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To clarify the function of cyclin A2 in colon homeostasis and colorectal cancer (CRC), we generated mice deficient for cyclin A2 in colonic epithelial cells (CECs). Colons of these mice displayed architectural changes in the mucosa and signs of inflammation, as well as increased proliferation of CECs associated with the appearance of low- and high-grade dysplasias. The main initial events triggering those alterations in cyclin A2-deficient CECs appeared to be abnormal mitoses and DNA damage. Cyclin A2 deletion in CECs promoted the development of dysplasia and adenocarcinomas in a murine colitis- associated cancer model. We next explored the status of cyclin A2 expression in clinical CRC samples at the mRNA and protein levels and found higher expression in tumors of patients with stage 1 or 2 CRC compared with those of patients with stage 3 or 4 CRC. A meta-analysis of 11 transcriptome data sets comprising 2239 primary CRC tumors revealed different expression levels of CCNA2 (the mRNA coding for cyclin A2) among the CRC tumor subtypes, with the highest expression detected in consensus molecular subtype 1 (CMS1) and the lowest in CMS4 tumors. Moreover, we found high expression of CCNA2 to be a new, independent prognosis factor for CRC tumors., Introduction Colorectal cancer (CRC) is one of the leading causes of malignancy-related death worldwide, with an increasing incidence (1). The disease status of patients can be classified according to histologic [...]

The luminal B molecular subtype of breast cancers (BC) accounts for more than a third of BCs and is associated with aggressive clinical behavior and poor prognosis. The use of endocrine therapy in BC treatment has significantly contributed to the decrease in the number of deaths in recent years. However, most BC patients with prolonged exposure to estrogen receptor (ER) selective modulators such as tamoxifen develop resistance and become non-responsive over time. Recent studies have implicated overexpression of the ZNF703 gene in BC resistance to endocrine drugs, thereby highlighting ZNF703 inhibition as an attractive modality in BC treatment, especially luminal B BCs. However, there is no known inhibitor of ZNF703 due to its nuclear association and non-enzymatic activity. Here, we have developed an antisense oligonucleotide (ASO) against ZNF703 mRNA and shown that it downregulates ZNF703 protein expression. ZNF703 inhibition decreased cell proliferation and induced apoptosis. Combined with cisplatin, the anti-cancer effects of ZNF703-ASO9 were improved. Moreover, our work shows that ASO technology may be used to increase the number of targetable cancer genes. [ABSTRACT FROM AUTHOR]

Background: LIV1 is a transmembrane protein that may become a new therapeutic target through the development of antibody–drug conjugates (ADCs). Few studies are available regarding the assessment of LIV1 expression in clinical breast cancer (BC) samples. Methods: We analyzed LIV1 mRNA expression in 8982 primary BC. We searched for correlations between LIV1 expression and clinicopathological data, including disease-free survival (DFS), overall survival (OS), pathological complete response to chemotherapy (pCR), and potential vulnerability and actionability to anti-cancer drugs used or under development in BC. Analyses were performed in the whole population and each molecular subtype separately. Results: LIV1 expression was associated with good-prognosis features and with longer DFS and OS in multivariate analysis. However, patients with high LIV1 expression displayed a lower pCR rate than patients with low expression after anthracycline-based neoadjuvant chemotherapy, including in multivariate analysis adjusted on grade and molecular subtypes. LIV1-high tumors were associated with higher probabilities of sensitivity to hormone therapy and CDK4/6 inhibitors and lower probabilities of sensitivity to immune-checkpoint inhibitors and PARP inhibitors. These observations were different according to the molecular subtypes when analyzed separately. Conclusions: These results may provide novel insights into the clinical development and use of LIV1-targeted ADCs by identifying prognostic and predictive value of LIV1 expression in each molecular subtype and associated vulnerability to other systemic therapies. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma (HCC) represents the third cause of cancer-related death in the world, and identification of new prognostic factors and/or therapeutic targets remains a major issue. Recently, immune checkpoint inhibitors (ICIs) have opened promising therapeutic options for this disease. Using a large series of transcriptomic data of clinically annotated HCC samples, we provide evidence that the TIGIT/DNAM-1 axis, and notably the PVRIG molecule, might be an interesting therapeutic candidate for HCC tumors. Hepatocellular carcinoma (HCC) is a frequent and deadly cancer in need of new treatments. Immunotherapy has shown promising results in several solid tumors. The TIGIT/DNAM-1 axis gathers targets for new immune checkpoint inhibitors (ICIs). Here, we aimed at highlighting the potential of this axis as a new therapeutic option for HCC. For this, we built a large transcriptomic database of 683 HCC samples, clinically annotated, and 319 normal liver tissues. We interrogated this database for the transcriptomic expression of each member of the TIGIT/DNAM-1 axis and tested their prognostic value for survival. We then focused on the most discriminant one for these criteria, i.e., PVRIG, and analyzed the clinical characteristics, the disease-free and overall survivals, and biological pathways associated with PVRIG High tumors. Among all members of the TIGIT/DNAM-1 axis, PVRIG expression was higher in tumors than in normal liver, was heterogeneous across tumors, and was the only member with independent prognostic value for better survival. PVRIG High tumors were characterized by a higher lymphocytic infiltrate and enriched for signatures associated with tertiary lymphoid structures and better anti-tumor immune response. These results suggest that patients with PVRIG High tumors might be good candidates for immune therapy involving ICIs, notably ICIs targeting the TIGIT/DNAM-1 axis. Further functional and clinical validation is urgently required. [ABSTRACT FROM AUTHOR]

In some types of cancer, telomere length is maintained by the alternative lengthening of telomeres (ALT) mechanism. In many ALT cancers, the α‐thalassemia/mental retardation syndrome X‐linked (ATRX) gene is mutated leading to the conclusion that the ATRX complex represses ALT. Here, we report that most high‐grade pediatric osteosarcomas maintain their telomeres by ALT, and that the majority of these ALT tumors are ATRX wild‐type (wt) and instead carry an amplified 17p11.2 chromosomal region containing TOP3A. We found that TOP3A was overexpressed in the ALT‐positive ATRX‐wt tumors consistent with its amplification. We demonstrated the functional significance of these results by showing that TOP3A overexpression in ALT cancer cells countered ATRX‐mediated ALT inhibition and that TOP3A knockdown disrupted the ALT phenotype in ATRX‐wt cells. Moreover, we report that TOP3A is required for proper BLM localization and promotes ALT DNA synthesis in ALT cell lines. Collectively, our results identify TOP3A as a major ALT player and potential therapeutic target. Synopsis: There is an urgent need to treat pediatric osteosarcomas that present high frequency of alternative lengthening of telomeres (ALT). This study identifies TOP3A amplification as mutually exclusive with ATRX inactivation, promoting ALT and TOP3A action at telomeres as a novel therapeutic target. 17p11 amplification and ATRX mutation are exclusive genomic events in ALT high‐grade pediatric osteosarcomas.TOP3A overexpression is a feature of ATRX‐wt ALT osteosarcomas.Over‐expression of TOP3A correlates with the presence of ATRX in ATRX‐wt ALT cell lines.TOP3A is required for proper BLM localization in ALT osteosarcoma cell lines and promotes ALT‐mediated telomeric DNA synthesis. [ABSTRACT FROM AUTHOR]

Inflammatory breast cancer (IBC) is the most pro-metastatic form of breast cancer (BC). We previously demonstrated that protein overexpression of Myristoylated Alanine-Rich C Kinase Substrate (MARCKS) protein was associated with shorter survival in IBC patients. MARCKS has been associated with the PI3K/AKT pathway. MARCKS inhibitors are in development. Our objective was to investigate MARCKS, expressed preferentially in IBC that non-IBC (nIBC), as a novel potential therapeutic target for IBC. The biologic activity of MPS, a MARCKS peptide inhibitor, on cell proliferation, migration, invasion, and mammosphere formation was evaluated in IBC (SUM149 and SUM190) and nIBC (MDA-MB-231 and MCF7) cell lines, as well as its effects on protein expression in the PTEN/AKT and MAPK pathways. The prognostic relevance of MARCKS and phosphatase and tensin homolog (PTEN) protein expression as a surrogate marker of metastasis-free survival (MFS) was evaluated by immunohistochemistry (IHC) in a retrospective series of archival tumor samples derived from 180 IBC patients and 355 nIBC patients. In vitro MPS impaired cell proliferation, migration and invasion, and mammosphere formation in IBC cells. MARCKS inhibition upregulated PTEN and downregulated pAKT and pMAPK expression in IBC cells, but not in nIBC cells. By IHC, MARCKS expression and PTEN expression were negatively correlated in IBC samples and were associated with shorter MFS and longer MFS, respectively, in multivariate analysis. The combination of MARCKS-/PTEN+ protein status was associated with longer MFS in IBC patient only (p = 8.7 × 10−3), and mirrored the molecular profile (MARCKS-downregulated/PTEN-upregulated) of MPS-treated IBC cell lines. In conclusion, our results uncover a functional role of MARCKS implicated in IBC aggressiveness. Associated with the good-prognosis value of the MARCKS-/PTEN+ protein status that mirrors the molecular profile of MPS-treated IBC cell lines, our results suggest that MARCKS could be a potential therapeutic target in patients with MARCKS-positive IBC. Future preclinical studies using a larger panel of IBC cell lines, animal models and analysis of a larger series of clinical samples are warranted in order to validate our results. [ABSTRACT FROM AUTHOR]

In pancreatic ductal adenocarcinoma (PDAC), signaling from stromal cells is implicated in metastatic progression. Tumor-stroma cross-talk is often mediated through extracellular vesicles (EVs). We previously reported that EVs derived from cancer-associated stromal fibroblasts (CAFs) that are abundant in annexin A6 (ANXA6+ EVs) support tumor cell aggressiveness in PDAC. Here, we found that the cell surface glycoprotein and tetraspanin CD9 is a key component of CAF-derived ANXA6+ EVs for mediating this cross-talk. CD9 was abundant on the surface of ANXA6+ CAFs isolated from patient PDAC samples and from various mouse models of PDAC. CD9 colocalized with CAF markers in the tumor stroma, and CD9 abundance correlated with tumor stage. Blocking CD9 impaired the uptake of ANXA6+ EVs into cultured PDAC cells. Signaling pathway arrays and further analyses revealed that the uptake of CD9+ANXA6+ EVs induced mitogen-activated protein kinase (MAPK) pathway activity, cell migration, and epithelial-to-mesenchymal transition (EMT). Blocking either CD9 or p38 MAPK signaling impaired CD9+ANXA6+ EV–induced cell migration and EMT in PDAC cells. Analysis of bioinformatic datasets indicated that CD9 abundance was an independent marker of poor prognosis in patients with PDAC. Our findings suggest that CD9-mediated stromal cell signaling promotes PDAC progression. CD9 tags tumorigenic packages from CAFs: Extracellular vesicles (EVs) shed from pancreatic cancer-associated fibroblasts (CAFs) containing the membrane protein ANXA6 induce aggressive phenotypes in tumors. By comparing EVs isolated from ANXA6-positive and ANXA6-deficient CAFs from patient samples of pancreatic ductal carcinoma (PDAC) and mouse models of PDAC, Nigri et al. found that the cell surface glycoprotein CD9 mediated the uptake of ANXA6-positive EVs. Either blocking CD9 on isolated EVs or inhibiting the kinase p38 in PDAC cells prevented ANXA6-positive EVs from inducing cell migration and a mesenchymal protein signature. Given that CD9 correlated with tumor grade and predicted poor patient prognosis, the findings suggest that stromal CD9 detection may inform therapeutic intervention to slow disease progression in patients with PDAC. [ABSTRACT FROM AUTHOR]

Simple Summary: CISH is a member of the suppressors of cytokine signaling (SOCS) family of proteins and an important negative regulator of T cells and NK cells signaling and function. In this study, analyzing 1936 triple-negative breast cancer (TNBC) clinical samples, we highlighted correlation between CISH expression and tumor features. We demonstrated that high CISH upregulation was associated with better metastasis-free interval, especially when PDL1 was also upregulated. Moreover, we showed that the two-gene model (CISH and PDL1) provided more prognostic information than each gene alone and maintained its prognostic value in multivariate analysis. Such prognostic synergy between CISH and PDL1 expressions might reinforce the therapeutic relevance of co-targeting TNBC by a combination of CISH inhibition with an immune checkpoint inhibitor blocking the PD1/PDL1 axis. Strategies are being explored to increase the efficiency of immune checkpoint inhibitors (ICIs) targeting PD1/PDL1 in triple-negative breast cancer (TNBC), including combination with therapies inhibiting intracellular immune checkpoints such as CISH (Cytokine-induced SH2 protein). Correlation between CISH expression and TNBC features is unknown. We retrospectively analyzed CISH expression in 1936 clinical TNBC samples and searched for correlations with clinical variables, including metastasis-free interval (MFI). Among TNBCs, 44% were identified as "CISH-up" and 56% "CISH-down". High expression was associated with pathological axillary lymph node involvement, more adjuvant chemotherapy, and Lehmann's immunomodulatory and luminal AR subtypes. The "CISH-up" class showed longer 5-year MFI (72%) than the "CISH-down" class (60%; p = 2.8 × 10−2). CISH upregulation was associated with activation of IFNα and IFNγ pathways, antitumor cytotoxic immune response, and signatures predictive for ICI response. When CISH and PDL1 were upregulated together, the 5-year MFI was 81% versus 52% when not upregulated (p = 6.21 × 10−6). The two-gene model provided more prognostic information than each gene alone and maintained its prognostic value in multivariate analysis. CISH expression is associated with longer MFI in TNBC and refines the prognostic value of PDL1 expression. Such observation might reinforce the therapeutic relevance of combining CISH inhibition with an anti-PD1/PDL1 ICI. [ABSTRACT FROM AUTHOR]

Simple Summary: The goal of precision medicine is to deliver therapy matched to a relevant actionable genetic alteration (AGA) identified in the tumor. Few data are available regarding precision medicine in advanced urological cancers (AUC), the prognosis of which remains unfavorable. Sixty-four patients with refractory AUC were enrolled in the PERMED-01 clinical trial and underwent a tumor biopsy that was then profiled using sophisticated molecular analyses. The results were discussed in real-time during a weekly molecular tumor board meeting, and patients with a relevant AGA became candidates for an eventual matched therapy. A complete molecular profile was obtained in 77% of cases and an AGA was identified in 59%. Nineteen percent of patients received a matched therapy on progression, of which 42% showed a clinical benefit. The objective response, disease control rates, and the 6-year overall survival were higher in the "matched therapy group" than in the "non-matched therapy group". Introduction. The prognosis of advanced urological cancers (AUC) remains unfavorable, and few data are available regarding precision medicine. Methods: the PERMED-01 prospective clinical trial assessed the impact of molecular profiling in adults with refractory advanced solid cancer, in terms of number of patients with tumor actionable genetic alterations (AGA), feasibility, description of molecular alterations, treatment, and clinical outcome. We present here those results in the 64 patients enrolled with AUC. DNA extracted from a new tumor biopsy was profiled in real-time (targeted NGS, whole-genome array-comparative genomic hybridization), and the results were discussed during a weekly molecular tumor board meeting. Results: a complete molecular profile was obtained in 49 patients (77%). Thirty-eight (59%) had at least one AGA. Twelve (19%) received a matched therapy on progression, of which 42% had a PFS2/PFS1 ratio ≥ 1.3 versus 5% in the "non-matched therapy group" (n = 25). The objective response and disease control rates were higher in the "matched therapy group" (33% and 58%, respectively) than in the "non-matched therapy group" (13% and 22%), as was the 6-month OS (75% vs. 42%). Conclusion: the profiling of a newly biopsied tumor sample identified AGA in 59% of patients with AUC, led to "matched therapy" in 19%, and provided clinical benefit in 8%. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDA) tumor cells are deprived of oxygen and nutrients and therefore must adapt their metabolism to ensure proliferation. In some physiological states, cells rely on ketone bodies to satisfy their metabolic needs, especially during nutrient stress. Here, we show that PDA cells can activate ketone body metabolism and that β‐hydroxybutyrate (βOHB) is an alternative cell‐intrinsic or systemic fuel that can promote PDA growth and progression. PDA cells activate enzymes required for ketogenesis, utilizing various nutrients as carbon sources for ketone body formation. By assessing metabolic gene expression from spontaneously arising PDA tumors in mice, we find HMG‐CoA lyase (HMGCL), involved in ketogenesis, to be among the most deregulated metabolic enzymes in PDA compared to normal pancreas. In vitro depletion of HMGCL impedes migration, tumor cell invasiveness, and anchorage‐independent tumor sphere compaction. Moreover, disrupting HMGCL drastically decreases PDA tumor growth in vivo, while βOHB stimulates metastatic dissemination to the liver. These findings suggest that βOHB increases PDA aggressiveness and identify HMGCL and ketogenesis as metabolic targets for limiting PDA progression. Synopsis: The molecular mechanisms underlying metabolic flexibility of solid tumor cells exposed to oxygen deprivation remain poorly understood. This study identifies the ketogenic enzyme HMG‐CoA lyase (HMGCL) and its derivative β‐hydroxybutyrate (βOHB) as essential drivers of pancreatic cancer, highlighting ketone body metabolism as a regulatory nexus in metastasis. Systemic βOHB is metabolized by pancreatic adenocarcinoma (PDA) cells, fueling the TCA cycle.HMGCL and βOHB promote PDA tumor aggressiveness and metastatic dissemination.Ketone body metabolic enzymes are upregulated in PDA.PDA cells de novo generate ketone bodies from various carbon sources.Depletion of HMGCL limits oncogenic properties of pancreatic tumor cells in vivo, which is rescued by exogenous βOHB. [ABSTRACT FROM AUTHOR]