Tumor Cell Invasion Research Articles

UBE2Q1 as a novel cancer biomarker for lung adenocarcinoma: Short Title: Oncogenic function of UBE2Q1 in lung adenocarcinoma

PurposeUbiquitin-conjugating enzymes (E2s) participate in various tumor-promoting processes. UBE2Q1 is a member of the E2 family. This research aimed to detect the expression level of UBE2Q1 in human lung adenocarcinoma and to study its malignant biological function. MethodsWestern blot, qRT-PCR and immunohistochemistry was used to measure the expression of UBE2Q1 in human lung adenocarcinoma tissues. The association between UBE2Q1 expression and clinic-pathological variables in 99 lung adenocarcinoma samples was analyzed by immunohistochemistry. In vitro experiment, establishing UBE2Q1 knockdown pattern, the markers of apoptosis, cell cycle and epithelial-mesenchymal transition (EMT) were analyzed by Western blot. CCK8, colony formation, Transwell and invasion assay analyzed the effect of UBE2Q1 knockdown on the proliferation, metastasis and invasion of lung cancer cells. ResultsUBE2Q1 was overexpressed in lung adenocarcinoma, and the expression level of UBE2Q1 was related with TNM stage, tumor size, and lymph node metastasis. The high level of UBE2Q1 expression was also associated with poor survival and was an independent risk factor. In vitro, It was also confirmed that steady downregulation of UBE2Q1 could promote apoptosis, induce G2/M cell cycle arrest and regulate EMT. UBE2Q1 silencing dramatically reduce lung tumor cells proliferation, migration and invasion capacities. ConclusionsUBE2Q1 may serve as a prognostic biomarker and a new therapeutic target of lung adenocarcinoma.

Epigenetic reader ZMYND11 noncanonical function restricts HNRNPA1-mediated stress granule formation and oncogenic activity

Epigenetic readers frequently affect gene regulation, correlate with disease prognosis, and hold significant potential as therapeutic targets for cancer. Zinc finger MYND-type containing 11 (ZMYND11) is notably recognized for reading the epigenetic marker H3.3K36me3; however, its broader functions and mechanisms of action in cancer remain underexplored. Here, we report that ZMYND11 downregulation is prevalent across various cancers and profoundly correlates with poorer outcomes in prostate cancer patients. Depletion of ZMYND11 promotes tumor cell growth, migration, and invasion in vitro, as well as tumor formation and metastasis in vivo. Mechanistically, we discover that ZMYND11 exhibits tumor suppressive roles by recognizing arginine-194-methylated HNRNPA1 dependent on its MYND domain, thereby retaining HNRNPA1 in the nucleus and preventing the formation of stress granules in the cytoplasm. Furthermore, ZMYND11 counteracts the HNRNPA1-driven increase in the PKM2/PKM1 ratio, thus mitigating the aggressive tumor phenotype promoted by PKM2. Remarkably, ZMYND11 recognition of HNRNPA1 can be disrupted by pharmaceutical inhibition of the arginine methyltransferase PRMT5. Tumors with low ZMYND11 expression show sensitivity to PRMT5 inhibitors. Taken together, our findings uncover a previously unexplored noncanonical role of ZMYND11 as a nonhistone methylation reader and underscore the critical importance of arginine methylation in the ZMYND11-HNRNPA1 interaction for restraining tumor progression, thereby proposing novel therapeutic targets and potential biomarkers for cancer treatment.

On-treatment biopsies to predict response to neoadjuvant chemotherapy for breast cancer

BackgroundPatients with pathologic complete response (pCR) to neoadjuvant chemotherapy for invasive breast cancer (BC) have better outcomes, potentially warranting less extensive surgical and systemic treatments. Early prediction of treatment response could aid in adapting therapies.MethodsOn-treatment biopsies from 297 patients with invasive BC in three randomized, prospective neoadjuvant trials were assessed (GeparQuattro, GeparQuinto, GeparSixto). BC quantity, tumor-infiltrating lymphocytes (TILs), and the proliferation marker Ki-67 were compared to pre-treatment samples. The study investigated the correlation between residual cancer, changes in Ki-67 and TILs, and their impact on pathologic complete response (pCR) and disease-free survival (DFS).ResultsAmong the 297 samples, 138 (46%) were hormone receptor-positive (HR+)/human epidermal growth factor 2-negative (HER2−), 87 (29%) were triple-negative (TNBC), and 72 (24%) were HER2+. Invasive tumor cells were found in 70% of on-treatment biopsies, with varying rates across subtypes (HR+/HER2−: 84%, TNBC: 62%, HER2+: 51%; p < 0.001). Patients with residual tumor on-treatment had an 8% pCR rate post-treatment (HR+/HER2−: 3%, TNBC: 19%, HER2+: 11%), while those without any invasive tumor had a 50% pCR rate (HR+/HER2−: 27%; TNBC: 48%, HER2+: 66%). Sensitivity for predicting residual disease was 0.81, with positive and negative predictive values of 0.92 and 0.50, respectively. Increasing TILs from baseline to on-treatment biopsy (if residual tumor was present) were linked to higher pCR likelihood in the overall cohort (OR 1.034, 95% CI 1.013–1.056 per % increase; p = 0.001) and with a longer DFS in TNBC (HR 0.980, 95% CI 0.963–0.997 per % increase; p = 0.026). Persisting or increased Ki-67 was associated with with lower pCR probability in the overall cohort (OR 0.957, 95% CI 0.928–0.986; p = 0.004) and shorter DFS in TNBC (HR 1.023, 95% CI 1.001–1.047; p = 0.04).ConclusionOn-treatment biopsies can predict patients unlikely to achieve pCR post-therapy. This could facilitate therapy adjustments for TNBC or HER2 + BC. They also might offer insights into therapy resistance mechanisms. Future research should explore whether standardized or expanded sampling enhances the accuracy of on-treatment biopsy procedures.Trial registration GeparQuattro (EudraCT 2005-001546-17), GeparQuinto (EudraCT 2006-005834-19) and GeparSixto (EudraCT 2011-000553-23).

Machine learning-based discovery of UPP1 as a key oncogene in tumorigenesis and immune escape in gliomas.

Gliomas are the most common and aggressive type of primary brain tumor, with a poor prognosis despite current treatment approaches. Understanding the molecular mechanisms underlying glioma development and progression is critical for improving therapies and patient outcomes. The current study comprehensively analyzed large-scale single-cell RNA sequencing and bulk RNA sequencing of glioma samples. By utilizing a series of advanced computational methods, this integrative approach identified the gene UPP1 (Uridine Phosphorylase 1) as a novel driver of glioma tumorigenesis and immune evasion. High levels of UPP1 were linked to poor survival rates in patients. Functional experiments demonstrated that UPP1 promotes tumor cell proliferation and invasion and suppresses anti-tumor immune responses. Moreover, UPP1 was found to be an effective predictor of mutation patterns, drug response, immunotherapy effectiveness, and immune characteristics. These findings highlight the power of combining diverse machine learning methods to identify valuable clinical markers involved in glioma pathogenesis. Identifying UPP1 as a tumor growth and immune escape driver may be a promising therapeutic target for this devastating disease.

Targeting CBP and p300: Emerging Anticancer Agents.

CBP and p300 are versatile transcriptional co-activators that play essential roles in regulating a wide range of signaling pathways, including Wnt/β-catenin, p53, and HIF-1α. These co-activators influence various cellular processes such as proliferation, differentiation, apoptosis, and response to hypoxia, making them pivotal in normal physiology and disease progression. The Wnt/β-catenin signaling pathway, in particular, is crucial for cellular proliferation, differentiation, tissue homeostasis, and embryogenesis. Aberrant activation of this pathway is often associated with several types of cancer, such as colorectal tumor, prostate cancer, pancreatic and hepatocellular carcinomas. In recent years, significant efforts have been directed toward identifying and developing small molecules as novel anticancer agents capable of specifically inhibiting the interaction between β-catenin and the transcriptional co-activators CBP and p300, which are required for Wnt target gene expression and are consequently involved in the regulation of tumor cell proliferation, migration, and invasion. This review summarizes the most significant and original research articles published from 2010 to date, found by means of a PubMed search, highlighting recent advancements in developing both specific and non-specific inhibitors of CBP/β-catenin and p300/β-catenin interactions. For a more comprehensive view, we have also explored the therapeutic potential of CBP/p300 bromodomain and histone acetyltransferase inhibitors in disrupting the transcriptional activation of genes involved in various signaling pathways related to cancer progression. By focusing on these therapeutic strategies, this review aims to offer a detailed overview of recent approaches in cancer treatment that selectively target CBP and p300, with particular emphasis on their roles in Wnt/β-catenin-driven oncogenesis.

Tenascin-C in the early lung cancer tumor microenvironment promotes progression through integrin αvβ1 and FAK.

Pre-cancerous lung lesions are commonly initiated by activating mutations in the RAS pathway, but do not transition to lung adenocarcinomas (LUAD) without additional oncogenic signals. Here, we show that expression of the extracellular matrix protein Tenascin-C (TNC) is increased in and promotes the earliest stages of LUAD development in oncogenic KRAS-driven lung cancer mouse models and in human LUAD. TNC is initially expressed by fibroblasts and its expression extends to tumor cells as the tumor becomes invasive. Genetic deletion of TNC in the mouse models reduces early tumor burden and high-grade pathology and diminishes tumor cell proliferation, invasion, and focal adhesion kinase (FAK) activity. TNC stimulates cultured LUAD tumor cell proliferation and migration through engagement of αv-containing integrins and subsequent FAK activation. Intringuingly, lung injury causes sustained TNC accumulation in mouse lungs, suggesting injury can induce additional TNC signaling for early tumor cell transition to invasive LUAD. Biospecimens from patients with stage I/II LUAD show TNC in regions of FAK activation and an association of TNC with tumor recurrence after primary tumor resection. These results suggest that exogenous insults that elevate TNC in the lung parenchyma interact with tumor-initiating mutations to drive early LUAD progression and local recurrence.

Long non-coding RNA PVT1 regulates TGF-β and promotes the proliferation, migration and invasion of hypopharyngeal carcinoma FaDu cells

Hypopharyngeal carcinoma is one of the malignant tumors of the head and neck with a particularly poor prognosis. Recurrence and metastasis are important reasons for poor prognosis of hypopharyngeal cancer patients, and malignant proliferation, migration, and invasion of tumor cells are important factors for recurrence and metastasis of hypopharyngeal cancer. Therefore, elucidating hypopharyngeal cancer cells’ proliferation, migration, and invasion mechanism is essential for improving diagnosis, treatment, and prognosis. Plasmacytoma Variant Translocation 1 (PVT1) is considered a potential diagnostic marker and therapeutic target for tumors. However, it remains unclear whether PVT1 is related to the occurrence and development of hypopharyngeal cancer and its specific mechanism. In this study, the promoting effect of PVT1 on the proliferation, migration, and invasion of hypopharyngeal carcinoma FaDu cells was verified by cell biology experiments and animal studies, and it was found that PVT1 inhibited the expression of TGF-β, suggesting that PVT1 may regulate the occurrence and development of hypopharyngeal carcinoma FaDu cells through TGF-β.

Can alterations in cathepsin levels restrain the development of skin cancer?: A bidirectional multivariate Mendelian-randomization study.

Malignant skin tumors mainly include basal cell carcinoma, squamous cell carcinoma, and malignant melanoma. There is currently observational research suggesting that changes in cathepsin (CTS) may be a factor in the development of malignant skin tumors, but no studies have yet demonstrated a causal relationship between tissue protease changes and the occurrence of malignant skin tumors. Current studies have shown that cathepsin is involved in tumor cell invasion and metastasis by regulating growth factors and cellular immune function in tumor microenvironment, decomposing extracellular matrix and basement membrane, and promoting angiogenesis. In this study, we conducted a bidirectional Mendelian-randomization study using publicly available genome-wide association study (GWAS; GWAS Catalog) data. This study applies a bidirectional multivariate Mendelian randomization (MR) approach to investigate the causal relationship between cathepsin, basal cell carcinoma, squamous cell carcinoma, and malignant melanoma. In cases where multiple cathepsins are implicated as etiological factors in certain diseases, a multivariable analysis is conducted to assess the direct and indirect causal effects of the exposure factors. In this study, we present a comprehensive MR analysis to investigate the relationship between 9 cathepsin and basal cell carcinoma, squamous cell carcinoma, and malignant melanoma. Based on our MR analysis using the largest GWAS Catalog dataset available, we are able to draw relatively reliable conclusions. In the MR study, we found that tissue protease L2 can promote skin cancer, Cathepsin O, and Cathepsin F are associated with an increased risk of basal cell carcinoma. Cathepsin H can inhibit basal cell carcinoma and malignant melanoma. In the reverse MR study, it was found that squamous cell carcinoma may cause an increase in Cathepsin O expression. In the multivariate analysis, it was found that Cathepsin H is a direct factor in reducing the occurrence of skin cancer and melanoma, with no apparent causal relationship to non-melanoma skin cancer. Cathepsin has a dual impact on skin cancer cells, and the expression of different cathepsins at the edge of skin tumors may indicate different developmental tendencies of skin cancer. Cathepsin may serve as effective biomarkers for predicting tumors.

Bioresponsive Nanoparticles Boost Starvation Therapy and Prevent Premetastatic Niche Formation for Pulmonary Metastasis Treatment.

In the process of tumor metastasis, tumor cells can acquire invasion by excessive uptake of nutrients and energy and interact with the host microenvironment to shape a premetastatic niche (PMN) that facilitates their colonization and progression in the distal sites. Pyruvate is an essential nutrient that engages in both energy metabolism and remodeling of the extracellular matrix (ECM) in the lungs for PMN formation, thus providing a target for tumor metastasis treatment. There is a paucity of strategies focusing on PMN prevention, which is key to metastasis inhibition. Here, we design a bioresponsive nanoparticle (HP/GU) based on a disulfide-cross-linked hyperbranched polyethylenimine (D-PEI) core and a hyaluronic acid (HA) shell with a reactive oxygen species (ROS)-sensitive cross-linker between them to encapsulate glucose oxidase (GOX) and a mitochondrial pyruvate carrier (MPC) inhibitor via electrostatic interaction, which reinforces starvation therapy and reduces PMN formation in the lungs via inhibiting pyruvate metabolism. In tumor cells, GOX and MPC inhibitors can be rapidly released and synergistically reduce the energy supply of tumor cells by consuming glucose and inhibiting pyruvate uptake to decrease tumor cell invasion. MPC inhibitors can also reduce ECM remodeling by blocking cellular pyruvate metabolism to prevent PMN formation. Consequently, HP/GU achieves an efficient inhibition of both primary and metastatic tumors and provides an innovative strategy for the treatment of tumor metastases.

The TβRI promotes migration and metastasis through thrombospondin 1 and ITGAV in prostate cancer cells

AbstractTGFβ potently modifies the extracellular matrix (ECM), which is thought to favor tumor cell invasion. However, the mechanism whereby the cancer cells employ the ECM proteins to facilitate their motility is largely unknown. In this study we used RNA-seq and proteomic analysis to examine the proteins secreted by castration-resistant prostate cancer (CRPC) cells upon TGFβ treatment and found that thrombospondin 1 (THBS1) was observed to be one of the predominant proteins. The CRISPR Cas9, or siRNA techniques was used to downregulate TGFβ type I receptor (TβRI) to interfere with TGFβ signaling in various cancer cells in vitro. The interaction of ECM proteins with the TβRI in the migratory prostate cancer cells in response to TGFβ1 was demonstrated by several different techniques to reveal that THBS1 mediates cell migration by interacting with integrin subunit alpha V (ITGAV) and TβRI. Deletion of TβRI or THBS1 in cancer cells prevented their migration and invasion. THBS1 belongs to a group of tumorigenic ECM proteins induced via TGFβ signaling in CRPC cells, and high expression of THBS1 in human prostate cancer tissues correlated with the degree of malignancy. TGFβ-induced production of THBS1 through TβRI facilitates the invasion and metastasis of CRPC cells as shown in vivo xenograft animal experiments.

A thermosensitive hydrogel for the sustained delivery of exosomes extracted from menstrual blood mesenchymal stem cells and frizzled antibody on triple-negative breast cancer cells in vitro

Due to the heterogeneity of triple-negative breast cancer (TNBC), conventional treatments usually respond poorly and effective targeted therapies for this type of cancer are rare. Wnt signaling plays an important role in breast cancer metastasis and proliferation, as shown by analyzes of gene expression profiling and genome-wide sequencing. In addition, the role of endometrial cells in regulating angiogenesis during the menstrual cycle as an angiostatic state associated with the end of the cycle has been well established. Therefore, exosomes of menstrual blood-derived stem cells (Exo-Mens) could play a role as effective inhibitors of tumor-induced angiogenesis. However, repeated administration and systemic toxicity are major problems with conventional drug delivery methods. To minimize these drawbacks and maximize the therapeutic benefits of the drugs, hydrogels provide convenient methods for drug delivery. The aim of this study was therefore to investigate the effects of hydrogels containing Exo-Mens and Frizzled antibodies (anti-FZ) on breast cancer cells. First, the optimization and characterization of the hydrogel were performed, then the cell lines (MDA-MB-231 and HUVEC) were studied in four groups: Hydrogel (control), Hydrogel with anti-FZ, Exo-Mens and FZ + Exo. First, the IC50 of anti-FZ and Exo-Mens was determined and the degradability and release pattern of the investigated groups were measured. Western blot (VEGF, HIF-1α) and qRT-PCR (VEGF, HIF-α and KDR) were performed for the HUVEC cell line and scratch tests, colony formation and apoptosis for the MDA-MB-231 cell line. In addition, invasion and migration were performed for both cell lines. Our results showed that the optimal hydrogel is a suitable option for sustained release of the studied groups. The loaded compounds could be released within 7 days. The angiogenic activity of dual anti-FZ and Exo-Mens within the hydrogel, showed a significant shift in the expression of pro-angiogenic genes and related proteins, including HIF-1α, VEGF-A and KDR, in the treated HUVECs. The hydrogel treatment groups were also able to reduce migration and invasion in both cell lines compared to the control group. In addition, a reduction in colony formation and an increase in apoptosis were observed, especially in the cancer cells exposed to anti-FZ. Angiogenesis as well as proliferation and invasion of tumor cells were inhibited by the developed hydrogel system containing anti-FZ, Exo-Mens and a combination of both with slow release.

Coating Dormant Collagenase-Producing Bacteria with Metal-Anesthetic Networks for Precision Tumor Therapy.

Tumor malignancy highly depends on the stiffness of tumor matrix, which mainly consists of collagen. Despite the destruction of tumor matrix is conducive to tumor therapy, it causes the risk of tumor metastasis. Here, metal-anesthetic network-coated dormant collagenase-producing Clostridium is constructed to simultaneously destruct tumor matrix and inhibit tumor metastasis. By metal-phenolic complexation and π-π stacking interactions, a Fe3+-propofol network is formed on bacterial surface. Coated dormant Clostridium can selectively germinate and rapidly proliferate in tumor sites due to the ability of carried Fe3+ ions to promote bacterial multiplication. Intratumoral colonization of Clostridium produces sufficient collagenases to degrade tumor collagen mesh and the loaded propofol restrains tumor metastasis by inhibiting tumor cell migration and invasion. Meanwhile, the delivered Fe3+ ions are reduced to the Fe2+ form by intracellular glutathione, thereby inducing potent Fenton reaction to trigger lipid peroxidation and ultimate ferroptosis of tumor cells. In addition to a satisfactory safety, a single intratumoral injection of coated dormant Clostridium not only effectively retards the growth of established large primary tumors, but also significantly suppresses distal lung metastasis in two different orthotopic tumor models. This work proposes a strategy to develop advanced therapeutics for malignant tumor treatment and metastasis prevention.

In-situ nanoplatform with synergistic neutrophil intervention and chemotherapy to prevent postoperative tumor recurrence and metastasis

In addition to residual tumor cells, surgery-induced inflammation significantly contributes to tumor recurrence and metastasis by recruiting polymorphonuclear neutrophils (PMNs) and promoting their involvement in tumor cell proliferation, invasion and immune evasion. Efficiently eliminating residual tumor cells while concurrently intervening in PMN function represents a promising approach for enhanced postoperative cancer treatment. Here, a chitosan/polyethylene oxide electrospun fibrous scaffold co-delivering celecoxib (CEL) and doxorubicin-loaded tumor cell-derived microparticles (DOX-MPs) is developed for postoperative in-situ treatment in breast cancer. This implant (CEL/DOX-MPs@CP) ensures prolonged drug retention and sustained release within the surgical tumor cavity. The released DOX-MPs effectively eliminate residual tumor cells, while the released CEL inhibits the function of inflammatory PMNs, suppressing their promotion of residual tumor cell proliferation, migration and invasion, as well as remodeling the tumor immune microenvironment. Importantly, the strategy is closely associated with interference in neutrophil extracellular trap (NET) released from inflammatory PMNs, leading to a substantial reduction in postoperative tumor recurrence and metastasis. Our results demonstrate that CEL/DOX-MPs@CP holds great promise as an implant to enhance the prognosis of breast cancer patients following surgery.

Roles of small peptides encoded by non-coding RNAs in tumor invasion and migration.

Non-coding RNAs (ncRNAs), which are usually considered not to encode proteins, are widely involved in important activities including signal transduction and cell proliferation. However, recent studies have shown that small peptides encoded by ncRNAs (SPENs) have important roles in the development of malignant tumors. Some SPENs participate in the regulation of skeleton reorganization, intercellular adhesion, signaling and other processes of tumor cells, with effects on the invasive and migratory abilities of the cells. Therefore, SPENs have potential applications as therapeutic targets and biomarkers of malignant tumors. Invasion and migration of malignant tumor cells are the main reasons for poor prognosis of cancer patients and represent the most challenging aspects of treatment of malignant tumors. Currently, the main treatments for tumors include surgery, radiotherapy, targeted drug therapy. Surgery, however, is reserved for early stages of cancer and carries risks and costs. Radiotherapy and targeted therapy have serious side effects. This review describes the mechanisms of SPENs and their roles in tumor invasion and migration, with the aim of providing new targets for tumor diagnosis and treatment.

A comprehensive review on the potential of coumarin and related derivatives as multi-target therapeutic agents in the management of gynecological cancers.

Current treatments for gynecological cancers include surgery, radiotherapy, and chemotherapy. However, these treatments often have significant side effects. Phytochemicals, natural compounds derived from plants, offer promising anticancer properties. Coumarins, a class of benzopyrone compounds found in various plants like tonka beans, exhibit notable antitumor effects. These compounds induce cell apoptosis, target PI3K/Akt/mTOR signaling pathways, inhibit carbonic anhydrase, and disrupt microtubules. Additionally, they inhibit tumor multidrug resistance and angiogenesis and regulate reactive oxygen species. Specific coumarin derivatives, such as auraptene, praeruptorin, osthole, and scopoletin, show anti-invasive, anti-migratory, and antiproliferative activities by arresting the cell cycle and inducing apoptosis. They also inhibit metalloproteinases-2 and -9, reducing tumor cell migration, invasion, and metastasis. These compounds can sensitize tumor cells to radiotherapy and chemotherapy. Synthetic coumarin derivatives also demonstrate potent antitumor and anticancer activities with minimal side effects. Given their diverse mechanisms of action and minimal side effects, coumarin-class phytochemicals hold significant potential as therapeutic agents in gynecological cancers, potentially improving treatment outcomes and reducing side effects. This review will aid in the synthesis and development of novel coumarin-based drugs for these cancers.

Abstract C074: Influence of Cell Death and Stress on the Tumor Microenvironment and EMT in Pancreatic Ductal Adenocarcinoma Through Single Cell and Spatial Transcriptomics

Abstract Pancreatic cancer remains one of the most deadly cancers, with over 450,000 fatalities in 2022 alone. The most lethal variation of this cancer is Pancreatic Ductal Adenocarcinoma (PDAC), with a 5-year survival rate of under 10%. Combination chemotherapy has provided major advances in this disease but it remains challenging for many reasons including the immunosuppressive nature of the tumor microenvironment (TME). PDAC has a highly desmoplastic microenvironment that suppresses antitumor immunity and promotes tumor cell invasion, metastasis, and resistance through epithelial to mesenchymal transition (EMT) of cancer cells. Cancer cells can undergo various forms of cell death, notably apoptosis, necrosis, autophagy, pyroptosis, and ferroptosis. These mechanisms are triggered by different cellular stressors and shape the microenvironment. Through the use of 15 Visium spatial transcriptomics samples from publicly available primary PDAC tumors and paired single-cell RNA (scRNA) data, we aim to understand how cell stress and cell death shape the tumor microenvironment (TME) and epithelial-mesenchymal transition (EMT). By leveraging information from known pathways in literature, we will identify cellular programs related to stress, death, and EMT. We will explore intracellular correlations within single-cell data and extracellular interactions within the TME using spatial data to uncover how different forms of cell death and stress signatures influence the TME and EMT spectrum. The initial phase involves identifying the types of stress that lead to various forms of cell death intracellularly and validating these gene signatures. Subsequently, we will apply these validated signatures to the spatial data to correlate each score and search for significant overlapping programs. This will extend beyond stress and death, incorporating TME signatures corresponding to different cell types and the EMT spectrum. By understanding the signals that promote the death of various cell populations, we aim to identify combination treatments that target both ends of the EMT spectrum. Additionally, this research will provide insights into the inflammatory impact of cell death on the TME. Our approach aims to inform the development of therapies that disrupt resistance mechanisms, ultimately improving treatment outcomes for patients with PDAC. This research can potentially reveal new therapeutic targets and strategies, enhancing our ability to combat this deadly disease. Citation Format: Rahul Bansal, Izabella Zamora, Samuel Wright, Nir Hacohen, Arnav Mehta. Influence of Cell Death and Stress on the Tumor Microenvironment and EMT in Pancreatic Ductal Adenocarcinoma Through Single Cell and Spatial Transcriptomics [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C074.

Spatial transcriptomics reveals tumor-derived SPP1 induces fibroblast chemotaxis and activation in the hepatocellular carcinoma microenvironment

BackgroundThe tumor microenvironment (TME) exerts profound effects on tumor progression and therapeutic efficacy. In hepatocellular carcinoma (HCC), the TME is enriched with cancer-associated fibroblasts (CAFs), which secrete a plethora of cytokines, chemokines, and growth factors that facilitate tumor cell proliferation and invasion. However, the intricate architecture of the TME in HCC, as well as the mechanisms driving interactions between tumor cells and CAFs, remains largely enigmatic.MethodsWe analyzed 10 spatial transcriptomics and 12 single-cell transcriptomics samples sourced from public databases, complemented by 20 tumor tissue samples from liver cancer patients obtained in a clinical setting.ResultsOur findings reveal that tumor cells exhibiting high levels of SPP1 are preferentially localized adjacent to hepatic stellate cells (HSCs). The SPP1 secreted by these tumor cells interacts with the CD44 receptor on HSCs, thereby activating the PI3K/AKT signaling pathway, which promotes the differentiation of HSCs into CAFs. Notably, blockade of the CD44 receptor effectively abrogates this interaction. Furthermore, in vivo studies demonstrate that silencing SPP1 expression in tumor cells significantly impairs HSC differentiation into CAFs, leading to a reduction in tumor volume and collagen deposition within the tumor stroma.ConclusionsThis study delineates the SPP1-CD44 signaling axis as a pivotal mechanism underpinning the interaction between tumor cells and CAFs. Targeting this pathway holds potential to mitigate liver fibrosis and offers novel therapeutic perspectives for liver cancer management.

Mechanisms of traditional Chinese medicine in the treatment and prevention of gastric cancer

BackgroundGastric cancer (GC) ranks as the fifth most prevalent malignancy worldwide. Conventional treatments, including radiotherapy and chemotherapy, often induce severe side effects and significant adverse reactions, and they may also result in drug resistance. Consequently, there is a critical need for the development of new therapeutic agents. Traditional Chinese Medicine (TCM) and natural products are being extensively researched due to their low toxicity, multi-targeted approaches, and diverse pathways. Scholars are increasingly focusing on identifying active anticancer components within TCM. PurposeThis review aims to summarise research conducted over the past 14 years on the treatment of GC using TCM. The focus is on therapeutic targets, mechanisms, and efficacy of Chinese medicine and natural products, including monomer compounds, extracts or analogues, and active ingredients. MethodsRelevant articles on TCM and GC were retrieved from PubMed using appropriate keywords. The collected articles were screened and classified according to the types of TCM, with an emphasis on the molecular mechanisms underlying the treatment of GC. ResultsThe research on TCM indicates that TCM and natural products can effectively inhibit the metastasis, proliferation, and invasion of tumour cells. They can also induce apoptosis, autophagy and improve the chemosensitivity of drug-resistant cells. Additionally, injections derived from Chinese herbal medicine, when used as an adjunct to conventional chemotherapy, can significantly improve the prognosis of GC patients by reducing chemotherapy toxicity. ConclusionThis review summarises the progress of TCM treatment of GC over the past 14 years, and discusses its therapeutic application of GC, which proves that TCM is a promising treatment strategy for GC in the future.

NAC1 promotes stemness and regulates myeloid-derived cell status in triple-negative breast cancer

Triple negative breast cancer (TNBC) is a particularly lethal breast cancer (BC) subtype driven by cancer stem cells (CSCs) and an immunosuppressive microenvironment. Our study reveals that nucleus accumbens associated protein 1 (NAC1), a member of the BTB/POZ gene family, plays a crucial role in TNBC by maintaining tumor stemness and influencing myeloid-derived suppressor cells (MDSCs). High NAC1 expression correlates with worse TNBC prognosis. NAC1 knockdown reduced CSC markers and tumor cell proliferation, migration, and invasion. Additionally, NAC1 affects oncogenic pathways such as the CD44-JAK1-STAT3 axis and immunosuppressive signals (TGFβ, IL-6). Intriguingly, the impact of NAC1 on tumor growth varies with the host immune status, showing diminished tumorigenicity in natural killer (NK) cell-competent mice but increased tumorigenicity in NK cell-deficient ones. This highlights the important role of the host immune system in TNBC progression. In addition, high NAC1 level in MDSCs also supports TNBC stemness. Together, this study implies NAC1 as a promising therapeutic target able to simultaneously eradicate CSCs and mitigate immune evasion.

Integrating machine learning and multi-omics analysis to develop an immune-derived multiple programmed cell death signature for predicting clinical outcomes in gastric cancer

Abstract Objectives Metastasis of tumor cells is the leading reason for mortality among patients diagnosed with gastric cancer (GC). Emerging evidence indicated a strong correlation between programmed cell death (PCD) and the invasion and metastasis of tumor cells. Therefore, we aimed to develop a programmed cell death signature to assess the prognosis and therapeutic efficacy in GC patients. Methods Here, we collected 1911 PCD-related genes from 19 different PCD patterns, and developed an immune-derived multiple programmed cell death index (MPCDI) using the integrating machine learning and multi-omics analysis, and systematically dissected heterogeneity in GC patients. Subsequently, we divided GC patients into two categories, namely high-MPCDI group and low-MPCDI group, using the median MPCDI as the threshold. We performed a comprehensive analysis of the clinical characteristics, somatic mutations, immune infiltration, drug sensitivity, and immunotherapeutic efficacy of the two groups. Results Survival and immunotherapy response analyses indicated that the high-MPCDI patients experienced a poorer overall survival (p=0.018) and were more resistant to commonly used chemotherapeutic drugs but benefited from immunotherapy compared to the low-MPCDI patients. In addition, MPCDI was confirmed as a standalone risk factor for overall survival, and nomograms can provide a precise tool for the clinical diagnosis of GC patients. Conclusions Taken together, the MPCDI can serve as a robust clinical diagnostic classifier to guide medication administration and improve outcomes in GC patients.