro-angiogenic factors and promotes tumor progression and metastasis.

KRAS activation in gastric cancer stem-like cells promotes tumor angiogenesis and metastasis.

Gastric cancer is a highly prevalent and lethal disease worldwide. Given the insidious nature of the presenting symptoms, patients are frequently diagnosed with advanced, unresectable disease. However, many patients will present with locally advanced gastric cancer (LAGC), which is often defined as the primary tumor extending beyond the muscularis propria (cT3-T4) or having nodal metastases (cN+) disease and without distant metastases (cM0). LAGC is typically treated with surgical resection and perioperative chemotherapy. The treatment of LAGC remains a challenge, given the heterogeneity of this disease, and the optimal multimodal treatment regimen may be different for different LAGC subtypes. However, many promising treatments are on the horizon based on knowledge of molecular subtypes and key biomarkers of LAGC, such as microsatellite instability, HER2, Claudin 18.2, FGFR2, and PD-L1. This review will expand upon the discussion of current standard neoadjuvant and adjuvant therapies for LAGC and explore the ongoing and future clinical trials for novel therapies, with information obtained from searches in PubMed and ClinicalTrials.gov.

The Present and Future of Neoadjuvant and Adjuvant Therapy for Locally Advanced Gastric Cancer.

Sclerosing epithelioid fibrosarcoma (SEF) is an extremely rare subtype of sarcoma that appears histologically low-grade yet usually has a clinically aggressive course with a high rate of local recurrence and distant metastasis. However, these recurrences and metastases often occur years after initial treatment. Metastases can be to the lung as well as extra-pulmonary sites. In this case report, we discuss a patient who developed SEF in the deep soft tissue with metastases. This patient underwent checkpoint inhibitor therapy, with disease response. Thus, SEF is a sarcoma subtype with a unique tumor biology, and immunotherapy may be a promising avenue for treatment.

Article	Year
WITHDRAWN: FOXC1 modulates stem-like cell properties and chemoresistance through hedgehog and EMT signaling in gastric adenocarcinoma. Molecular therapy : the journal of the American Society of Gene Therapy\| PubMed ID: 34534693	2021
Extent of gastrectomy and lymphadenectomy for gastric adenocarcinoma. Surgical oncology\| PubMed ID: 34839198	2022
Open and minimally invasive gastrectomy in Eastern and Western patient populations: A review of the literature and reasons for differences in outcomes. Journal of surgical oncology\| PubMed ID: 35416303	2022
Treatment for local control of retroperitoneal and pelvis sarcomas: A review of the literature. Surgical oncology\| PubMed ID: 35834940	2022
Short and long-term outcomes of prophylactic total gastrectomy in 54 consecutive individuals with germline pathogenic mutations in the CDH1 gene. Journal of surgical oncology\| PubMed ID: 36063148	2022
Gastric Cancer and the Immune System: The Key to Improving Outcomes? Cancers\| PubMed ID: 36497422	2022
Patient-Derived Organoids from Locally Advanced Gastric Adenocarcinomas Can Predict Resistance to Neoadjuvant Chemotherapy. Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract\| PubMed ID: 36627466	2023
E-cadherin is a biomarker for ferroptosis sensitivity in diffuse gastric cancer. Oncogene\| PubMed ID: 36717701	2023
Surgical management of dermatofibrosarcoma protuberans. Journal of surgical oncology\| PubMed ID: 36999599	2023
KRAS activation in gastric cancer stem-like cells promotes tumor angiogenesis and metastasis. BMC cancer\| PubMed ID: 37481516	2023
The Present and Future of Neoadjuvant and Adjuvant Therapy for Locally Advanced Gastric Cancer. Cancers\| PubMed ID: 37627142	2023
Response to Immunotherapy in Sclerosing Epithelioid Fibrosarcoma: Case Report and Literature Review. Cureus\| PubMed ID: 38259411	2023

Sam S. Yoon

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