Abstract 4344: Membrane-type 1 matrix metalloproteinase-mediated pro-invasive properties of neuroblastoma initiating cells

Nyalendo, Carine; Hadj-Mimoune, Sarah; Cournoyer, Sonia; Beaunoyer, Mona; Benoît, Alexandre; Addioui, Anissa; Teira, Pierre; Haddad, Élie; Momparler, Richard L.; Sartelet, Hervé

doi:10.1158/1538-7445.am2011-4344

Cited by 7 publications

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Oncogenic PIK3CA promotes cellular stemness in an allele dose-dependent manner

Madsen

Knox

Pearce

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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ThePIK3CAgene, which encodes the p110α catalytic subunit of PI3 kinase (PI3K), is mutationally activated in cancer and in overgrowth disorders known asPIK3CA-related overgrowth spectrum (PROS). To determine the consequences of geneticPIK3CAactivation in a developmental context of relevance to both PROS and cancer, we engineered isogenic human induced pluripotent stem cells (iPSCs) with heterozygous or homozygous knockin ofPIK3CAH1047R. While heterozygous iPSCs remained largely similar to wild-type cells, homozygosity forPIK3CAH1047Rcaused widespread, cancer-like transcriptional remodeling, partial loss of epithelial morphology, up-regulation of stemness markers, and impaired differentiation to all three germ layers in vitro and in vivo. Genetic analysis ofPIK3CA-associated cancers revealed that 64% had multiple oncogenicPIK3CAcopies (39%) or additional PI3K signaling pathway-activating “hits” (25%). This contrasts with the prevailing view thatPIK3CAmutations occur heterozygously in cancer. Our findings suggest that a PI3K activity threshold determines pathological consequences of oncogenicPIK3CAactivation and provide insight into the specific role of this pathway in human pluripotent stem cells.

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Oncogenic PIK3CA promotes cellular stemness in an allele dose-dependent manner

Madsen

Knox

Pearce

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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A Comprehensive Survey of Genomic Mutations in Breast Cancer Reveals Recurrent Neoantigens as Potential Therapeutic Targets

Liu

Chen

Zhang

2020

Preprint

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11Neoantigens are newly formed antigens generated by cancer cells but absent in 12 normal cells. With their high specificity and immunogenicity characteristic, 13 neoantigens are considered as an ideal target for immunotherapy. This study was 14 aimed to investigate the signature of neoantigens in breast cancer. Somatic mutations, 15including SNVs and indels, were obtained from cBioPortal of 5991 breast cancer 16 patients. For neoantigen prediction, 738 non-silent somatic variants present in at least 17 3 patients were selected., PIK3CA (38%), the highly mutated gene in breast cancer, 18can produce the highest number of neoantigens per gene. Some pan-cancer hotspot 19 mutations, such as PIK3CA E545K (6.93%), can be recognized by at least one HLA 20 molecule. Since there are more SNVs than indels in breast cancer, SNVs are the major 21 source of neoantigens. Patients with hormone receptor positive or HER2 positive are 22 more competent to produce neoantigens. Age, but not clinical stage, is a significant 23 contributory factor of neoantigens production. We believe a detailed description of 24 breast cancer neoantigens signatures could contribute to neoantigens based 25 immunotherapy development. 26

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Transcriptomically-inferred PI3K activity and stemness show a counterintuitive correlation withPIK3CAgenotype in breast cancer

Madsen

Rueda

Robin

et al. 2020

Preprint

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ABSTRACTThe development of reliable, prognostically informative molecular tests to direct targeted cancer therapy is a major challenge. In 2019, the PI3Kα inhibitor alpelisib was approved for the treatment of advanced breast cancer, in combination with the oestrogen receptor degrader fulvestrant, with some evidence for improved therapeutic response in patients classified as having tumours which were positive for mutation in PIK3CA, the gene encoding PI3Kα. Using human pluripotent stem cells, we recently demonstrated that the PIK3CAH1047R oncogenic hotspot variant shows marked PIK3CA allele dose-dependent activation of PI3K signalling and induction of self-sustained stemness. Together with recent discoveries of multi-copy and double-cis PIK3CA mutations in human cancers, this calls for a re-evaluation of the PIK3CA genotype-phenotype relationship and the current use of binary stratification by PIK3CA mutation status. Using computational analyses, we thus investigated the relationship between PIK3CA mutational status, PI3K activity/signalling strength and stemness. Stemness and PI3K activity scores were calculated using open-source methods and well-established transcriptional signatures. We report that a high PI3K pathway activity score, but not the presence of PIK3CA mutation per se, predicts increased breast cancer dedifferentiation and higher stemness, correlating with reduced overall survival. Our data (1) corroborate reports that the presence of a PIK3CA mutation per se does not predict high PI3K pathway activation or poor prognosis; (2) suggest that stratification of breast cancer for PI3K-based therapy might benefit from the use of a PI3K pathway activity score rather than binary PIK3CA mutation status alone; (3) suggest that combination of PI3K pathway inhibitors with differentiation-promoting treatments warrants evaluation in aggressive breast cancers with high PI3K activity and stemness scores.

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Abstract 4344: Membrane-type 1 matrix metalloproteinase-mediated pro-invasive properties of neuroblastoma initiating cells

Cited by 7 publications

References 0 publications

Oncogenic PIK3CA promotes cellular stemness in an allele dose-dependent manner

Oncogenic PIK3CA promotes cellular stemness in an allele dose-dependent manner

A Comprehensive Survey of Genomic Mutations in Breast Cancer Reveals Recurrent Neoantigens as Potential Therapeutic Targets

Transcriptomically-inferred PI3K activity and stemness show a counterintuitive correlation withPIK3CAgenotype in breast cancer

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