Early Infiltration of Innate Immune Cells to the Liver Depletes HNF4α and Promotes Extrahepatic Carcinogenesis

Goldman, Omer; Adler, Lital N.; Hajaj, Emma; Croese, Tommaso; Darzi, Naama; Galai, Sivan; Tishler, Hila; Ariav, Yarden; Lavie, Dor; Fellus-Alyagor, Liat; Oren, Roni; Kuznetsov, Yuri; David, Eyal; Jaschek, Rami; Stossel, Chani; Singer, Oded; Malitsky, Sergey; Barak, Renana; Seger, Rony; Erez, Neta; Amit, Ido; Tanay, Amos; Saada, Ann; Golan, Talia; Rubinek, Tami; Lee, Joo Sang; Ben‐Shachar, Shay; Wolf, Ido; Erez, Ayelet

doi:10.1158/2159-8290.cd-22-1062

Cited by 8 publications

(3 citation statements)

References 61 publications

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“…On the other hand, genes related to liver function decrease in premalignant and tumour samples. HNF4A, which controls liver function, is known to be inhibited by increased inflammation (immune activity) in liver fibrosis [39,40]. The expression of HNF4A leads to the restoration of metabolic function and reversing (attenuation) of liver fibrosis and cirrhosis via controlling macrophages and hepatic stellate cells [41].…”

Section: Plos Onementioning

confidence: 99%

Gene expression signatures of stepwise progression of Hepatocellular Carcinoma

Porukala,

Vinod

2023

PLoS ONE

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The molecular pathogenesis of Hepatocellular Carcinoma (HCC) is a complex process progressing from premalignant stages to cancer in a stepwise manner. Mostly, HCC is detected at advanced stages, leading to high mortality rates. Hence, characterising the molecular underpinnings of HCC from normal to cancer state through precancerous state may help in early detection and improve its prognosis and treatment. In this work, we analysed the transcriptomic profile of tumour and premalignant samples from HCC or chronic liver disease patients, who had undergone either total or partial hepatectomy. The normal samples from patients with metastatic cancer/polycystic liver disease/ cholangiocarcinoma were also included. A gene co-expression network approach was applied to identify hierarchical changes: modules, pathways, and genes related to different trajectories of HCC and patient survival. Our analysis shows that the progression from premalignant conditions to tumour is accompanied by differences in the downregulation of genes associated with HNF4A activity and the immune system and upregulation of cell cycle genes, bringing about variability in patient outcomes. However, an increase in immune and cell cycle activity is observed in premalignant samples. Interestingly, co-expression modules and genes from premalignant stages are associated with survival. THBD, a classical marker for dendritic cells, is a predictor of survival at the premalignant stage. Further, genes linked to microtubules, kinetochores, and centromere are altered in both premalignant and tumour conditions and are associated with survival. Our analysis revealed a three-way molecular axis of liver function, immune pathways, and cell cycle driving HCC pathogenesis.

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Section: Plos Onementioning

confidence: 99%

Gene expression signatures of stepwise progression of Hepatocellular Carcinoma

Porukala,

Vinod

2023

PLoS ONE

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“…12 Systemic inflammation induced by cancer leads to liver infiltration of myeloid cells and metabolic reprogramming. 13 Although the role of the TME in regulating remote tissues has been revealed, the progression-dependent responses of TAMs and their precursors remain unclear. Therefore, the landscape of TAMs, both in the tumor microenvironment and in the corresponding development organs, is required to understand the compositional and functional changes of the systemic immune system, which may bring new strategies for cancer treatment.…”

Section: ■ Introductionmentioning

confidence: 99%

“…For instance, PKR-like endoplasmic reticulum kinase (PERK)-mediated HSPC reprogramming into committed myeloid-derived suppressor cells (MDSCs) precursors in the spleen via PERK-ATF4-C/EBPβ signaling . Systemic inflammation induced by cancer leads to liver infiltration of myeloid cells and metabolic reprogramming . Although the role of the TME in regulating remote tissues has been revealed, the progression-dependent responses of TAMs and their precursors remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive Proteomics Analysis Reveals Dynamic Phenotypes of Tumor-Associated Macrophages and Their Precursor Cells in Tumor Progression

Liu,

Liu

et al. 2024

J. Proteome Res.

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Tumor-associated macrophages (TAMs) are key regulators in tumor progression, but the precise role of bone marrow-derived monocytes (Mons) as TAM precursors and their dynamic phenotypes regulated by the tumor microenvironment (TME) remain unclear. Here, we developed an optimized microproteomics workflow to analyze lowcell-number mouse myeloid cells. We sorted TAMs and their corresponding Mons (1 × 10 5 per sample) from individual melanoma mouse models at both the early and late stages. We established the protein expression profiles for these cells by mass spectrometry. Subsequently, we analyzed the dynamics phenotypes of TAMs and identified a characteristic protein expression profile characterized by upregulated cholesterol metabolism and downregulated immune responses during tumor progression. Moreover, we found the downregulation of both STAT5 and PYCARD expression not only in late-stage TAMs but also in late-stage Mons, indicating a loss of the ability to induce inflammatory responses prior to Mons infiltration into TME. Taken together, our study provides valuable insights into the progression-dependent transitions between TAMs and their precursor cells, as well as the cross-organ communications of tumor and bone marrow.

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