Emerging Role of Podocalyxin in the Progression of Mature B-Cell Non-Hodgkin Lymphoma

Tamayo-Orbegozo, Estíbaliz; Amo, Laura; Díez-García, Javier; Amutio, Elena; Riñón, Marta; Alonso, Marta M.; Arana, Paula; Maruri, Natalia; Larrucea, Susana

doi:10.3390/cancers12020396

“…Consistently, a positive relationship between SALL2 and PODXL expression is found in several tissues, including brain and colon cancers, and PODXL expression is perturbed upon CRISPR/Cas9-mediated SALL2 knock-out in a human epithelial colon cell line. Podocalyxin ( PODXL ) is a transmembrane protein belonging to the CD34 family of sialomucins expressed in multiple normal cell types, including podocytes, vascular endothelium, platelets, hematopoietic progenitors, embryonic stem cells, and a subset of neurons ( Tamayo-Orbegozo et al, 2020 ). It is overexpressed in various tumor cell types and is associated with their aggressiveness and poor prognosis ( Xu et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Characterization of SALL2 Gene Isoforms and Targets Across Cell Types Reveals Highly Conserved Networks

Farkas

¹

,

Quiroz

²

,

Álvarez

³

et al. 2021

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The SALL2 transcription factor, an evolutionarily conserved gene through vertebrates, is involved in normal development and neuronal differentiation. In disease, SALL2 is associated with eye, kidney, and brain disorders, but mainly is related to cancer. Some studies support a tumor suppressor role and others an oncogenic role for SALL2, which seems to depend on the cancer type. An additional consideration is tissue-dependent expression of different SALL2 isoforms. Human and mouse SALL2 gene loci contain two promoters, each controlling the expression of a different protein isoform (E1 and E1A). Also, several improvements on the human genome assembly and gene annotation through next-generation sequencing technologies reveal correction and annotation of additional isoforms, obscuring dissection of SALL2 isoform-specific transcriptional targets and functions. We here integrated current data of normal/tumor gene expression databases along with ChIP-seq binding profiles to analyze SALL2 isoforms expression distribution and infer isoform-specific SALL2 targets. We found that the canonical SALL2 E1 isoform is one of the lowest expressed, while the E1A isoform is highly predominant across cell types. To dissect SALL2 isoform-specific targets, we analyzed publicly available ChIP-seq data from Glioblastoma tumor-propagating cells and in-house ChIP-seq datasets performed in SALL2 wild-type and E1A isoform knockout HEK293 cells. Another available ChIP-seq data in HEK293 cells (ENCODE Consortium Phase III) overexpressing a non-canonical SALL2 isoform (short_E1A) was also analyzed. Regardless of cell type, our analysis indicates that the SALL2 long E1 and E1A isoforms, but not short_E1A, are mostly contributing to transcriptional control, and reveals a highly conserved network of brain-specific transcription factors (i.e., SALL3, POU3F2, and NPAS3). Our data integration identified a conserved molecular network in which SALL2 regulates genes associated with neural function, cell differentiation, development, and cell adhesion between others. Also, we identified PODXL as a gene that is likely regulated by SALL2 across tissues. Our study encourages the validation of publicly available ChIP-seq datasets to assess a specific gene/isoform’s transcriptional targets. The knowledge of SALL2 isoforms expression and function in different tissue contexts is relevant to understanding its role in disease.

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“…The upregulation of podocalyxin appears necessary for the epithelial–mesenchymal transition, characterized by migratory and invasive behavior and the involvement metastatic events in cancer 41 – 43 . Podocalyxin has been shown to promote cancer cell proliferation, prevent apoptosis, promote tumorigenesis and participate in cancer cell renewal 40 , 41 , 49 , 50 . Some studies suggest that metastatic, circulating PDAC cells employ podocalyxin as a functional E- and L-selectin ligand promoting cell adhesion to vascular endothelia in metastasis 27 , 29 .…”

Section: Discussionmentioning

confidence: 99%

Impact of histological response after neoadjuvant therapy on podocalyxin as a prognostic marker in pancreatic cancer

Eurola

¹

,

Ristimäki

²

,

Mustonen

³

et al. 2021

Sci Rep

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Podocalyxin overexpression associates with poor survival in pancreatic cancer (PDAC). We investigated whether podocalyxin expression correlates with treatment response or survival in neoadjuvant-treated PDAC. Through immunohistochemistry, we evaluated podocalyxin expression in 88 neoadjuvant and 143 upfront surgery patients using two antibodies. We developed a six-tier grading scheme for neoadjuvant responses evaluating the remaining tumor cells in surgical specimens. Strong podocalyxin immunopositivity associated with poor survival in the patients responding poorly to the neoadjuvant treatment (HR 4.16, 95% CI 1.56–11.01, p = 0.004), although neoadjuvant patients exhibited generally low podocalyxin expression (p = 0.017). Strong podocalyxin expression associated with perineural invasion (p = 0.003) and lack of radiation (p = 0.036). Two patients exhibited a complete neoadjuvant response, while a strong neoadjuvant response (≤ 5% of residual tumor cells) significantly associated with lower stage, pT-class and grade, less spread to the regional lymph nodes, less perineural invasion, and podocalyxin negativity (p < 0.05, respectively). A strong response predicted better survival (HR 0.28, 95% CI 0.09–0.94, p = 0.039). In conclusion, strong podocalyxin expression associates with poor survival among poorly responding neoadjuvant patients. A good response associates with podocalyxin negativity. A strong response associates with better outcome.

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“…The upregulation of podocalyxin appears necessary for the epithelial-mesenchymal transition, characterized by migratory and invasive behavior and the involvement metastatic events in cancer [41][42][43] . Podocalyxin has been shown to promote cancer cell proliferation, prevent apoptosis, promote tumorigenesis and participate in cancer cell renewal 40,41,49,50 . Some studies suggest that metastatic, circulating PDAC cells employ podocalyxin as a functional E-and L-selectin ligand promoting cell adhesion to vascular endothelia in metastasis 27,29 .…”

Section: Discussionmentioning

confidence: 99%

Impact of histological response after neoadjuvant therapy on podocalyxin as a prognostic marker in pancreatic cancer

Eurola

¹

,

Ristimäki

²

,

Mustonen

³

et al. 2021

Pancreatology

0

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Podocalyxin overexpression associates with poor survival in pancreatic cancer (PDAC). We investigated whether podocalyxin expression correlates with treatment response or survival in neoadjuvant-treated PDAC. Through immunohistochemistry, we evaluated podocalyxin expression in 88 neoadjuvant and 143 upfront surgery patients using two antibodies. We developed a six-tier grading scheme for neoadjuvant responses evaluating the remaining tumor cells in surgical specimens. Strong podocalyxin immunopositivity associated with poor survival in the patients responding poorly to the neoadjuvant treatment (HR 4.16, 95% CI 1.56-11.01, p = 0.004), although neoadjuvant patients exhibited generally low podocalyxin expression (p = 0.017). Strong podocalyxin expression associated with perineural invasion (p = 0.003) and lack of radiation (p = 0.036). Two patients exhibited a complete neoadjuvant response, while a strong neoadjuvant response (≤ 5% of residual tumor cells) significantly associated with lower stage, pT-class and grade, less spread to the regional lymph nodes, less perineural invasion, and podocalyxin negativity (p < 0.05, respectively). A strong response predicted better survival (HR 0.28, 95% CI 0.09-0.94, p = 0.039). In conclusion, strong podocalyxin expression associates with poor survival among poorly responding neoadjuvant patients. A good response associates with podocalyxin negativity. A strong response associates with better outcome.Pancreatic cancer has now become the third most common cause of cancer-related death. In recent decades, the incidence of pancreatic cancer has increased, and survival rates remain poor and largely unchanged, with an overall five-year survival rate of 6% to 10% 1 . Under the most optimal situation, with localized, resectable disease, five-year survival can reach up to 37% [2][3][4] .Many studies have shown that neoadjuvant therapy (NAT) is safe and effective for locally advanced and borderline-resectable disease [5][6][7][8][9] . Assessing the histological NAT effect in a post-pancreatectomy pancreatic ductal adenocarcinoma (PDAC) specimen is challenging, since some histological features of the treatment response, such as necrosis, fibrosis, and tumor cell atypia, overlap with features seen in untreated PDAC 10 . Furthermore, few schemes for evaluating the histopathological grading of the residual, viable tumor cells in the post-pancreatectomy specimen have emerged. Such schemes rely on the percentage of visible, severely degenerative, or viable residual cancer cells in the specimen [11][12][13][14] . Among these schemes, the Evans and the College of American Pathologists (CAP) grading systems appear to correlate with overall and disease-free survival (DFS) [15][16][17] . These systems have been criticized, however, for their lack of precision, clarity, simplicity, and clinical utility 18 . Recently, the Amsterdam International Consensus Meeting provided an overview listing statements regarding neoadjuvant response scoring in pancreatic cancer. Among other statements, response sh...

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Emerging Role of Podocalyxin in the Progression of Mature B-Cell Non-Hodgkin Lymphoma

Cited by 7 publications

References 146 publications

Characterization of SALL2 Gene Isoforms and Targets Across Cell Types Reveals Highly Conserved Networks

Characterization of SALL2 Gene Isoforms and Targets Across Cell Types Reveals Highly Conserved Networks

Impact of histological response after neoadjuvant therapy on podocalyxin as a prognostic marker in pancreatic cancer

Impact of histological response after neoadjuvant therapy on podocalyxin as a prognostic marker in pancreatic cancer

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