Inter- and intra-tumor heterogeneity of genetic and immune profiles in inherited renal cell carcinoma

Tabata, Mariko; Sato, Yusuke; Kogure, Yasunori; McClure, Marni B.; Oshikawa-Kumade, Yuji; Saito, Yuki; Shingaki, Sumito; Ito, Yuta; Yuasa, Mitsuhiro; Koya, Junji; Yoshida, Kenichi; Miyama, Yu; Morikawa, Teppei; Chiba, Kenichi; Okada, Ai; Ogawa, Seishi; Ushiku, Tetsuo; Shiraishi, Yuichi; Kume, Haruki; Kataoka, Keisuke

doi:10.1016/j.celrep.2023.112736

Cited by 4 publications

(2 citation statements)

References 51 publications

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“…The question is even more complicated if we take into account intratumor heterogeneity, which is the difference between different areas of the same neoplastic mass. This has been demonstrated to be impactful for many genomic alterations in ccRCC [81]. The high heterogeneity of ccRCC does not allow us to easily develop a one-size-fits-all strategy.…”

Section: Discussion and Future Perspectivesmentioning

confidence: 99%

Genomic Profiling and Molecular Characterization of Clear Cell Renal Cell Carcinoma

Pezzicoli,

Ciciriello,

Musci

et al. 2023

Current Oncology

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Clear cell renal cell carcinoma (ccRCC) treatment has undergone three major paradigm shifts in recent years, first with the introduction of molecular targeted therapies, then with immune checkpoint inhibitors, and, more recently, with immune-based combinations. However, to date, molecular predictors of response to targeted agents have not been identified for ccRCC. The WHO 2022 classification of renal neoplasms introduced the molecularly defined RCC class, which is a first step in the direction of a better molecular profiling of RCC. We reviewed the literature data on known genomic alterations of clinical interest in ccRCC, discussing their prognostic and predictive role. In particular, we explored the role of VHL, mTOR, chromatin modulators, DNA repair genes, cyclin-dependent kinases, and tumor mutation burden. RCC is a tumor whose pivotal genomic alterations have pleiotropic effects, and the interplay of these effects determines the tumor phenotype and its clinical behavior. Therefore, it is difficult to find a single genomic predictive factor, but it is more likely to identify a signature of gene alterations that could impact prognosis and response to specific treatment. To accomplish this task, the interpolation of large amounts of clinical and genomic data is needed. Nevertheless, genomic profiling has the potential to change real-world clinical practice settings.

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Section: Discussion and Future Perspectivesmentioning

confidence: 99%

Genomic Profiling and Molecular Characterization of Clear Cell Renal Cell Carcinoma

Pezzicoli,

Ciciriello,

Musci

et al. 2023

Current Oncology

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“…VHL mutations have been identified as one of the genetic determinants driving ccRCC development, intratumoral heterogeneity and invasion [ 4 ]. Very recently, it has been elegantly shown that patients with VHL disease are at risk of developing spatially and temporally multiple ccRCCs, which offers a valuable opportunity to analyze inter- and intra-tumor heterogeneity of genetic and immune profiles within the same patient [ 5 ]. The VHL-C162F mutation, a substitution of a cysteine in phenylalanine in position 162, is classified as type 1 with low risk to develop a pheochromocytoma [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Sunitinib Treatment of VHL C162F Cells Slows Down Proliferation and Healing Ability via Downregulation of ZHX2 and Confers a Mesenchymal Phenotype

Buart,

Diop,

Damei

et al. 2023

Cancers

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von Hippel-Lindau (VHL) disease, due to mutations of the tumor suppressor VHL gene, is a rare hereditary syndrome with a high risk of developing clear cell renal cell carcinoma (ccRCC). We asked whether the VHL-C162F mutation interferes with proliferation, migration, healing and forming colony ability by using wild-type VHL (WT VHL) and VHL-C162F reconstituted cells. We then analyzed the in vitro impact of the sunitinib treatment on VHL-C162F cells. We showed that VHL-C162F mutations have no impact on cell morphology, colony formation and migration ability but confer a significant higher healing ability than in WT VHL cells. RNA sequencing analysis revealed that VHL-C162F mutation upregulates genes involved in hypoxia and epithelial mesenchymal transition (EMT) pathways by comparison with VHL WT cells. We next showed a decrease in healing ability in VHL-C162F cells depleting on ZHX2, an oncogenic driver of ccRCC, highlighting the potential involvement of ZHX2 in aggressiveness of the VHL-C162F cells. Moreover, we found that sunitinib treatment inhibits ZHX2 expression and induces a reduced proliferation correlating with downregulation of P-ERK. Sunitinib treatment also conferred a more mesenchymal profile to VHL-C162F cells with significant downregulation of E-cadherin and upregulation of N-cadherin, Slug and AXL. Sunitinib therapy may therefore promote disease progression in VHL-C162F patients.

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Modeling NK-cell lymphoma in mice reveals its cell-of-origin and microenvironmental changes and identifies therapeutic targets

Koya,

Tanigawa,

Mizuno

et al. 2024

Nat Commun

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Extranodal NK/T-cell lymphoma (ENKTCL) is an Epstein-Barr virus (EBV)-related neoplasm preferentially involving the upper aerodigestive tract. Here we show that NK-cell-specific Trp53 disruption in mice leads to the development of NK-cell lymphomas after long latency, which involve not only the hematopoietic system but also the salivary glands. Before tumor onset, Trp53 knockout causes extensive gene expression changes, resulting in immature NK-cell expansion, exclusively in the salivary glands. Both human and murine NK-cell lymphomas express tissue-resident markers, suggesting tissue-resident NK cells as their cell-of-origin. Murine NK-cell lymphomas show recurrent Myc amplifications and upregulation of MYC target gene signatures. EBV-encoded latent membrane protein 1 expression accelerates NK-cell lymphomagenesis and causes diverse microenvironmental changes, particularly myeloid propagation, through interferon-γ signaling. In turn, myeloid cells support tumor cells via CXCL16-CXCR6 signaling and its inhibition is effective against NK-cell tumors in vivo. Remarkably, KLRG1-expressing cells expand in the tumor and are capable of repopulating tumors in secondary recipients. Furthermore, targeting KLRG1 alone or combined with MYC inhibition using an eIF4 inhibitor is effective against NK-cell tumors. Therefore, our observations provide insights into the pathogenesis and highlight potential therapeutic targets, including CXCL16, KLRG1, and MYC, in ENKTCL, which can help improve its diagnostic and therapeutic strategies.

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Inter- and intra-tumor heterogeneity of genetic and immune profiles in inherited renal cell carcinoma

Cited by 4 publications

References 51 publications

Genomic Profiling and Molecular Characterization of Clear Cell Renal Cell Carcinoma

Genomic Profiling and Molecular Characterization of Clear Cell Renal Cell Carcinoma

Sunitinib Treatment of VHL C162F Cells Slows Down Proliferation and Healing Ability via Downregulation of ZHX2 and Confers a Mesenchymal Phenotype

Modeling NK-cell lymphoma in mice reveals its cell-of-origin and microenvironmental changes and identifies therapeutic targets

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