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WITHDRAWN: FOXC1 modulates stem-like cell properties and chemoresistance through hedgehog and EMT signaling in gastric adenocarcinoma.

Bidirectional signalling between the tumour and stroma shapes tumour aggressiveness and metastasis. ATF4 is a major effector of the Integrated Stress Response, a homeostatic mechanism that couples cell growth and survival to bioenergetic demands. Using conditional knockout ATF4 mice, we show that global, or fibroblast-specific loss of host ATF4, results in deficient vascularization and a pronounced growth delay of syngeneic melanoma and pancreatic tumours. Single-cell transcriptomics of tumours grown in Atf4 mice uncovered a reduction in activation markers in perivascular cancer-associated fibroblasts (CAFs). Atf4 fibroblasts displayed significant defects in collagen biosynthesis and deposition and a reduced ability to support angiogenesis. Mechanistically, ATF4 regulates the expression of the Col1a1 gene and levels of glycine and proline, the major amino acids of collagen. Analyses of human melanoma and pancreatic tumours revealed a strong correlation between ATF4 and collagen levels. Our findings establish stromal ATF4 as a key driver of CAF functionality, malignant progression and metastasis.

A stromal Integrated Stress Response activates perivascular cancer-associated fibroblasts to drive angiogenesis and tumour progression.

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.

Children with Down syndrome (DS, trisomy 21) are at a significantly higher risk of developing acute leukemia compared to the overall population. Many studies investigating the link between trisomy 21 and leukemia initiation and progression have been conducted over the last two decades. Despite improved treatment regimens and significant progress in iden - tifying genes on chromosome 21 and the mechanisms by which they drive leukemogenesis, there is still much that is unknown. A focused group of scientists and clinicians with expertise in leukemia and DS met in October 2022 at the Jérôme Lejeune Foundation in Paris, France for the 1st International Symposium on Down Syndrome and Leukemia. This meeting was held to discuss the most recent advances in treatment regimens and the biology underlying the initiation, progression, and relapse of acute lymphoblastic leukemia and acute myeloid leukemia in children with DS. This review provides a summary of what is known in the field, challenges in the management of DS patients with leukemia, and key questions in the field.

Down syndrome and leukemia: from basic mechanisms to clinical advances.

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.

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
A stromal Integrated Stress Response activates perivascular cancer-associated fibroblasts to drive angiogenesis and tumour progression. Nature cell biology\| PubMed ID: 35654839	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
Down syndrome and leukemia: from basic mechanisms to clinical advances. Haematologica\| PubMed ID: 37439336	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

Sandra Ryeom

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