Veronica Rendo

Veronica Rendo

@vrendo.bsky.social

Group Leader, Uppsala University 🇸🇪 | Studying brain tumor evolution and treatment resistance

79 followers81 following26 posts

Veronica Rendo reposted

bendavidlab.bsky.social
@bendavidlab.bsky.social

Excited to get the #EMBOChromoploidy meeting started! 3 days of fantastic science and fun in beautiful Stresa are beginning now! meetings.embo.org/event/25-ane...

meetings.embo.orgChromosome Segregation and AneuploidyAneuploidy is a hallmark of cancer and developmental disorders such as Down syndrome. Understanding how cells accomplish faithful chromosome segregation and how chromosomal instability (CIN) impacts …
Veronica Rendo
@vrendo.bsky.social

2/5 We mimic BRD4 focal deletions using CRISPR-Cas9 technology and show that these focal deletions rescue ovarian cancer cells from toxicity associated with BRD4 overexpression, suggesting that BRD4 levels must be fine-tuned for cancer cell proliferation.

Veronica Rendo
@vrendo.bsky.social

3/5 Words cannot describe how thrilled I am to see this paper out! It's not only my first publication as a senior author, but also the result of a wonderful collaboration with the dream team Jeremiah Wala, Simona Dalin, Sophie Webster, and others! 🤩

Veronica Rendo
@vrendo.bsky.social

So excited to see this paper out! An example of how window of opportunity trials can help dissect the mechanisms of response and resistance associated with targeted therapies in glioblastoma 🧠 www.science.org/doi/10.1126/... Thanks to the patients and scientific team who made this study possible.

science.orgA window-of-opportunity trial reveals mechanisms of response and resistance to navtemadlin in patients with recurrent glioblastomaIn patients with glioblastoma, navtemadlin resistance is not mediated by TP53-inactivating mutations, and combination with TMZ may improve efficacy.
Veronica Rendo
@vrendo.bsky.social

11/ Overall, our study establishes a compendium of genes compensated across human cancers, with functional evidence for toxicity effects associated with gene overexpression in the context of this disease. Many targets to explore pan-cancer and in specific tumor types!

Veronica Rendo
@vrendo.bsky.social

9/ We additionally find that RBM14 overexpression can induce an innate immune response, activating the STING-STAT3 axis (we interpret changes in STING perinuclear localization as a marker of pathway activation) and rendering cells more sensitive to STAT3 inhibition.

Veronica Rendo
@vrendo.bsky.social

10/ RBM14 amplification (which occurs in the CCND1 locus) is clinically actionable! We find that RBM14 amplification status is correlated with survival in a recently published cohort of >1000 colorectal cancer patients treated with irradiation as standard of care.

Veronica Rendo
@vrendo.bsky.social

7/ We observe a similar effect with RBM14, encoding a member of the family of RNA binding proteins and the HDP-RNP paraspeckle complex. RBM14 is focally amplified on chromosome 11 and results toxic to breast and lung cancer cells when overexpressed.

Veronica Rendo
@vrendo.bsky.social

8/ Given its role in c-NHEJ-mediated DNA repair, we evaluated the effects of RBM14 overexpression in DNA damage response. We found that gene overexpression increases reliance on DNA repair by c-NHEJ (an error-prone process) over HR, increasing the rate of aberrant cell divisions.

Veronica Rendo
@vrendo.bsky.social

5/ The overlap between “compensated” and “toxic” genes identified eight ARGOS gene candidates across cancers, from which we selected CDKN1A and RBM14 for follow-up validation.

Veronica Rendo
@vrendo.bsky.social

6/ The well-known cell cycle inhibitor CDKN1A (p21) is an ARGOS gene amplified at the arm-level in chromosome 6p. By creating inducible cell line models, we show that overexpression of CDKN1A impairs the growth of breast cancer cells.

Veronica Rendo
@vrendo.bsky.social

3/ The expression of these collaterally altered genes should scale with their copy number. However, by integrating data from >8000 tumors in TCGA & CCLE, we identify amplified genes that are consistently expressed at lower levels than expected, and term them “compensated genes”.

Veronica Rendo
@vrendo.bsky.social

4/ By analyzing data from 17 ORF screens conducted by many of our wonderful collaborators and co-authors @broadinstitute.org, we identify many genes that result detrimental (i.e. cause growth inhibition or cell death) to cancer cells when overexpressed. We term these “toxic genes”.

Veronica Rendo
@vrendo.bsky.social

1/ We describe a new class of cancer genes which we have termed ARGOS. Just like the multi-eyed giant in Greek mythology, ARGOS genes have multiple copies in cancer cells, yet are expressed at lower levels than expected by their copy number and result toxic when overexpressed.

Veronica Rendo
@vrendo.bsky.social

2/ Our study stems from the observation that large chromosomal regions are often gained or lost in cancer. These copy number changes impact not only driver genes but also nearby genes, which become “collaterally altered”.

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